專利名稱：：生產(chǎn)刺糖噻殺蟲劑所用的生物合成基因的制作方法
技術(shù)領(lǐng)域：
：本發(fā)明提供了新的生物合成基因，包含該生物合成基因的載體，被該生物合成基因轉(zhuǎn)化的刺糖多孢菌(Saccharopolysporaspinosa)菌株，使用所述基因增加刺糖噻(Spinosyn)殺蟲大環(huán)內(nèi)酯產(chǎn)量的方法，和使用所述基因或其片段改變生產(chǎn)刺糖噻的刺糖多孢菌菌株所生產(chǎn)的產(chǎn)物的方法。如美國專利5,362,634所述，發(fā)酵產(chǎn)物A83543是由刺糖多孢菌生產(chǎn)的相關(guān)化合物家族。該家族的已知成員被稱為因子或組分，每一個成員都有一個識別用的字母標(biāo)識。下文將這些化合物稱為刺糖噻A,B等。刺糖噻化合物可用于防治蜘蛛剛動物、線蟲和昆蟲，尤其是鱗翅目(Lepidoptera)和雙翅目(Diptera)昆蟲，它們不會污染環(huán)境，并具有理想的毒理學(xué)分布圖。表1和2鑒定了多種已知刺糖噻化合物的結(jié)構(gòu)表1表2天然產(chǎn)生的刺糖噻化合物由融合于12-員大環(huán)內(nèi)酯的5,6,5-三環(huán)體系、中性糖(鼠李糖)和氨基糖(forosamine)組成(見Kirst等(1991))。如果不含氨基糖，可將化合物稱為假苷元A,D等，如果不含中性糖，可將化合物稱為逆向假苷元A,D等。更優(yōu)選的命名是將假苷元稱為刺糖噻A17-Psa，刺糖噻D17-Psa等，將逆向假苷元A,D稱為刺糖噻A9-Psa，刺糖噻D9-Psa等。通過發(fā)酵培養(yǎng)物NRRL18395,18537,18538,18539,18719,18720,18743和18823可產(chǎn)生天然的刺糖噻化合物，這些培養(yǎng)物已被保藏于美國農(nóng)業(yè)部農(nóng)業(yè)研究服務(wù)中心下屬的中西部北方研究中心原種培養(yǎng)物保藏中心(1815NorthUniversityStreet,Peoria,IL61604)。美國專利5,362,634和相應(yīng)的歐洲專利申請375316A1描述了刺糖噻A,B,C,D,E,F,G,H和J。這些化合物是通過培養(yǎng)新的微生物刺糖多孢菌菌株產(chǎn)生的，所述菌株選自NRRL18395,NRRL18537,NRRL18538和NRRL18539。WO93/09126描述了刺糖噻L,M,N,Q,R,S和T。其中還描述了兩個刺糖噻J生產(chǎn)菌株NRRL18719和NRRL18720，以及一個生產(chǎn)刺糖噻Q,R,S和T的菌株NRRL18823。WO94/20518和US5,6704,486描述了刺糖噻K,O,P,U,V,W和Y及其衍生物。還描述了刺糖噻-K生產(chǎn)菌株NRRL18743。生產(chǎn)刺糖噻化合物的困難在于很大的發(fā)酵體積僅能生產(chǎn)很少量的刺糖噻。非常需要增加刺糖噻的生產(chǎn)效率，籍此增加刺糖噻的產(chǎn)率，同時降低其花費(fèi)。含有刺糖噻生物合成酶基因的經(jīng)克隆的DNA片段能復(fù)制編碼刺糖噻生產(chǎn)過程中的限速酶的基因。當(dāng)其中一個編碼活性可限制所需刺糖噻的合成時，在任何情況下都可使用上述DNA片段來增加產(chǎn)量。通過復(fù)制編碼限速酶(將大菌素轉(zhuǎn)變?yōu)樘肪氐募谆D(zhuǎn)移酶)的基因，可在弗氏鏈霉菌(Streptomycesfradiae)的發(fā)酵過程中獲得這種類型的產(chǎn)量增加(Baltz等，1997)。在另一個例子中，WO97/06266描述了將第二個eryG拷貝插入紅色糖多孢菌(Sac.erythraea)染色體的非必需區(qū)域，以改良6-脫氧紅霉素D向6,12-雙脫氧紅霉素A的轉(zhuǎn)變過程?？寺〉纳锖铣苫蛞部商峁┥a(chǎn)新的具有不同殺蟲活性譜的刺糖噻衍生物的方法。之所以需要新的衍生物是因為盡管已知的刺糖噻具有廣譜的抗蟲活性，但它們不能控制所有的害蟲。生物合成的刺糖噻中間體或其在體內(nèi)產(chǎn)生的衍生物或其在體外經(jīng)化學(xué)修飾所得的衍生物可提供不同的控制模式。通過突變的刺糖多孢菌菌株可合成特定的中間體(或其天然衍生物)，所述突變菌株中的某些編碼刺糖噻生物合成所用酶的基因已被破壞。通過經(jīng)由同源重組整合含有靶基因內(nèi)部片段的誘變質(zhì)?？僧a(chǎn)生上述突變菌株。通過質(zhì)粒整合形成了兩個不完全的生物合成基因拷貝，從而消除了該基因所編碼的酶的功能。通過發(fā)酵該突變菌株應(yīng)能積累該酶的底物或所述底物的某些天然衍生物。使用該策略可有效產(chǎn)生生產(chǎn)新的6-脫氧紅霉素衍生物所用的紅色糖多孢菌菌株(Weber&amp;McAlpine,1992)。通過刺糖多孢菌突變菌株也可合成新的中間體，所述突變菌株中某些編碼刺糖噻生物合成之酶的基因部分已被在體外經(jīng)特異性突變的相同基因部分(或得自其它生物體的相應(yīng)基因部分)所取代。通過經(jīng)由雙重同源重組與誘變質(zhì)粒交換靶區(qū)域即可產(chǎn)生該突變菌株，所述誘變質(zhì)粒在側(cè)翼于靶區(qū)域的非突變序列之間含有新的片段。雜合基因可產(chǎn)生功能有所變化的蛋白質(zhì)，該蛋白質(zhì)或者缺乏活性或者能進(jìn)行新的酶促轉(zhuǎn)化。通過發(fā)酵突變菌株可積累新的衍生物，使用該策略可產(chǎn)生生產(chǎn)新的脫水紅霉素衍生物所用的紅色糖多孢菌菌株(Donadio等，1993)。本發(fā)明的核酸可用于生產(chǎn)WO93/13663和US5,824,513中所述類型的經(jīng)改造的聚酮化合物合酶，WO98/01546,WO98/49315和WO98/51695中所述類型的雜合聚酮化合物合酶，并可用于構(gòu)建WO96/40968,WO98/49315,WO98/27203,US5,783,431,US5,824,485和US5,811,238中所述的聚酮化合物合酶文庫和聚酮化合物文庫。通過逐步縮合和修飾2-和3-碳羧酸前體，產(chǎn)生線性聚酮化合物，環(huán)化并橋連所述化合物以產(chǎn)生四環(huán)苷元即可進(jìn)行刺糖噻的生物合成。接著形成假苷元(含有三-O-甲基化鼠李糖)，再加入二-N-甲基化forosamine即可完成生物合成(Broughton等，1991)。其它大環(huán)內(nèi)酯，如抗生素紅霉素、抗寄生蟲劑除蟲菌素和免疫抑制劑納巴霉素也是以類似的方式合成的。在生產(chǎn)這些化合物的細(xì)菌中，大多數(shù)大環(huán)內(nèi)酯生物合成基因簇集在基因組的70-80kb區(qū)域(Donadio等，1991；MacNeil等，1992；Schwecke等，1995)。這些簇的中心是3-5個高度保守的基因，所述基因編碼很大的多功能的Ⅰ型聚酮化合物合酶(PolyketidesynthasePKS)蛋白質(zhì)。多肽合在一起形成了由一個起始組件和幾個延伸組件組成的復(fù)合物，各個組件為正在生成的聚酮化合物鏈添加了特定的脂酰-CoA前體，并以特殊的方式修飾β-酮基，因此，PKS中各組件的組成和順序決定了聚酮化合物的結(jié)構(gòu)。組件含有幾個各自行使其特殊功能的結(jié)構(gòu)域。起始組件由?；D(zhuǎn)移酶(AT)結(jié)構(gòu)域組成，該結(jié)構(gòu)域負(fù)責(zé)將前體的?；鶊F(tuán)添加至?；d體蛋白(ACP)結(jié)構(gòu)域。延伸組件含有上述結(jié)構(gòu)域以及通過脫羧縮合將預(yù)先存在的聚酮化合物鏈添加至新的酰基-ACP的β-酮基合酶(KS)結(jié)構(gòu)域。延伸組件中還可含有其它組件以進(jìn)行特定的β-酮基修飾β-酮基還原酶(KR)結(jié)構(gòu)域?qū)ⅵ?酮基還原為羥基，脫水酶(DH)結(jié)構(gòu)域除去羥基留下雙鍵，烯脂酰還原酶(ER)結(jié)構(gòu)域還原雙鍵留下飽和的碳。最后一個延伸組件以硫酯酶(TE)結(jié)構(gòu)域終止，該結(jié)構(gòu)域以大環(huán)的內(nèi)酯的形式從PKS酶上釋放出聚酮化合物。通過另加修飾(如甲基化和還原態(tài)的改變)并添加不尋常的糖即可由大環(huán)的內(nèi)酯衍生得到大環(huán)內(nèi)酯。上述修飾以及合成和結(jié)合糖所需的大多數(shù)基因都簇集在PKS基因的周圍。在大環(huán)內(nèi)酯類抗生素，如紅霉素和泰樂菌素的生產(chǎn)菌株(Donadio等，1993；Merson-Davies&amp;Cundliffe,1994)以及胞外多糖，如沙門氏菌屬和耶爾森氏菌屬的O-抗原的生產(chǎn)菌株(Jiang等，1991；Kessler等，1993)中，編碼脫氧糖生物合成酶的基因相似。所有這些合成涉及通過添加核苷酸二磷酸，接著進(jìn)行脫水，還原和/或差向異構(gòu)來激活葡萄糖。所得糖可經(jīng)一次或多次修飾，如脫氧，轉(zhuǎn)氨基和甲基化，這取決于大環(huán)內(nèi)酯中存在的糖組成成分的類型。通過特定糖基轉(zhuǎn)移酶的作用將糖摻入大環(huán)內(nèi)酯。參與合成和結(jié)合糖的基因緊密簇集，甚至作為單個操縱子被轉(zhuǎn)錄，但它們也可以是分散的(Decker&amp;Hutchinson,1993；Jarvis&amp;Hutchinson,1994)。刺糖噻的合成還包括內(nèi)酯核的橋連，該活性在大環(huán)內(nèi)酯生產(chǎn)菌株中很少見。因此，刺糖噻生物合成基因簇獨一無二地另外還含有編碼具有此功能之酶的基因。本文所用術(shù)語的定義如下AmR-賦予阿泊拉霉素抗性的基因ApR-賦予氨芐青霉素抗性的基因ACP-?；d體蛋白AT-?；D(zhuǎn)移酶bp-堿基對克隆-將DNA區(qū)段摻入重組DNA克隆載體并用重組DNA轉(zhuǎn)化宿主細(xì)胞的方法CmR-賦予氯霉素抗性的基因密碼子偏好-使用特殊密碼子指定特定氨基酸的偏好，對刺糖多孢菌而言，其偏愛使用胞嘧啶或鳥嘌呤作為第三個堿基的密碼子互補(bǔ)-通過克隆基因使突變菌株回復(fù)至其正常表型接合-遺傳物質(zhì)由一個細(xì)菌細(xì)胞轉(zhuǎn)移至另一個細(xì)菌細(xì)胞的過程COS-λ粘端序列粘粒-重組DNA克隆載體，它是質(zhì)粒，不僅能以質(zhì)粒的方式在宿主細(xì)胞中復(fù)制，也可被包裝入噬菌體頭部DH-脫水酶ER-烯脂酰還原酶接合后體-由接合交配得到的重組菌株基因-編碼多肽的DNA序列基因組文庫-一系列重組DNA克隆載體，其中已克隆了基本上能代表特定生物體之所有DNA序列的DNA區(qū)段同源性-序列之間的相似程度雜交-兩個單鏈DNA分子退火形成雙鏈DNA分子的過程，它可以是也可以不是完全的堿基配對體外包裝-體外將DNA包裹在外被蛋白內(nèi)以產(chǎn)生病毒樣顆粒，所述病毒樣顆粒可通過感染將DNA導(dǎo)入宿主細(xì)胞kb-千堿基對KR-β-酮基還原酶KS-酮基合酶誘變-使DNA序列發(fā)生變化，它們可以是隨機(jī)的或靶向的，可以在體內(nèi)或體外產(chǎn)生，突變可以是沉默的，或?qū)е路g產(chǎn)物之氨基酸序列的變化，所述變化可改變蛋白質(zhì)的特性并產(chǎn)生突變的表型NmR-賦予新霉素抗性的基因ORF-開放閱讀框ori-質(zhì)粒的復(fù)制起點(oriR)或轉(zhuǎn)移起點(oriT)PKS-聚酮化合物合酶啟動子-介導(dǎo)轉(zhuǎn)錄起始的DNA序列重組DNA克隆載體-任何自主復(fù)制或整合的載體，包括但不限于質(zhì)粒，其中含有DNA分子，該DNA分子中能添加或已添加了一個或多個其它的DNA分子重組DNA方法學(xué)-用于產(chǎn)生，表征和修飾克隆至重組DNA載體中的DNA區(qū)段的技術(shù)限制性片段-通過一個或多個限制性酶的作用而產(chǎn)生的任何線性DNA分子刺糖噻-由利用所有或大多數(shù)刺糖噻基因的微生物產(chǎn)生的，特征在于融合于12-員大環(huán)內(nèi)酯的5,6,5-三環(huán)體系，中性糖(鼠李糖)和氨基糖(forosamine)的發(fā)酵產(chǎn)物，或類似的大環(huán)內(nèi)酯發(fā)酵產(chǎn)物刺糖噻基因-編碼刺糖噻生物合成所需產(chǎn)物的DNA序列，更具體地為如下文所述的基因spnA,spnB,spnC,spnB,spnE,spnF,spnG,spnH,spnI,spnJ,spnK,spnL,spnM,spnN,spnO,spnP,spnQ,spnR,spnS,刺糖多孢菌gtt，刺糖多孢菌gdh，刺糖多孢菌epi和刺糖多孢菌kre，或其功能等同物亞克隆-具有插入DNA的克隆載體，所述DNA衍生自另一個同樣大小或更大的DNATE-硫酯酶轉(zhuǎn)化-將DNA(異源或同源)導(dǎo)入受體宿主細(xì)胞以改變表型并導(dǎo)致受體細(xì)胞發(fā)生變化附圖簡述圖1圖示了刺糖噻的生物合成途徑。圖2圖示了刺糖多孢菌DNA之克隆區(qū)域的BamHⅠ片段排列和開放閱讀框。圖3是粘粒pOJ436的限制性位點和功能圖譜。圖4是粘粒pOJ260的限制性位點和功能圖譜。圖5是pDAB1523的限制性位點和功能圖譜。發(fā)明簡述克隆了刺糖噻生物合成基因和相關(guān)的ORF，并測定了它們的DNA序列。下文將克隆的基因和ORF稱為spnA,spnB,spnC,spnD,spnE,spnF,spnG,spnH，spnI,spnJ,spnK，spnL,spnM,spnN,spnO,spnP,spnQ,spnR,spnS,ORFL15,ORFL16,ORFR1,ORFR2，刺糖多孢菌gtt，刺糖多孢菌gdh，刺糖多孢菌epi和刺糖多孢菌kre。在圖1和下文的討論中鑒定了克隆的基因在刺糖噻生物合成中的功能。在本發(fā)明的一個方面，提供了分離的DNA分子，其含有編碼刺糖噻生物合成酶的DNA序列，其中所述酶由選自SEQIDNO2-5,7-24,26,27,29和33的氨基酸序列限定，或者所述酶由上述氨基酸序列中的一個來限定，該氨基酸序列中具有一個或多個氨基酸取代，但不會影響到編碼酶的功能特性。在優(yōu)選的實施方案中，DNA序列選自基因spnA,spnB,spnC,spnD,spnE,spnF,spnG,spnH,spnI,spnJ,spnK,spnL,spnM,spnN,spnO,spnP,spnQ,spnR,spnS,ORFL15,ORFL16,ORFR1,ORFR2，刺糖多孢菌gtt，刺糖多孢菌gdh，刺糖多孢菌epi和刺糖多孢菌kre，所述基因分別描述于SEQIDNO1的堿基21111-28898,28916-35374,35419-44931,44966-59752,59803-76569,20168-20995,18541-19713,17749-18501,16556-17743,14799-16418,13592-14785,12696-13547,11530-12492,10436-11434,8967-10427,7083-8450,5363-6751,4168-5325,3416-4165,2024-2791,1135-1971,76932-77528和77729-79984,SEQIDNO27的堿基334-1119,SEQIDNO24的堿基88-1077,SEQIDNO31的堿基226-834，和SEQIDNO24的堿基1165-1992。本發(fā)明的另一方面提供了分離的DNA分子，其含有編碼選自KSi,ATi,ACPi,KS1,AT1,KR1和ACP1的刺糖噻PKS結(jié)構(gòu)域的DNA序列，所述結(jié)構(gòu)域分別描述于SEQIDNO2的氨基酸6-423,528-853,895-977,998-1413,1525-1858,2158-2337和2432-2513。在優(yōu)選的實施方案中，DNA序列選自SEQIDNO1的堿基21126-22379,22692-23669,23793-24041,24102-25349,25683-26684,27582-28121和28404-28649。本發(fā)明的另一方面提供了分離的DNA分子，其含有編碼選自KS2,AT2,DH2,ER2,KR2和ACP2的刺糖噻PKS結(jié)構(gòu)域的DNA序列，所述結(jié)構(gòu)域分別描述于SEQIDNO3的氨基酸1-424,536-866,892-1077,1338-1683,1687-1866和1955-2034。在優(yōu)選的實施方案中，DNA序列選自SEQIDNO1的堿基29024-30295,30629-31621,31697-32254,33035-34072,34082-34621,34886-35125。本發(fā)明的另一方面提供了分離的DNA分子，其含有編碼選自KS3,AT3,KR3,ACP3,KS4,AT4,KR4和ACP4的刺糖噻PKS結(jié)構(gòu)域的DNA序列，所述結(jié)構(gòu)域分別描述于SEQIDNO4的氨基酸1-423,531-280,1159-1337,1425-1506,1529-1952,2066-2396,2700-2880和2972-3053。在優(yōu)選的實施方案中，DNA序列選自SEQIDNO1的堿基35518-36786,37108-38097,38992-39528,39790-40035,40102-41373,41713-42705,43615-44157和44431-44676。本發(fā)明的另一方面提供了分離的DNA分子，其含有編碼選自KS5,AT5,DH5,KR5,ACP5,KS6,AT6,KR6,ACP6,KS7,AT7,KR7和ACP7的刺糖噻PKS結(jié)構(gòu)域的DNA序列，所述結(jié)構(gòu)域分別描述于SEQIDNO5的氨基酸1-424,539-866,893-1078,1384-1565,1645-1726,1748-2172,2283-2613,2916-3095,3188-3269,3291-3713,3825-4153,4344-4638和4725-4806。在優(yōu)選的實施方案中，DNA序列選自SEQIDNO1的堿基45077-46348,46691-47674,47753-48310,49226-49771,50009-50254,50318-51592,51923-52915,53822-54361,54638-54883,54947-56215,56549-57535,58106-58990和59249-59494。本發(fā)明的另一方面提供了分離的DNA分子，其含有編碼選自KS8,AT8,DH8,KR8,ACP8,KS9,AT9,DH9,KR9,ACP9,KS10,AT10,DH10,KR10,ACP10和TE10的刺糖噻PKS結(jié)構(gòu)域的DNA序列，所述結(jié)構(gòu)域分別描述于SEQIDNO6的氨基酸1-424,530-848,883-1070,1369-1552,1648-1726,1749-2173,2287-2614,2640-2800,3157-3341,3422-3500,3534-3948,4060-4390,4413-4597,4900-5078,5172-5253和5302-5555。在優(yōu)選的實施方案中，DNA序列選自SEQIDNO1的堿基59902-61173,61489-62445,62548-63111,64006-64557,64843-65079,65146-66420,66760-67743,67819-68301,69370-69924,70165-70401,70471-71745,72079-73071,73138-73692,74599-75135,75415-75660和75805-76566。本發(fā)明的另一方面提供了分離的DNA分子，其含有編碼刺糖噻PKS組件的DNA序列，所述組件選自SEQIDNO2的氨基酸6-1413,SEQIDNO2的1525-2513,SEQIDNO3的1-2034,SEQIDNO4的1-1506,SEQIDNO4的1529-3053,SEQIDNO5的1-1726,SEQIDNO5的1748-3269,SEQIDNO5的3291-4806,SEQIDNO5的1-1726,SEQIDNO6的1-1726,SEQIDNO6的1749-3500和SEQIDNO6的35434-5555。在優(yōu)選的實施方案中,DNA序列選自SEQIDNO1的堿基21126-24041,24102-28649,29024-35125,35518-40035,40102-44676,45077-50254,50318-54883,54947-59494,59902-65079,65146-70401和70471-76566。本發(fā)明的另一方面提供了重組DNA載體，其含有如上所述的本發(fā)明的DNA序列。本發(fā)明的另一方面提供了被上述本發(fā)明重組載體轉(zhuǎn)化的宿主細(xì)胞。本發(fā)明的另一方面提供了提高刺糖噻生產(chǎn)微生物之刺糖噻生產(chǎn)能力的方法，所述方法包括下列步驟1)用重組DNA載體或其部分轉(zhuǎn)化利用生物合成途徑生產(chǎn)刺糖噻或刺糖噻前體的微生物，所述載體或其部分含有如上所述的本發(fā)明的DNA序列，所述DNA序列編碼所述途徑中限速活性的表達(dá)，和2)在適于細(xì)胞生長和分裂，表達(dá)所述DNA序列和生產(chǎn)刺糖噻的條件下培養(yǎng)被所述載體轉(zhuǎn)化的所述微生物。本發(fā)明的另一方面提供了生產(chǎn)刺糖噻的微生物，其含有可操縱的刺糖噻生物合成基因，其中至少一個刺糖噻生物合成基因spnA,spnB,spnC,spnD,spnE,spnF,spnG,spnH,spnI,spnJ,spnK,spnL,spnM,spnN,spnO,spnP,spnQ,spnR,spnS刺糖多孢菌gTT，刺糖多孢菌gdh，刺糖多孢菌epi或刺糖多孢菌kre已被復(fù)制。本發(fā)明的另一方面提供了生產(chǎn)刺糖噻的微生物，所述微生物的基因組中含有刺糖噻生物合成基因，其中所述生物合成基因中的至少一個基因已通過與該基因的內(nèi)部片段重組而被破壞，其余所述基因可有效產(chǎn)生刺糖噻，而不是被破壞的基因有效時產(chǎn)生的產(chǎn)物。優(yōu)選微生物是刺糖多孢菌突變菌株。本發(fā)明還提供了生產(chǎn)刺糖噻的微生物，所述微生物的基因組中含有可操作的刺糖噻生物合成基因，其中所述基因a)包括至少一個可操作的PKS組件，所述組件比SEQIDNO1中的所述組件少一個以上或至少少一個；或b)包括通過缺失，失活或添加KR,DH或ER結(jié)構(gòu)域，或通過取代AT結(jié)構(gòu)域而與SEQIDNO1所述的相應(yīng)組件有所不同的PKS組件。優(yōu)選微生物是刺糖多孢菌突變菌株。本發(fā)明還提供了通過培養(yǎng)本發(fā)明的新微生物而產(chǎn)生的刺糖噻。本發(fā)明的另一方面提供了分離刺糖噻生物合成基因的方法，所述方法包括制備刺糖噻生產(chǎn)微生物的基因組文庫，并將長度至少為20個堿基的經(jīng)標(biāo)記的SEQIDNO1片段用作雜交探針。發(fā)明詳述由通過用Sau3AⅠ部分消化產(chǎn)生的片段構(gòu)建刺糖多孢菌(NRRL18395)DNA的粘粒文庫。將它們克隆至載體pOJ436的BamHⅠ位點(見圖3)(Bierman等，1992)，并通過體外包裝和轉(zhuǎn)導(dǎo)將其導(dǎo)入大腸桿菌細(xì)胞。通過使用Solenberg&amp;Burgett(1989)的方法進(jìn)行雜交，從所得重組細(xì)菌的文庫中篩選與兩個經(jīng)放射性標(biāo)記的DNA探針的同源性。一個探針是400kb的SpeⅠ片段，在通過轉(zhuǎn)化或用N-甲基-N'-硝基-N-亞硝基胍誘變得到的不能生產(chǎn)刺糖噻的刺糖多孢菌菌株中，該SpeⅠ片段經(jīng)常被缺失(Matsushima等，1994)。第二個探針是300bp的刺糖多孢菌DNA片段，該片段編碼不參與刺糖噻生物合成的酮基合酶部分(B.E.Schoner，個人通訊)。它包括在所有聚酮化合物和脂肪酸合酶基因中高度保守的區(qū)域，因此預(yù)期可與刺糖噻PKS基因交叉雜交。粘粒9A6和2C10是與兩個探針都能雜交的7個克隆中的兩個。通過與粘粒9A6經(jīng)放射性標(biāo)記的SgrAⅠ-BamHⅠ片段(SEQIDNO1的堿基26757-26936)雜交，可從基因組文庫中篩選出粘粒3E11。為了測定粘粒9A6中插入物的核苷酸序列，將BamHⅠ片段亞克隆至質(zhì)粒pOJ260的BamHⅠ位點(見圖4)(Bierman等，1992)。通過兩種方法中的任一種測定所述質(zhì)粒之插入物的序列。在一個方法中，用Sau3AⅠ部分消化經(jīng)亞克隆的片段，將選定大小的片段克隆至噬菌體M13mp19DNA的BamHⅠ位點。由隨機(jī)選擇的重組子制備單鏈DNA，根據(jù)Burgett&amp;Rosteck(1994)的方法，使用購自ABI(AppliedBiosystems公司，F(xiàn)oster,CA)的試劑和儀器通過熒光循環(huán)測序法進(jìn)行測序。各個質(zhì)粒的噬菌體亞克隆的序列被裝配成一個鄰接的序列。在另一個測序方法中，用經(jīng)設(shè)計可與以前測定的序列末端附近的區(qū)域互補(bǔ)的單鏈寡核苷酸反復(fù)引發(fā)雙鏈質(zhì)粒DNA。因此，一系列部分重疊的序列可匯集成完整的序列。根據(jù)廠商說明，使用Prism-Ready測序試劑盒(ABI)，并在ABI373A測序儀上進(jìn)行分析。對穿過雙鏈9A6DNA之BamHⅠ位點的序列使用相同的策略。使用MacVector程序的AssemblyLIGN組件(OxfordMolecular,Campbell,KY)，用上述數(shù)據(jù)排列經(jīng)亞克隆的序列，并確定各序列相互之間的方向，從而組裝出粘粒9A6中刺糖多孢菌DNA的完整的核苷酸序列。通過對克隆至噬菌體M13(SeqWright,Houston,TX)的隨機(jī)DNA片段進(jìn)行熒光循環(huán)測序以測定粘粒2C10和3E11的完整序列。粘粒2C10和3E11中的插入物重疊，3E11中的插入物與粘粒9A6中的插入物末端重疊。見圖2，這三個粘粒插入物合在一起跨越了約80kb長的獨特的序列(SEQIDNO1)。下表3鑒定了包括在上述各個插入物中的SEQIDNO1部分。表3圖2圖示了3個插入物與80kb序列的關(guān)系。應(yīng)注意的是粘粒2C10缺失了SEQIDNO1的G41877,C45570,C57845和G73173。將這些缺失確定為克隆假象。缺失產(chǎn)生了截短的PKS多肽的框內(nèi)終止密碼子，其中一個出現(xiàn)在粘粒3E11的克隆區(qū)域，但不存在于已得到序列的3E11區(qū)域。因此，可直接由刺糖多孢菌(NRRL18395)基因組中的PCR-擴(kuò)增區(qū)域測定跨越PKS區(qū)域中的所有8個終止密碼子的未經(jīng)克隆的DNA的序列。未經(jīng)克隆的DNA的序列證明ACP結(jié)構(gòu)域的末端存在4個終止密碼子，并證明其它編碼區(qū)內(nèi)的4個移碼是粘粒2C10所獨有的克隆假象。PKS基因SEQIDNO1包括約55kb的中間區(qū)域，該區(qū)域與編碼已知大環(huán)內(nèi)酯生產(chǎn)微生物之聚酮化合物合酶的DNA具有顯著的同源性(Donadio等，1991；MacNeil等，1992；Schwecke等，1995；Dehoff等，1997)。刺糖噻PKSDNA區(qū)域由5個ORF組成，在ACP結(jié)構(gòu)域的末端具有框內(nèi)終止密碼子，這與其它大環(huán)內(nèi)酯生產(chǎn)細(xì)菌中的PKSORF類似。5個刺糖噻PKS基因按頭-對-尾的方式排列(見圖2)，而對非PKS功能，如紅霉素PKS基因AⅠ和AⅡ之間的插入元件(Donadio等，1993)沒有任何干擾。將它們稱為spnA,spnB,spnC,spnD,spnE。下表4鑒定了5個刺糖噻PKS基因各自的核苷酸序列和對應(yīng)的多肽。表4spnA編碼起始組件(SEQIDNO1，堿基21126-24041)和延伸組件1(SEQIDNO1，堿基24102-28649)。下表5鑒定了起始組件和延伸組件1中的各個功能域的核苷酸序列和對應(yīng)的氨基酸序列。表5spnB編碼延伸組件2(SEQIDNO1，堿基29024-35125)。下表6鑒定了延伸組件2中的各個功能域的核苷酸序列和對應(yīng)的氨基酸序列。表6spnC編碼延伸組件3(SEQIDNO1，堿基35518-40035)和延伸組件4(SEQIDNO1，堿基40102-44676)。下表7鑒定了延伸組件3和4中的各個功能域的核苷酸序列和對應(yīng)的氨基酸序列。表7spnD編碼延伸組件5(SEQIDNO1，堿基45077-50254)，延伸組件6(SEQIDNO1，堿基50318-54883)和延伸組件7(SEQIDNO1，堿基54947-59494)。下表8鑒定了延伸組件5,6和7中的各個功能域的核苷酸序列和對應(yīng)的氨基酸序列。表8spnE編碼延伸組件8(SEQIDNO1，堿基59902-65079)，延伸組件8(SEQIDNO1，堿基65146-70401)和延伸組件10(SEQIDNO1，堿基70471-76566)。下表9鑒定了延伸組件8,9和10中的各個功能域的核苷酸序列和對應(yīng)的氨基酸序列。表9上表5-9中鑒定的50個結(jié)構(gòu)域的邊界及功能是根據(jù)與其它聚酮化合物合酶，尤其是紅霉素聚酮化合物合酶之結(jié)構(gòu)域的保守氨基酸序列的相似性推測的(Donadio等，1992)。假定位于起始組件氨基末端的非預(yù)期的KSi結(jié)構(gòu)域是非功能性的，因為它在氨基酸172處含有谷氨酰胺殘基而不是β-酮基合酶活性所需的半胱氨酸(Siggard-Andersen,1993)。在泰樂菌素PKS的起始組件中也發(fā)現(xiàn)了類似的非功能性KS結(jié)構(gòu)域(Dehoff等，1997)。其它刺糖噻PKS結(jié)構(gòu)域是功能性的。它們無一具有紅霉素和納巴霉素PKS基因之失活結(jié)構(gòu)域的序列特征(Donadio等，1992；Aparicio等，1996)。其中的這些基因被破壞的刺糖多孢菌菌株不能發(fā)酵產(chǎn)生刺糖噻的現(xiàn)象表明克隆的PKS基因是刺糖噻生物合成所必需的。通過使用本領(lǐng)域技術(shù)人員眾所周知的方法，將基因的內(nèi)部片段克隆至質(zhì)粒pOJ260(圖4)即可破壞基因。然后，使用Matsushima等(1994)的方法通過接合將得自大腸桿菌的重組質(zhì)粒導(dǎo)入刺糖多孢菌，并選擇阿泊拉霉素抗性接合后體?；趐OJ260的質(zhì)粒不能在刺糖多孢菌中獨立復(fù)制，通過經(jīng)由克隆DNA和基因組中該DNA的同源序列之間的重組，將質(zhì)粒整合至染色體中，即可穩(wěn)定維持該質(zhì)粒。整合在染色體中產(chǎn)生了兩個不完整的靶基因形式(一個缺乏5’序列，一個缺乏3’序列)，它們之間是pOJ260DNA。通過用分別對應(yīng)于下列區(qū)段SEQIDNO121365-22052,22052-24338或24338-26227的BamHⅠ片段V,N或K破壞spnAORF即可阻斷刺糖噻生物合成。用分別對應(yīng)于下列區(qū)段SEQIDNO1堿基48848-50578,50578-52467或55207-55888的BamHI片段G,E或K破壞spnDORF也可阻斷刺糖噻生物合成。用分別對應(yīng)于下列區(qū)段SEQIDNO163219-63989,65406-66733,66733-68997,69369-70731和70731-72675的BamHⅠ片段J,I,D,H和F破壞spnEORF也可阻斷刺糖噻生物合成。經(jīng)由BamHⅠ片段C(SEQIDNO1的堿基44612-47565)或B(SEQIDNO1的堿基55936-63219)整合不能阻斷刺糖噻生物合成，因為它們對任何一個基因而言都不是內(nèi)部片段；BamHⅠ片段C跨越了spnC和spnD之間的連接部分，BamHⅠ片段B跨越了spnD和spnE之間的連接部分。在這些情況下，整合留下了各個基因的一個完整的版本。與PKS鄰接的負(fù)責(zé)其它修飾的基因在PKS基因上游的DNA(克隆至粘粒9A6)中，有16個開放閱讀框(ORF)，各由至少100個密碼子組成，以ATG或GTG開始，以TAA,TAG或TGA終止，生物體之蛋白質(zhì)編碼區(qū)的預(yù)期密碼子偏好為其DNA含有高百分比的鳥嘌呤和胞嘧啶殘基(Bibb等，1984)。圖2的右下方圖示了9A6中的16個ORF。根據(jù)下文中將要討論的證據(jù)，將其中14個ORF稱為刺糖噻生物合成基因，即spnF,spnG,spnH,spnl,spnJ,spnK,spnL,spnM,spnN,spnO,spnP,spnQ,spnR和spnS(圖2中以F-S表示)。在下表10中，鑒定了所述各個基因以及緊接spnS上游的2個ORF(ORFL15和ORFL16)的DNA序列和相應(yīng)多肽的氨基酸序列。表10中還鑒定了位于PKS基因下游的ORFR1和ORFR2(克隆至粘粒2C10)的核苷酸序列以及相應(yīng)的氨基酸序列。表10<tablesid="table3"num="003"><table>基因SEQIDNO1中的堿基多肽spnF20168-20995SEQIDNO7spnG18541-19713(C)SEQIDNO8spnH17749-18501(C)SEQIDNO9spnI16556-17743SEQIDNO10spnJ14799-16418(C)SEQIDNO11spnK13592-14785(C)SEQIDNO12spnL12696-13547(C)SEQIDNO13spnM11530-12492(C)SEQIDNO14spnN10436-11434SEQIDNO15spnO8967-10427SEQIDNO16spnP7083-8450SEQIDNO17spnQ5363-6751(C)SEQIDNO18spnR4168-5325(C)SEQIDNO19spnS3416-4165(C)SEQIDNO20ORFL152024-2791SEQIDNO21ORFL161135-1971(C)SEQIDNO22ORFR176932-77528SEQIDNO23ORFR277729-79984SEQIDNO24</table></tables>(C)表示序列表中給出互補(bǔ)鏈。為了確定表10中鑒定的多肽的功能，利用了三條證據(jù)線索與已知功能之序列的相似性，靶基因破壞實驗的結(jié)果和生物轉(zhuǎn)化實驗的結(jié)果。使用BLAST算法規(guī)則將推測多肽的氨基酸序列與國立生物技術(shù)信息中心(NCBI，華盛頓)的數(shù)據(jù)庫中采集的序列相比較以確定它們與已知蛋白質(zhì)的相關(guān)程度。周期性重復(fù)對NCBI數(shù)據(jù)庫的BLAST檢索，以從其它同源性中得到新的線索。表11是根據(jù)1998年1月12日的基本BLAST檢索結(jié)果給出的最佳匹配。表11*較高的相似性與較高的BLAST評分相關(guān)(Altschul等，1990)。在破壞靶基因時，通過PCR擴(kuò)增由粘粒DNA產(chǎn)生內(nèi)部片段并克隆至質(zhì)粒pOJ260。然后將所得質(zhì)粒接合至刺糖多孢菌(NRRL18395)，分離并發(fā)酵阿泊拉霉素-抗性接合后體。如上所述，破壞實驗的基礎(chǔ)是當(dāng)攜有內(nèi)部基因片段的質(zhì)粒被整合時，產(chǎn)生兩個不完整的生物合成基因拷貝，從而消除了酶功能。分析所得發(fā)酵產(chǎn)物以確定積累了何種刺糖噻。表12概述了靶基因破壞實驗的結(jié)果。在生物轉(zhuǎn)化研究中，檢測刺糖噻合成被改變的菌株將可用的刺糖噻中間體轉(zhuǎn)變?yōu)槠渌烫青绲哪芰?。所用中間體是刺糖噻A苷元(AGL)，刺糖噻P(P)，刺糖噻K(K)和刺糖噻A9-Psa(PSA)。表12概述了生物轉(zhuǎn)化實驗的結(jié)果。表12下面將在逐個基因的基礎(chǔ)上詳細(xì)討論由BLAST檢索，基因破壞實驗和生物轉(zhuǎn)化研究得出的結(jié)論。PKS上游的11個基因參與刺糖噻生物合成，這是因為所述11個基因被破壞的菌株中不能積累主要的刺糖噻A和D(表12)。再往上游的2個基因(ORFL15,ORFL16)和PKS下游的大基因(ORFR2)對刺糖噻生產(chǎn)沒有貢獻(xiàn)，這是因為將它們破壞不會影響發(fā)酵(表12)。未嘗試破壞緊接PKS基因下游的ORF(ORFR1)，這是因為它太小以致于不能產(chǎn)生以可接受的頻率重組的內(nèi)部片段。也未嘗試破壞spnQ,spnR和spnS基因，這是因為早期BLAST檢索的結(jié)果表明這些基因與已知參與不同尋常的脫氧糖的生物合成之酶具有顯著的相似性。spnQ的基因產(chǎn)物與參與合成腸沙門氏菌細(xì)胞表面脂多糖的阿比可糖組成成分的CDP-4-酮基-6-脫氧-D-葡萄糖-3-脫水酶之間，具有53％的同一性(Jiang等，1991)；spnR的基因產(chǎn)物與一組據(jù)稱有脫氧糖轉(zhuǎn)氨酶功能的蛋白質(zhì)之間的同一性達(dá)40％(Thorson等，1993)；spnS的基因產(chǎn)物與合成含forosamine的抗生素螺旋霉素的微生物產(chǎn)二素鏈霉菌的SrmX產(chǎn)物之間的同一性為42％(Geistlich等，1992)。從最近的BLAST檢索結(jié)果看，相似性甚至更強(qiáng)(表11)。根據(jù)這些相似性和這些基因與其它刺糖噻生物合成基因的緊密聯(lián)系，可以得出下列結(jié)論，即spnQ,spnR和spnS參與生產(chǎn)刺糖噻的forosamine組成成分。spnF,spnJ,spnL,spnMspnF,spnJ,spnL或spnM基因被破壞的菌株不會將任何刺糖噻積累至顯著的水平(spnM突變株中低水平的刺糖噻A可能是由其羧基末端缺失的基因產(chǎn)物的某些殘留活性引起的)。然而，它們將外源提供的苷元生物轉(zhuǎn)化為刺糖噻A，因此，它們含有刺糖噻生物合成的后序步驟所必需的所有酶。這些特定的基因必定參與由PKS基因的推定的大環(huán)內(nèi)酯產(chǎn)物產(chǎn)生苷元的步驟。spnF和spnL在碳-碳橋形成過程中的作用同其與使碳原子甲基化的酶的相似性(表11)是一致的。引起被阻斷的突變株中經(jīng)部分修飾的中間體缺乏的原因可能是化合物的不穩(wěn)定性，或者與泰樂菌素途徑類似，由于缺乏起正調(diào)節(jié)劑作用的糖基化分子而使生物合成降低(Fish&amp;Cundliffe,1997)。spnG,spnH,spnI,spnK破壞spnG也可防止刺糖噻產(chǎn)生，但突變菌株不能生物轉(zhuǎn)化苷元，因此刺糖噻生物合成途徑的后序步驟需要該基因(表12)。該基因的序列與已知糖基轉(zhuǎn)移酶基因的相似性(表11)暗示spnG編碼向苷元添加第一個糖所需的鼠李糖基轉(zhuǎn)移酶。spnG被破壞的突變菌株也缺乏功能性的4’-O-甲基轉(zhuǎn)移酶(OMT)，原因是它將3’,4’-雙脫甲基刺糖噻(P)轉(zhuǎn)變?yōu)?’-脫甲基刺糖噻(K)，而不是完全甲基化的刺糖噻A。4’-OMT活性可能不在突變菌株中表達(dá)，原因是編碼基因(spnH)位于相同操縱子中處于破壞中的整合的下游。通過破壞BamHⅠ片段T可證實該操縱子的存在，所述片段跨越spnG和spnH之間的連接部分，但對任何開放閱讀框而言都不是內(nèi)部片段。然而，該片段的破壞改變了刺糖噻合成，因此該片段對包含兩個基因的單個轉(zhuǎn)錄物而言必定是內(nèi)部片段。除了預(yù)期的由spnH編碼的4’-OMT活性喪失外，該破壞還可使非預(yù)期的3’-OMT功能喪失，導(dǎo)致刺糖噻P積累(表12)。3’-OMT活性似乎由匯集于下游的基因spnI編碼。該基因的大多數(shù)序列與黑胡桃鏈霉菌的ORFY基因相似(表11)。ORFY產(chǎn)物的功能未知，但黑胡桃鏈霉菌產(chǎn)生了與刺糖噻A的三-甲基化鼠李糖相似的異常的四-甲基化脫氧糖(nogalose)，因此這兩個基因可能都參與糖的甲基化。與該假說一致的是，破壞spnI產(chǎn)生的突變體將刺糖噻P只生物轉(zhuǎn)化成3’-脫甲基刺糖噻(J)而不是刺糖噻A(表12)。破壞作用可防止刺糖噻在任何未補(bǔ)料的發(fā)酵中積累。spnK序列類似于spnI和ORFY，可能編碼2’-OMT。破壞該基因也可防止刺糖噻在任何未補(bǔ)料的發(fā)酵中積累(表12)。spnN,spnO,spnP破壞基因spnN,spnO和spnP導(dǎo)致假苷元積累(表12)，因此，這些基因參與生物合成或添加forosamine糖。spnP與糖基轉(zhuǎn)移酶的相似性(表11)表明它編碼刺糖噻forosamyl轉(zhuǎn)移酶。spnO和2,3脫水酶之間的高水平的相似性(表11)說明spnO參與forosamine合成的2’-脫氧步驟。鼠李糖基因克隆至粘粒9A6,3E11和2C10的重疊插入物不含編碼由葡萄糖生產(chǎn)鼠李糖所需的4種酶的基因(Liu&amp;Thorson,1994)。第一種酶是葡萄糖胸苷酸轉(zhuǎn)移酶(gtt)或功能等同的酶，該酶通過添加核苷酸基二磷酸(NDP)激活葡萄糖。第二種酶是葡萄糖脫水酶(gdh)，該酶可產(chǎn)生很多脫氧糖生物合成途徑所共有的中間體NDP-4-酮基-6-脫氧-葡萄糖。還需要鼠李糖合成所特有的差向異構(gòu)酶(epi)和酮基還原酶(kre)以將NDP-4-酮基-6-脫氧-葡萄糖轉(zhuǎn)變?yōu)镹DP-L-鼠李糖，該激活糖是糖基轉(zhuǎn)移酶將鼠李糖添加至苷元所需的底物。刺糖多孢菌中編碼這些酶的基因克隆自λ載體ZAPExpressTM(Stratagene,LaJolla,CA)中的7-12kb部分Sau3AⅠ片段的獨立文庫。通過隨機(jī)引物延伸(BoehringerMannheim,Indianapolis,IN)含有紅色糖多孢菌gdh(Linton等，1995)和gtt基因的質(zhì)粒pESCl的片段來制備經(jīng)放射性標(biāo)記的探針。在嚴(yán)緊洗滌條件(0.5×SSC,0.1％SDS,65℃,1小時)下進(jìn)行噬斑雜交以篩選噬菌體文庫。從3個雜交噬菌體中的2個中切下含有插入物的載體的質(zhì)粒(pDAB1620和pDAB1621)部分，使用Prism-Ready測序試劑盒(ABI)和多個引物進(jìn)行部分測序。pDAB1620之插入物的測序部分(SEQIDNO25)包括編碼329-氨基酸多肽(SEQIDNO26)的ORF，所述多肽與紅色糖多孢菌的gdh產(chǎn)物具有82％的同一性。與該基因鄰接的是編碼275-氨基酸多肽(SEQIDNO27)的ORF，所述多肽與紅色糖多孢菌的kre基因產(chǎn)物具有72％的同一性。pDAB1621之插入物的測序部分(SEQIDNO28)含有編碼261-氨基酸多肽(SEQIDNO29)的ORF，所述多肽與紅色糖多孢菌gtt的基因產(chǎn)物具有83％的同一性。使用基于已知epi蛋白之保守氨基酸區(qū)域(Jiang等，1991；Linton等，1995)的簡并寡核苷酸引物(SEQIDNO30和SEQIDNO31)，通過PCR擴(kuò)增刺糖多孢菌基因組DNA以制備鼠李糖基因的第二個探針。在GeneAmp9600熱循環(huán)儀中，用AmpliTaq聚合酶(Perkin-Elmer)進(jìn)行共30輪PCR反應(yīng)循環(huán)，每個循環(huán)的具體反應(yīng)條件為94℃30秒，60℃30秒和72℃45秒。探針與7-12kb文庫中的一個噬菌體雜交；切下含有該插入物之載體的質(zhì)粒部分(pDAB1622)并進(jìn)行部分測序(SEQIDNO32)。它包括編碼202-氨基酸多肽(SEQIDNO33)的ORF，所述多肽與紅色糖多孢菌的epi蛋白具有57％的同源性。通過與含有內(nèi)部片段(SEQIDNO25的堿基382-941,SEQIDNO25的1268-1867,SEQIDNO28的447-994或SEQIDNO32的346-739)的質(zhì)粒重組可破壞基因。在所有情況下都能得到阿泊拉霉素-抗性接合后體，但它們僅能在滲透性穩(wěn)定化的培養(yǎng)基，如添加有200g/L蔗糖的CSM或R6中生長(Matsushima等，1994)。甚至在這些條件下，它們也比刺糖多孢菌親本菌株(NRRL18395)生長緩慢，形態(tài)也有所不同，它們具有高度片段化的菌絲體。這些結(jié)果的成因是刺糖多孢菌細(xì)胞壁中存在鼠李糖，該微生物正常的細(xì)胞壁合成需要這4個基因。這些基因被破壞的突變體生長得非常緩慢以致于不能在已知可生產(chǎn)刺糖噻的條件下發(fā)酵。然而，刺糖多孢菌基因組DNA與紅色糖多孢菌的gtt/gdh探針(洗滌條件為2×SSC,0.1％SDS,65℃,1小時)或簡并epi探針(洗滌條件為0.1×SSC,0.1％SDS,65℃,1小時)的Southern雜交結(jié)果表明刺糖多孢菌基因組中不存在這些基因的其它同系物。因此，這4個克隆的刺糖多孢菌基因必定是細(xì)胞壁形成和刺糖噻生物合成所需鼠李糖的唯一來源。下表13鑒定了產(chǎn)生鼠李糖所需的4個刺糖多孢菌基因各自的核苷酸序列和相應(yīng)的氨基酸序列。表13<tablesid="table4"num="004"><table>基因DNA序列氨基酸序列刺糖多孢菌gttSEQIDNO28，堿基334-1119SEQIDNO29刺糖多孢菌gdhSEQIDNO25，堿基88-1077SEQIDNO26刺糖多孢菌epiSEQIDNO32，堿基226-834SEQIDNO33刺糖多孢菌kreSEQIDNO25，堿基1165-1992SEQIDNO27</table></tables>因此，可確定刺糖多孢菌的23個基因在生物合成刺糖噻過程中的作用5個PKS基因產(chǎn)生大環(huán)內(nèi)酯，4個基因?qū)⒋蟓h(huán)內(nèi)酯修飾為苷元，5個基因合成并添加鼠李糖，3個基因使鼠李糖甲基化，6個基因合成并添加forosamine。假擬的生物合成途徑概述于圖1。實用性克隆的刺糖多孢菌DNA有很多用途?？墒褂每寺〉幕蚋纳拼烫青绲漠a(chǎn)量并生產(chǎn)新的刺糖噻。通過將雙份拷貝的基因整合至特定菌株的基因組中即可使產(chǎn)量提高，其中所述基因編碼該菌株中的任一限速酶。當(dāng)特定突變菌株中的生物合成途徑因缺乏所需的酶而被阻斷的極端條件下，通過整合一拷貝所需基因即可恢復(fù)所需刺糖噻的生產(chǎn)。下文實施例1-3和6將闡明通過整合多拷貝刺糖噻基因而獲得的產(chǎn)量改善。使用克隆DNA的片段破壞刺糖噻的生物合成步驟即可生產(chǎn)新的刺糖噻。這種破壞作用可導(dǎo)致前體或“支路”產(chǎn)物(前體經(jīng)天然加工的衍生物)積累。可用于進(jìn)行破壞的片段是基因的內(nèi)部片段，也即基因的5’和3’末端堿基被除去的片段。利用所述片段的同源重組事件導(dǎo)致兩個部分拷貝的基因一個缺失了5’末端除去的堿基，一個缺失了3’末端除去的堿基。片段每個末端被除去的堿基數(shù)目必須足夠大以使部分拷貝的基因都不能保留活性。一般從每個末端至少除去50個堿基，更優(yōu)選從每個末端除去至少100個堿基。部分基因片段的長度必須足夠大以使重組頻率高得足以進(jìn)行實際的實驗。用于破壞的片段必須至少為300個堿基長，更優(yōu)選至少約為600個堿基長。由破壞基因產(chǎn)生的經(jīng)修飾的刺糖噻自身可以是昆蟲控制劑，或可用作其它化學(xué)修飾的底物，產(chǎn)生新的半合成的具有獨特特性和活性譜的刺糖噻。下文實施例4闡明了破壞的用途。通過誘變克隆的基因，用突變基因取代刺糖噻生產(chǎn)微生物中未經(jīng)突變的該基因?qū)?yīng)物也可生產(chǎn)新的刺糖噻。誘變包括例如1)缺失或滅活KR,DH或ER結(jié)構(gòu)域以使一個或多個所述功能被阻斷，菌株產(chǎn)生的刺糖噻具有內(nèi)酯核，該內(nèi)酯核具有刺糖噻A的核中不存在的雙鍵，羥基或酮基(見Donadio等，1993)；2)取代AT結(jié)構(gòu)域以使不同的羧酸摻入內(nèi)酯核(見Ruan等，1997)；3)在現(xiàn)存的PKS組件中添加KR,DH或ER結(jié)構(gòu)域以使菌株產(chǎn)生的刺糖噻具有內(nèi)酯核，該內(nèi)酯核具有刺糖噻A的核中不存在的飽和鍵，羥基或雙鍵；或4)添加或除去完整的PKS組件以使環(huán)狀內(nèi)酯核具有較多或較少數(shù)目的碳原子。實施例5闡明了使用誘變產(chǎn)生具有經(jīng)修飾之功能性的刺糖噻?？蓪⒋烫青缁虼貐^(qū)域的DNA用作雜交探針以鑒定同源序列，因此，可使用此處克隆的DNA確定得自刺糖多孢菌基因文庫，與此處所述的區(qū)域重疊但也含有得自鄰接區(qū)域的以前未被克隆的DNA的其它質(zhì)粒在刺糖多孢菌基因組中的位置。另外，也可使用得自此處克隆的區(qū)域的DNA鑒定其它生物體中不相同但相似的序列。雜交探針一般至少約20個堿基長，并被標(biāo)記以進(jìn)行檢測?？墒褂萌缑绹鴮＠?,362,634所述的常規(guī)方法培養(yǎng)本發(fā)明提供的經(jīng)改良的菌株以提供刺糖噻。提供下列實施例是為了更完整地理解本發(fā)明，不應(yīng)將它們看成是對本發(fā)明的限制。實施例1通過用粘粒9A6轉(zhuǎn)化改善刺糖噻A和D的產(chǎn)量于30℃，在250mlErlenmeyer燒瓶中的50mlCSM培養(yǎng)基(胰胨豆胨培養(yǎng)液30g/l，酵母提取物3g/l，硫酸鎂2g/l，葡萄糖5g/l，麥芽糖4g/l)中，以300rpm的振蕩速度將刺糖多孢菌菌株NRRL18538的營養(yǎng)培養(yǎng)物培養(yǎng)48小時。發(fā)酵培養(yǎng)物中含有分散在7mlINF202中的1ml該營養(yǎng)培養(yǎng)物的接種物，INF202是與Strobel&amp;Nakatsukasa(1993)所述類似的適宜培養(yǎng)基。在30℃的恒溫室中，用按10×10個模件安排的30ml塑料瓶以300rpm的振蕩速度將培養(yǎng)物培養(yǎng)3,5或7天。用4倍體積的乙腈提取培養(yǎng)液，然后通過流過C-18反相柱的等度高壓液相層析(HPLC)分析刺糖噻A+D(Strobel&amp;Nakatsukasa(1993))。由250nm下的光吸收值測定刺糖噻的量。對每個時間點而言，由10個發(fā)酵瓶測定刺糖噻A+D。另外通過稍加改動的HPLC系統(tǒng)分析每套重復(fù)實驗中的2個代表性樣品中的假苷元(PSA)，假苷元是缺乏forosamine的刺糖噻前體。在該系統(tǒng)中，流動相是35∶35∶30的乙腈/甲醇/0.5％(w/v)醋酸銨水溶液(R.wijayaratne，未公開)。培養(yǎng)物中不僅含有具有殺昆蟲活性的刺糖噻A和D，還含有假苷元(表14)。表14菌株NRRL18538中的刺糖噻生產(chǎn)上述數(shù)值是平均值±95％置信水平。假苷元(forosamine缺失的刺糖噻A前體)的積累表明在這些條件下培養(yǎng)的該菌株中，forosamine的供應(yīng)和/或添加限制了刺糖噻A+D的產(chǎn)量。使用Matsushima等(1994)的方法將大腸桿菌S17-1中的粘粒9A6(Simon等，1983)接合至刺糖多孢菌菌株NRRL18538中。隨后，在上述發(fā)酵條件下培養(yǎng)6個被粘粒9A6轉(zhuǎn)化的獨立的分離物并分析刺糖噻因子的生產(chǎn)情況。發(fā)酵3天后這些菌株的刺糖噻A+D平均產(chǎn)量高于其親本菌株達(dá)35μg/ml，發(fā)酵5天后高37μg/ml。在整個發(fā)酵過程中，轉(zhuǎn)化培養(yǎng)物中的假苷元的量低于其親本菌株(表15)。表15被粘粒9A6轉(zhuǎn)化的NRRL18538衍生物中的刺糖噻生產(chǎn)上述數(shù)值是平均值±95％置信水平。在發(fā)酵過程中的不同時間分析菌株NRRL18538和6個被粘粒9A6轉(zhuǎn)化的獨立的分離物中的刺糖噻含量。對每個菌株而言，由10個發(fā)酵瓶測定刺糖噻A+D(表16)。另外對每套重復(fù)實驗中的2個樣品中的假苷元含量進(jìn)行分析(表17)。表16粘粒9A6對NRRL18538中的刺糖噻A+D的作用上述數(shù)值是μg/ml平均值±95％置信水平。表17粘粒9A6對NRRL18538中的假苷元積累的作用上述數(shù)值是μg/ml平均值±95％置信水平。因此闡明用粘粒9A6轉(zhuǎn)化能改善將前體假苷元加工為刺糖噻的效率。在NRRL18538中，發(fā)酵3天后刺糖噻A+D產(chǎn)量增加35％，發(fā)酵5天后增加14％(表15)。限速方法似乎是供應(yīng)和/或添加forosamine，因為在整個發(fā)酵過程中，親本中存在的假苷元約為120μg/ml，但在轉(zhuǎn)接合子中，3天降低為約30μg/ml，隨后基本上耗盡(表15)。盡管未用數(shù)量表示轉(zhuǎn)變，但該數(shù)據(jù)與被粘粒9A6轉(zhuǎn)化的菌株中將假苷元加工為刺糖噻A+D的效率有所改善的結(jié)果是一致的。該效果可能是由復(fù)制forosamine生物合成基因，即forosaminyl轉(zhuǎn)移酶基因或聯(lián)合改善所引起的。發(fā)酵7或9天后，用或未用粘粒9A6轉(zhuǎn)化的NRRL18358菌株的刺糖噻A+D產(chǎn)量在統(tǒng)計學(xué)上沒有顯著差異。轉(zhuǎn)接合子中的假苷元仍在減少，但在通過此發(fā)酵階段積累的刺糖噻的較高背景之下，檢測不到通過由假苷元轉(zhuǎn)變產(chǎn)生的額外的刺糖噻A+D。實施例2通過粘粒9A6修正菌株NRRL18823中的甲基化缺陷盡管菌株NRRL18823中的forosamine供應(yīng)/添加可限制刺糖噻合成，其它生物合成功能在其它菌株中也被限制。刺糖多孢菌菌株NRRL18823積累刺糖噻H(2’-脫甲基-刺糖噻A；Kirst等，1992)而不是刺糖噻A。刺糖噻H不是刺糖噻A生物合成途徑中的中間體，而是在未發(fā)生2’-O-甲基化時天然合成的“支路”產(chǎn)物。使用上述方法將大腸桿菌菌株S17-1中的粘粒9A6接合至菌株NRRL18823中。當(dāng)2個所得接合后體發(fā)酵時可產(chǎn)生顯著水平的刺糖噻A，而僅產(chǎn)生極少量的刺糖噻H(表18)。表18<tablesid="table9"num="009"><table>菌株H(μg/ml)A+D(μg/ml)NRRL18823NRRL18823/9A6-2NRRL18823/9A6-532336450551646</table></tables>表18表明用粘粒9A6進(jìn)行轉(zhuǎn)化能克服對刺糖噻生產(chǎn)的第二種限制，即菌株NRRL18823中的甲基化缺陷。實施例3通過粘粒9A6修正菌株NRRL18743中的4’-O-甲基化缺陷刺糖多孢菌菌株NRRL18743積累刺糖噻K(4’-脫甲基-刺糖噻A)。刺糖噻K是刺糖噻A生物合成途徑中的中間體。含有粘粒9A6的菌株NRRL18743的2個接合后體產(chǎn)生顯著水平的刺糖噻A，而僅產(chǎn)生極少量的刺糖噻K，第3個接合后體未產(chǎn)生可測水平的刺糖噻K(表19)。表19表19表明用粘粒9A6進(jìn)行轉(zhuǎn)化能克服對刺糖噻生產(chǎn)的第三種限制，即菌株NRRL18743中的甲基化缺陷。實施例4通過破壞spnP導(dǎo)致刺糖噻前體積累在使用SEQIDNO34和SEQIDNO35中給出的引物的聚合酶鏈反應(yīng)中擴(kuò)增spnP的內(nèi)部片段(堿基7391-8159)。根據(jù)廠商說明，在100μl含有20pmol各種引物和1μg9A6DNA的反應(yīng)溶液中使用AmpliTaq聚合酶(PerkinElmer,FosterCity,CA)。將混合物在94℃60秒，37℃60秒和72℃120秒的條件下進(jìn)行25輪PCR循環(huán)。將擴(kuò)增產(chǎn)物作為EcoRⅠ-HindⅢ片段克隆至質(zhì)粒載體pOJ260(Bierman等，1992)，然后由大腸桿菌S17-1接合至刺糖多孢菌NRRL18538中。由質(zhì)粒攜有的序列和染色體序列之間的單次同源重組事件產(chǎn)生的穩(wěn)定的接合后體，在兩個不完整的spnP拷貝之間含有一拷貝整合至染色體中的載體DNA。當(dāng)這些接合后體發(fā)酵時可積累forosamine-缺失的前體假苷元，而不是終產(chǎn)物刺糖噻A和D(表20)。表20<tablesid="table11"num="011"><table>菌株P(guān)SA(μg/ml)A+D(μg/ml)NRRL18538NRRL18538/1614-2NRRL18538/1615-1NRRL18538/1615-2NRRL18538/1615-5NRRL18538/1615-6794163725434765042842221211918</table></tables>假苷元是用于制備已知殺蟲劑的中間體(國際申請WO93/09126)。實施例5修飾PKS結(jié)構(gòu)域ER2之后積累新的刺糖噻設(shè)計重疊，互補(bǔ)的寡核苷酸SEQIDNO36和SEQIDNO37以修飾編碼刺糖噻PKS之組件2中的烯酯酰還原酶功能的基因。這些誘變引物可用序列TCACC取代SEQIDNO1的堿基33563-33567處的GGTGG，以使序列編碼推定NAD(P)H-結(jié)合基元中的絲氨酸-脯氨酸二肽而不是甘氨酸-甘氨酸二肽。類似的取代被成功用于滅活紅霉素ER而不會影響任何其它PKS功能(Donadio等，1993)。取代同時還導(dǎo)入了新的PinAⅠ限制性位點并消除了SgrAⅠ位點，以便于檢測重組生物體中經(jīng)改造的DNA。在誘變的第一個步驟中，進(jìn)行兩個獨立的PCR擴(kuò)增，一個使用誘變引物SEQIDNO36和側(cè)翼引物SEQIDNO38，另一個使用誘變引物SEQIDNO37和側(cè)翼引物SEQIDNO39；第二步，將第一步反應(yīng)的產(chǎn)物稀釋100倍，合并后僅用側(cè)翼引物SEQIDNO38和SEQIDNO39進(jìn)行擴(kuò)增；第三步，根據(jù)廠商說明(InVitrogen,SanDiego,CA)將第二步PCR反應(yīng)的產(chǎn)物克隆至質(zhì)粒pCRⅡ中。以Van911-NheⅠ片段的形式切下突變的ER2結(jié)構(gòu)域部分(跨越SEQIDNO1的堿基33424-33626)，插入以取代克隆至質(zhì)粒pBluescriptSK-(Stratagene)中的粘粒3E11之3.5kbEcoRⅠ片段中的野生型Van911-NheⅠ片段(SEQIDNO1的堿基32162-35620)。然后將經(jīng)突變的EcoRⅠ片段轉(zhuǎn)移至接合質(zhì)粒pDAB1523(圖5)，所述質(zhì)粒是pOJ260的衍生物，其中含有玫瑰孢鏈霉菌的rpsL基因，該基因可賦予反向選擇的氯霉素-敏感表型(Hosted&amp;Baltz,1997)。使用Matsushima等(1994)的方法，將所得的含有突變EcoRⅠ片段的質(zhì)粒由大腸桿菌S17-1(Simon等，1983)中接合至刺糖多孢菌菌株NRRL18538之自發(fā)鏈霉素-抗性衍生物SS15中。(本領(lǐng)域技術(shù)人員易于分離刺糖多孢菌菌株NRRL18538之自發(fā)鏈霉素-抗性衍生物)。通過使用經(jīng)地高辛配基標(biāo)記的探針(BoehringerMannheim)進(jìn)行Southern雜交，證明阿泊拉霉素-抗性接合后體含有野生型和突變形式的ER2結(jié)構(gòu)域。它們也含有玫瑰孢鏈霉菌rpsL基因，因此，它們在含有150mg/L鏈霉素的BHI瓊脂(Difco,Detroit,MI)上生長緩慢并且不能產(chǎn)生氣生菌絲體?；谒鼈冊诤?50mg/L鏈霉素的BHI瓊脂上生長并產(chǎn)生白色的氣生菌絲體的能力，選擇自發(fā)回復(fù)為鏈霉素抗性的回復(fù)體。Southern分析表明這些菌株不再含有玫瑰孢鏈霉菌rpsL基因或任何其它pDAB1523序列。一些菌株失去了整簇刺糖噻生物合成基因，包括ER2結(jié)構(gòu)域以及pDAB1523。在其它菌株中，pDAB1523序列與突變的ER2結(jié)構(gòu)域一起被切下，重新產(chǎn)生親本基因結(jié)構(gòu)。在第三種類型的鏈霉素抗性菌株中，pDAB1523與野生型ER2結(jié)構(gòu)域一起被切下，后一位置上只剩下突變形式的ER2結(jié)構(gòu)域。當(dāng)?shù)谌N類型的菌株發(fā)酵時，可產(chǎn)生新的代謝物，通過使用乙腈∶甲醇∶2％醋酸銨(44∶44∶12)為流動相，在C18柱(ODS-AQ,YMC,Wilmington,NC)上進(jìn)行液相層析即可將該代謝物與刺糖噻A分開。通過電噴射離子化和使用三聯(lián)四極質(zhì)譜儀(TSQ700,FinniganMAT,SanJose,CA)的串聯(lián)質(zhì)譜術(shù)(Balcer等，1996)分析新的代謝物實體。預(yù)期其具有C18∶C19-無水刺糖噻A的特性，分子量為729.5道爾頓，并產(chǎn)生142道爾頓的forosamine片段。我們的結(jié)論是修飾編碼PKS結(jié)構(gòu)域的DNA導(dǎo)致產(chǎn)生新的發(fā)酵產(chǎn)物。實施例6通過用鼠李糖生物合成基因轉(zhuǎn)化NRRL18538以改善刺糖噻A和D的產(chǎn)量將含有鼠李糖生物合成基因的片段獨自克隆至接合載體pOJ260(Bierman等，1992)中。所得質(zhì)粒列于表21。表21通過Matsushima等(1994)的方法，將各個質(zhì)粒由大腸桿菌S17-1(Simon等，1983)中接合至刺糖多孢菌菌株NRRL18538中。選擇并發(fā)酵可能含有通過同源重組整合至染色體中的質(zhì)粒的阿泊拉霉素抗性接合后體(表22)。表22被鼠李糖基因轉(zhuǎn)化的NRRL15328衍生物中刺糖噻的產(chǎn)生數(shù)值為平均值±95％置信限。在被gtt或epi轉(zhuǎn)化或者被gdh和kre聯(lián)合轉(zhuǎn)化的NRRL15328衍生物中，刺糖噻的產(chǎn)量沒有一致的增加。將含有g(shù)tt和gdh+kre基因的片段同時放在一個質(zhì)粒中。分離出2個含有g(shù)tt,gdh和kre基因組合的質(zhì)粒(pDAB1654和pDAB1655)，通過Matsushima等(1994)的方法，將各個質(zhì)粒由大腸桿菌S17-1(Simon等，1983)中接合至刺糖多孢菌菌株NRRL18538中。選擇并發(fā)酵阿泊拉霉素抗性接合后體(表23)。表23被鼠李糖基因轉(zhuǎn)化的NRRL15328衍生物中刺糖噻的產(chǎn)生數(shù)值為平均值±95％置信限。在被gtt,gdh和kre基因轉(zhuǎn)化的NRRL15328衍生物中，觀察到刺糖噻的產(chǎn)量顯著增加，這可能是由通過同時增加gtt和gdh基因產(chǎn)物(刺糖噻生物合成所必需的酶)的量而克服了NDP-4-酮基-6-脫氧-葡萄糖的限速供應(yīng)所引起的(見圖1)。提供較多的NDP-4-酮基-6-脫氧-葡萄糖中間體可使鼠李糖和forosamine的產(chǎn)量增加，因此將苷元轉(zhuǎn)變?yōu)榇烫青鏏+D的能力更強(qiáng)。與此假說一致的是，在NRRL18538中，脫氧糖的供應(yīng)限制刺糖噻的產(chǎn)生，很多forosamine合成或添加被阻斷的突變菌株能將PSA積累至很高水平。還可制備更多的此類中間體，因為它僅需要一個脫氧糖，而相比之下刺糖噻A或D需要2個脫氧糖。本發(fā)明并不限于含有本發(fā)明的刺糖噻基因的特定載體，還包括位于能將基因?qū)胫亟M宿主細(xì)胞中的任何載體上的生物合成基因。另外，由于遺傳密碼的簡并性，本領(lǐng)域技術(shù)人員熟知制備編碼與天然基因序列相同或功能上相同之活性的DNA序列的合成方法。類似地，本領(lǐng)域技術(shù)人員熟知修飾或突變基因序列以制備編碼與天然序列相同或基本上相同之多肽活性的新序列的技術(shù)。因此，本發(fā)明還包括這些合成的突變體和經(jīng)修飾的基因形式以及這些基因的表達(dá)產(chǎn)物。上述所有專利和文獻(xiàn)都列入本文作為參考。參考文獻(xiàn)1．Altschul,S.F.,W.Gish,W.Miller,E.W.Myers和DavidJ.Lipman(1990).基本的局部序列對比檢索工具，分子生物學(xué)雜志215403-10.2．Aparicio,J.F.,I.Molnar,T.Schwecke,A.Konig,S.F.Haydock,L.E.Khaw,J.Staunton&amp;J.F.Leadlay(1996)?！拔溍咕屑{巴霉素生物合成基因簇的構(gòu)成分析聚酮化合物合酶組件中的酶結(jié)構(gòu)域”基因1699-16。3．Balcer,J.L.,S.M.Brown&amp;D.F.Berard(1996).“使用ESI/MS/MS鑒定Spinosad光裂解產(chǎn)物的快速篩選技術(shù)”Proc.44”ConfAmer.Soc.Massspec。4．Baltz,R.H.,M.A.McHenney,C.A.Cantwell,S.W.Qucener&amp;P.J.Solenberg(1997)?！霸谏a(chǎn)抗生素的鏈霉菌中使用轉(zhuǎn)座誘變”Ant.vanLeeuw.71179-187。5．Bibb,M.J.,P.R.Findlay&amp;M.W.Johnson(1984)?！凹?xì)菌基因的堿基組成和密碼子使用之間的關(guān)系及其用于簡單可靠地鑒定蛋白質(zhì)編碼序列的用途”基因30157-166。6．Bierman,M.,R.Logan,K.O＇Brien,E.T.Seno,R.N.Rao&amp;B.E.Schoner(1992)?！皩NA從大腸桿菌中接合轉(zhuǎn)移至鏈霉菌中所用的質(zhì)粒克隆載體"基因1164349。7．Broughton,M.C.,M.L.B.Huber,L.C.Creemer,H.A.Kirst&amp;J.A.Turner(1991)?！巴ㄟ^刺糖多孢菌生物合成大環(huán)內(nèi)酯殺蟲劑化合物A83543”Ann.Mtg.Amer.Soc.Microbio1。8．Burgett,S.G.&amp;P.R.J.Rosteck(1994)。“使用二甲基亞砜改善熒光Taq循環(huán)測序，見于自動化DNA測序和分析”.M.Adams,C.Fields&amp;J.C.Venter，編NY,AcademicPresspp.211-215。9．Dehoff,B.S.,S.A.Kuhstoss,P.R.Rosteck&amp;K.L.Sutton(1997)。“聚酮化合物合酶基因”EPA0791655。10．Don,ILH.,P.T.Cox,B.J.Wainwright,K.Baker&amp;J.S.Mattick(1991)?！胺乐够驍U(kuò)增過程中的假引發(fā)發(fā)生的‘Touchdown’PCR”核酸研究194008。11．Donadio,S.,J.B.McAlpine,P.S.Sheldon,M.Jackson&amp;L.Katz(1993)?！巴ㄟ^重新安排聚酮化合物合成的程序產(chǎn)生紅霉素類似物”Proc.Natn.Acad.Sci.USA907119-7123。12．Donadio,S.&amp;L.Katz(1992)?！皡⑴c紅色糖多孢菌中的紅霉素形成的多功能聚酮化合物合酶中的酶結(jié)構(gòu)域構(gòu)成”基因11151-60。13．Donadio,S.,MJ.Staver,lB.McAlpine,SJ.Swanson&amp;L.Katz(1991)。“復(fù)雜的聚酮化合物生物合成所需基因的組件構(gòu)成”科學(xué)252675-679。14．Fish,S.A.&amp;E.Cundliffe(1997)。“在弗氏鏈霉菌中通過泰樂菌素及其糖基化前體刺激聚酮化合物代謝”微生物學(xué)1433871-3876。15．Geistlich,M.,R.Losick,J.R.Turner&amp;R.N.Rao(1992)?！拌b定產(chǎn)二素鏈霉菌中控制聚酮化合物合酶基因表達(dá)的新的調(diào)節(jié)基因”分子微生物學(xué)62019-2029。16．Hosted,T.J.&amp;RH.Baltz(1997)。“在玫瑰孢鏈霉菌中使用rpsL進(jìn)行顯性選擇和基因取代”，細(xì)菌學(xué)雜志179180-186。17．lnouye,M.,H.Suzulci,Y.Takada,N.Muto,S.Horinouchi&amp;T.Beppu(1994)?！盎衣约t小單孢菌中編碼mycinamicinⅢO-甲基轉(zhuǎn)移酶的基因”基因141121-124。18．Jiang,X.M.,B.Neal,F.Santiago,S.J.Lee,L.KRomana&amp;P.R.Reeves(1991)?！笆髠抽T氏菌血清種(菌株LT2)之rfb(O抗原)基因簇的結(jié)構(gòu)和序列”分子微生物學(xué)5695-713。20．Kirst,H.A.,K.H.Michel,J.S.Mynderse,E.H.Chio,R.C.Yao,W.M.Nakatsukasa,L.D.Boeck,IL.Occlowitz,J.W.Pasehal,J.B.Deeter&amp;G.D.Thompson(1992)。“發(fā)現(xiàn)，分離結(jié)構(gòu)獨特的，發(fā)酵得到的四環(huán)大環(huán)內(nèi)酯并闡明其結(jié)構(gòu)，見于SyntheesisandChemistryofAgrochemicalsHI,”D.R.Baker,J.G．Fenycs&amp;J.J.Steffens，編.Washington,DC,AmericanChemicalSocietypp.214-225。21．Linton,K.J.,B.W.Jarvis&amp;C.R.Hutchinson(1995)?！皬纳a(chǎn)紅霉素的Saccharopolysporaerytliraca中克隆編碼胸苷二磷酸葡萄糖4,6-脫水酶和胸苷二磷酸-酮基-6-脫氧葡萄糖3,5-差向異構(gòu)酶的基因”22．Liu,H.W.&amp;J.S.Thorson(1994)?！巴ㄟ^細(xì)菌生物合成新的脫氧糖的途徑和機(jī)理”微生物學(xué)年評48223-256。23．Matsushima,P.,M.C.Broughton,J.ILTurner&amp;RH.Baltz(1994)?！睂⒄沉NA由大腸桿菌中接合轉(zhuǎn)移至刺糖多孢菌染色體插入對大環(huán)內(nèi)酯A83543生產(chǎn)的影響”基因1463945。24．Ruan,X.等(1997)。“紅霉素聚酮化合物合酶中的?；D(zhuǎn)移酶結(jié)構(gòu)域取代產(chǎn)生了新的紅霉素衍生物”細(xì)菌學(xué)雜志179,6416。25．Siggard-Andersen,M.(1993)?！爸舅岷厦钢s合酶結(jié)構(gòu)域中的保守殘基和相關(guān)序列”ProteinSeq.DataAnaL5325-335。26．Simon,R,U.Preifer&amp;A.Puhier(1983)?！绑w內(nèi)基因工程所用的廣宿主范圍轉(zhuǎn)移系統(tǒng)革蘭氏陰性細(xì)菌的轉(zhuǎn)座子誘變”Bio/Technology178～791。27．Solenberg,P.J.&amp;S.G.Burgett(1989)?！皬臏\青紫鏈霉菌中選擇可轉(zhuǎn)座的DNA和鑒定新的插入序列IS493的方法”細(xì)菌學(xué)雜志1714807-4813。28．Strobel,ILJ.&amp;W.M.Nakarsukasa(1993)。“最優(yōu)化新的大環(huán)內(nèi)酯生產(chǎn)微生物刺糖多孢菌的反應(yīng)表面法”Jind.Microbiol11121-127。29．Thorson,3.5.,S.F.Lo&amp;H.Liu(1993)?！吧锖铣?,6-二脫氧己糖通過2,6-二脫氧，4,6-二脫氧和氨基糖構(gòu)建反映新機(jī)理”JAm.Chem.Soc.1156993-6994。30．Weber,J.M.&amp;J.B.McAlpine(1992)?！凹t霉素衍生物”美國專利5,141,926。序列表&lt;110&gt;Baltz,RichardHBroughton,MaryCCrawford,KathrynPMadduri,KrishnamurthyTreadway,PattiJTurner,JanRWaldron,Clive&lt;120&gt;刺糖噻殺蟲劑生物合成基因&lt;130&gt;50489&lt;140&gt;&lt;141&gt;&lt;150&gt;US09/36987&lt;151&gt;1998-03-09&lt;160&gt;39&lt;170&gt;PatentInVer.2.0&lt;210&gt;1&lt;211&gt;80161&lt;212&gt;DNA&lt;213&gt;刺糖多孢菌&lt;400&gt;1gatctccatgaagctcaacgtaggcacggacggtcaggtggactgggtgatcgcccgcga60cctgctggccgacgggctgatcgccgaggcaggcgaaggcgatgtgcggatcggccctcg120acggggttttccggggttggtcgtgatcgagatgagctcgccgtcggggcaggcctcctt180cgaggtgaatgctgaccagcttgcggacttcttgaacgacacctacgacgtggtcgaacc240tggtgatgaacaccggtggatgaacgtcgacgaggtgctgagccagctgctctcgccaac300ctgtaatggcccagctctcccgaagcgccgcacgccaaagcgctggctgcgggacctggc360ggcgctgaacaccgccacgctgtgtctccgagctccagctggaccacgtcggtgccgtgc420gcccggctcggtcaggccgaaggtgctgatcttctccaggcgcgccatcggcgcaggaag480cgctgcttctgctcccgccgcagtaccgtcgtgtcatggccacggacagcttcgattcct540cgaagctacaggcggccgtggcatcgagcgtcgcgtcgtgcgtctcggaagtcagccgag600acgtctacacgcacctgattaccgaggctccgcagttgcgagccgatgagatcgtcctca660gcattctacggacgagtgttgaggaaaatatcgccacattgccgcacgttctcgaattcg720agattccgttgggatattcgccgggtcctgctgcggtgttggagtatccgcgacgactgg780cgaaacatttccatcaacgcgctgatcagggccaaccgcatcgggcacttccgcttcctg840tagtgatgcctcgacgagatccgccgccaatgcgccgacgaggccgtatccgcagcgacc900acgcaacgaatgctcgcaaccagcttcggctacatcgaccgcgtcacggagcagatcgcc960gaaacctaccagctcgaacgggaccgctggctcctggcgacgggacggccgtgaggtctc1020tgcggcatccgcatagcgtcttctcccgctgaggcacatgaggtgttgcgcgcggtcgtt1080tccggcagtcgcacggcattcgtcctagctgcgggcaattgagggagcgaagatttagag1140gagtgtggccacgcggaccaagccggcgagtgctcgggagcggctgtggggcggccaggc1200gatgactgtcgtcacgtccggcgcgtctagaaccggtacggcggcgaggccttcgagcag1260gttgacgcgactggattcgggcatgaccacggtagtgcggccgagtgcgatcatttggaa1320cagttgcgtctggttgcgtacttccacgccggggccatctggatagacgccgtcggggcc1380gggccagcgcgcaagcgggagatccggcagtgagctgacatccgccatccgtacatgggg1440ctcgctggcaagcggatgcgaggtcggaagaatggcgacttgttgctcggtgttcagaat1500ttcgatgtcgagttcggccgtcgggtcgaagggttgatgcaacagcgccacgtcggcccg1560gccgtcatgcagcgttttctggggctgggattcgcagagcagcaggtcgacggccacggc1620tcccggctcggcggcgtacgcgtcgagcaacttcgccagcagctcaccggaggcgccggc1680cttggcagccaggactagcgagggctggctcgtcgcggcacgctgggtgcgtcgctcggc1740tgctgccagcgcgccgaggatcgcccggccttcggtcagcagcattgccccggcttcggt1800gagcgagactttgcggctggtgcgttgcagcaacacgactccgagtcgttgctcgagctg1860ggcgatcgtccgcgacagcggcggctgggcgatgcccaggcgctgggcggcccggccgaa1920gtgcaactcctcggcgactgcaacgaagtaccgcaactcccgcgtctccatccgtcgagc1980ctaccgctgattcatatcagctgggtatcggtgtgagacctagatggtgttggttccccg2040ccggtttcgggccacgctagaaagcatgagcgaacagacgattgcactggtcaccggcgc2100aaacaagggaatcggatacgagatcgcggccgggctcggcgcgctggggtggagcgtcgg2160aatcggggcacgggaccaccagcgcggggaggatgccgtggcgaaattgcgtgcggacgg2220cgtcgatgcgttcgcggtatccctggacgtgacagacgacgcgagcgtcgcggctgctgc2280ggctctgctcgaggagcgcgccggccggctcgatgtgctggttaataacgccggcatcgc2340cggggcatggccggaggagccctcgaccgtcacaccggcgagcctccgggcggtggtgga2400gacca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spValArgAlaAsnGlyTyrValArgGlyGluGlyGlyGly225230235240LeuValValLeuLysLysAlaAspGlnAlaHisAlaAspGlyAspArg245250255IleTyrCysLeuIleArgGlySerAlaValAsnAsnAspGlyGlyGly260265270AlaGlyLeuThrValProAlaAlaAspAlaGlnAlaGluLeuLeuArg275280285GlnAlaTyrArgAsnAlaGlyValAspProAlaAlaValGlnTyrVal290295300GluLeuHisGlySerAlaThrArgValGlyAspProValGluAlaAla305310315320AlaLeuGlyAlaValLeuGlyAlaAlaArgArgProGlyAspGluLeu325330335ArgValGlySerAlaLysThrAsnValGlyHisLeuGluAlaAlaAla340345350GlyValThrGlyLeuLeuLysThrAlaLeuSerIleTrpHisArgGlu355360365LeuProProSerLeuHisPheThrAlaProAsnProGluIleProLeu370375380AspGluLeuAsnLeuArgValGlnArgAspLeuArgProTrpProGlu385390395400SerGluGlyProLeuLeuAlaGlyValSerAlaPheG1yMetGlyGly405410415ThrAsnCysHisLeuValLeuSerGlyThrSerArgValGluArgArg420425430ArgSerGlyProAlaGluAlaThrMetProTrpValLeuSerAlaArg435440445ThrProValAlaLeuArgAlaGlnAlaAlaArgLeuHisThrHisLeu450455460AsnThrAlaGlyGlnSerProLeuAspValAlaTyrSerLeuAlaThr465470475480ThrArgSerAlaLeuProHisArgAlaAlaLeuValAlaAspAspGlu485490495ProLysLeuLeuAlaGlyLeuLysAlaLeuAlaAspGlyAspAspAla500505510ProThrLeuCysHisGlyAlaThrSerGlyGluArgAlaAlaValPhe515520525ValPheProGlyGlnGlySerGlnTrpIleGlyMetGlyArgGlnLeu530535540LeuGluThrSerGluValPheAlaAlaSetMetSerAspCysAlaAsp54S550555560AlaLeuAlaProHisLeuAspTrpSerLeuLeuAspValLeuArgAsn565570575AlaAlaGlyAlaAlaHisLeuAspHisAspAspValValGlnProAla580585590LeuPheAlaIlaMetValSerLeuAlaGluLeuTrpArgSerTrpGly595600605ValArgProValAlaValValGlyHisSerGlnGlyGluIleAlaAla610615620AlaCysValAlaGlyAlaLeuSerValArgAspAlaAlaArgValVal625630635640AlaValArgSerArgLeuLeuThrAlaLeuAlaGlySerGlyAlaMet645650655AlaSerLeuGlnHisProAlaGluGluValArgGlnIleLeuLeuPro660665670TrpArgAspArgIleGlyValAlaGlyValAsnGlyProSerSerThr675680685LeuValSerGlyAspArgGluAlaMetAlaGluLeuLeuAlaGluCys690695700AlaAspArgGluLeuArgMetArgArgIleProValGluTyrAlaSer705710715720HisSerProHisIleGluValValArgAspGluLeuLeuGlyLeuLeu725730735AlaProValGluProArgThrGlySerIlePrcIleTyrSerThrThr740745750ThrGlyAspLeuLeuAspArgProMetAspAlaAspTyrTrpTyrArg755760765AsnLeuArgGlnProValLeuPheGluAlaAlaValGluAlaLeuLeu770775780LysArgGlyTyrAspAlaPheIleGluIleSerProHisProValLeu785790795800ThrAlaAshIleGlnGluThrAlaValArgAlaGlyArgGluValVal805810815AlaLeuGlyThrLeuArgArgGlyGluGlyGlyMetArgGlnAlaLeu820825830ThrSerLeuAlaArgAlaHisValHisGlyValAlaAlaAspTrpHis835840845AlaValPheAlaGlyThrGlyAlaGlnArgValAspLeuProThrTyr850855860AlaPheGlnArgGlnArgTyrTrpLeuAspAlaLysLeuProAspVal865870875880AlaMetProGluSerAspValSerThrAlaLeuArgGluLysLeuArg885890895SerSerProArgAlaAspValAspSerThrThrLeuThrMetIleArg900905910AlaGlnAlaAlaValValLeuGlyHisSerAspProLysGluValAsp915920925ProAspArgThrPheLysAspLeuGlyPheAspSerSerMetValVal930935940GluLeuCysAspArgLeuAshAlaAlaThrGlyLeuArgLeuAlaPro945950955960SerValValPheAspCysProThrProAspLysLeuAlaArgGlnVal965970975ArgThrLeuLeuLeuGlyGluProAlaProMetThrSerHisArgPro980985990AspSerAspAlaAspGluProIleAlaValIleGlyMetGlyCysArg99510001005PheProGlyGlyValSerSerProGluGluLeuTrpGlnLeuValAla101010151020AlaGlyArgAspValValSerGluPheProAlaAspArgGlyTrpAsp1025103010351040LeuGluArgAlaGlyThrSerHisValArgAlaGlyGlyPheLeuHis104510501055GlyAlaProAspPheAspProGlyPhePheArgIleSerProArgGlu106010651070AlaLeuAlaMetAspProGlnGlnArgLeuLeuLeuGluIleAlaTrp107510801085GluAlaValGluArgGlyGlyIleAsnProGlnHisLeuHisGlySar109010951100GlnThrGlyValPheValGlyAlaThrSerLeuAspTyrGlyProArg1105111011151120LeuHisGluAlaSerGluGluAlaAlaGlyTyrValLeuThrGlySer112511301135ThrThrSerValAlaSerGlyArgValAlaTyrSerPheGlyPheGlu114011451150GlyProAlaValThrValAspThrAlaCysSerSerSerLeuValAla115511601165LeuHisLeuAlaCysGlnSerLeuArgSerGlyGluCysAspLeuAla117011751180LeuAlaGlyGlyValThrValMetAlaThrProGlyMetPheValGlu1185119011951200PheSerArgGlnArgGlyLeuAlaProAspGlyArgCysLysSerPhe120512101215AlaGluAlaAlaAspGlyThrGlyTrpSerGluGlyAlaGlyLeuVal122012251230LeuLeuGluArgLeuSerAspAlaArgArgAsnGlyHisGluValLeu123512401245AlaValValArgGlySerAlaValAsnGlnAspGlyAlaSerAsnGly125012551260LeuThrAlaProAsnGlySerSerGlnGlnArgValIleAlaGlnAla1265127012751280LeuAlaSerAlaGlyLeuSerValSerAspValAspAlaValGluAla128512901295HisGlyThrGlyThrArgLeuGlyAspProIleGluAlaGlnAlaLeu130013051310IleAlaThrTyrGlyGlnGlyArgLeuProGluArgProLeuTrpLeu131513201325GlySerMetLysSerAsnIleGlyHisAlaGlnAlaAlaAlaGlyIle133013351340AlaGlyValMetLysMetValMetAlaMetArgHisGlyGlnLeuPro1345135013551360ArgThrLeuHisValAspGluProThrSerGlyValAspTrpSerAla136513701375GlyThrValGlnLeuLeuThrGluAsnThrProTrpProGlySerGly138013851390ArgValArgArgValGlyValSerSerPheGlyIleSerGlyThrAsn139514001405AlaHisValIleLeuGluGlnProProGlyValProSerGlnSerAla141014151420GlyProGlySerGlySerValValAspValProValValProTrpMet1425143014351440ValSerGlyLysThrProGluAlaLeuSerAlaGlnAlaThrAlaLeu144514501455MetThrTyrLeuAspGluArgProAspValSerSerLeuAspValGly146014651470TyrSerLeuAlaLeuThrArgSerAlaLeuAspGluArgAlaValVal147514801485LeuGlySerAspArgGluThrLeuLeuCysGlyValLysAlaLeuSer149014951500AlaGlyHisGluAlaSerGlyLeuValThrGlySerValGlyAlaGly1505151015151520GlyArgIleGlyPheValPheSerGlyGlnGlyGlyGlnTrpLeuGly152515301535MetGlyArgGlyLeuTyrArgAlaPheProValPheAlaAlaAlaPhe154015451550AspGluAlaCysAlaGluLeuAspAlaHisLeuGlyGlnGluIleGly155515601565ValArgGluValValSerGlySerAspAlaGlnLeuLeuAspArgThr157015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GlyAlaAlaLeuArgValArg467546804685LeuSerProLeuGlySerGlyAlaValSerLeuThrLeuValAspAla469046954700ThrGlyArgArgValAlaAlaValGluSerLeuSerThrArgProVal4705471047154720SerThrAspGlnIleGlyAlaGlyArgGlyAspGlnGluArgLeuLeu472547304735HisValGluTrpValArgSerAlaGluSerAlaGlyMetSerLeuThr474047454750SerCysAlaValValGlyLeuGlyGluProGluTrpHisAlaAlaLeu475547604765LysThrThrGlyValGlnValGluSerHisAlaAspLeuAlaSerLeu477047754780AlaThrGluValAlaLysArgGlySerAlaProGlyAlaValIleVal4785479047954800ProCysProArgProArgAlaMetGlnGluLeuProThrAlaAlaArg480548104815ArgAlaThrGlnGlnAlaMetAlaMetLeuGlnGlnTrpLeuAlaAsp482048254830AspArgPheValSerThrArgLeuIleLeuLeuThrHisArgAlaVal483548404845SerAlaValAlaGlyGluAspValLeuAspLeuValHisAlaProLeu485048554860TrpGlyLeuValArgSerAlaGlnAlaGluHisProAspArgPheAla4865487048754880LeuIleAspMetAspAspGluArgAlaSerGlnThrAlaLeuAlaGlu488548904895AlaLeuThrAlaGlyGluAlaGlnLeuAlaValArgSerGlyValVal490049054910LeuAlaProArgLeuGlyGlnValLysValSerGlyGlyGluAlaPhe491549204925ArgTrpAspGluGlyThrValLeuValThrGlyGlyThrGlyGlyLeu493049354940GlyAlaLeuLeuAlaArgHisLeuValSerAlaHisGlyValArgHis4945495049554960LeuLeuLeuAlaSerArgArgGlyLeuAlaAlaProGlyAlaAspGlu496549704975LeuValAlaGluLeuGluGlnAlaGlyAlaAspValAlaValValAla498049854990CysAspSerAlaAspArgAspSerLeuAlaArgLeuValAlaSerVal499550005005ProAlaGluAsnProLeuArgValValValHisAlaAlaGlyValLeu501050155020AspAspGlyValLeuMetSerMetSerProGluArgLeuAspAlaVal5025503050355040LeuArgProLysValAspAlaAlaTrpTyrLeuHisGluLeuThrArg504550505055GluLeuGlyLeuSerAlaPheValLeuPheSerSerValAlaGlyLeu506050655070PheGlyGlyAlaGlyGlnSerAsnTyrAlaAlaGlyAsnAlaPheLeu507550805085AspAlaLeuAlaHisCysArgGlnAlaGlnGlyLeuProAlaLeuSer509050955100LeuAlaSerGlyLeuTrpAlaSerIleAspGlyMetAlaGlyAspLeu5105511051155120AlaAlaAlaAspValGluArgLeuSerArgAlaGlyIleGlyProLeu512551305135SarAlaProGlyGlyLeuAlaLeuPheAspAlaAlaValGlySerAsp514051455150GluProLeuLeuAlaProValArgLeuAspValGluAlaLeuArgVal515551605165GlnAlaArgSerValGlnThrArgIleProGluMetLeuHisGlyMet517051755180AlaMetGlyProSerArgArgThrProPheThrSerArgValGluPro5185519051955200LeuHisGluArgLeuAlaGlyLeuSerGluGlyGluArgArgGlnGln520552105215ValLeuGlnArgValArgAlaAspIleAlaValValLeuGlyHisGly522052255230ArgSerSerAspValAspIleGluLysProLeuAlaGluLeuGlyPhe523552405245AspSerLeuThrAlaIleGluLeuArgAsnArgLeuAlaThrAlaThr525052555260GlyLeuArgLeuProAlaThrLeuAlaPheAspHisGlyThrAlaAla5265527052755280AlaLeuAlaGlnHisValCysAlaGlnLeuGlyThrAlaThrAlaPro528552905295AlaProArgArgThrAspAspAsnAspAlaThrGluProValArgSar530053055310LeuPheGlnGlnAlaTyrAlaAlaGlyArgIleLeuAspGlyMetAsp531553205325LeuValLysValAlaAlaGlnLeuArgProValPheGlySerProGly533053355340GluLeuGluSerLeuProLysProValGlnLeuSerArgGlyProGlu5345535053555360GluLeuAlaLeuValCysMetProAlaLeuIleGlyMetProProAla536553705375GlnGlnTyrAlaArgIleAlaAlaGlyPheArgAspValArgAspVal538053855390SerValIleProMetProGlyPheIleAlaGlyGluProLeuProSer539554005405AlaIleGluValAlaValArgThrGlnAlaGluAlaValLeuGlnGlu541054155420PheAlaGlyGlySerPheValLeuValGlyHisSerSerGlyGlyTrp5425543054355440LeuAlaHisGluValAlaGlyGluLeuGluArgArgGlyValValPro544554505455AlaGlyValValLeuLeuAspThrTyrIleProGlyGluIleThrPro546054655470ArgPheSerValAlaMetAlaHisArgThrTyrGluLysLeuAlaThr547554805485PheThrAspMetGlnAspValGlyIleThrAlaMetGlyGlyTyrPhe549054955500ArgMetPheThrGluTrpThrProThrProIleGlyAlaProThrLeu5505551055155520PheValArgThrGluAspCysValAlaAspProGluGlyArgProTrp552555305535ThrAspAspSerTrpArgProGlyTrpThrLeuAlaAspAlaThrVal554055455550GlnValProGlyAspHisPheSerMetMetAspGluHisAlaGlySer555555605565ThrAlaGlnAlaValAlaSerTrpLeuAspLysLeuAsnGlnArgThr557055755580AlaArgGlnArg5585&lt;210&gt;7&lt;211&gt;275&lt;212&gt;PRr&lt;213&gt;刺糖多孢菌&lt;400&gt;7ValLeuProGlyGlyAlaProThrSerGlnGlnValGlyGlnMetTyr151015AspLeuValThrProLeuLeuAsnSerValAlaGlyGlyProCysAla202530IleHisHisGlyTyrTrpGluAsnAspGlyArgAlaSerTrpGlnGln354045AlaAlaAspArgLeuThrAspLeuValAlaGluArgThrValLeuAsp505560GlyGlyValArgLeuLeuAspValGlyCysGlyThrGlyGlnProAla65707580LeuArgValAlaArgAspAsnAlaIleGlnIleThrGlyIleThrVal859095SerGlnValGlnValAlaIleAlaAlaAspCysAlaArgGluArgGly100105110LeuSerHisArgValAspPheSerCysValAspAlaMetSerLeuPro115120125TyrProAspAsnAlaPheAspAlaAlaTrpAlaMetGlnSerLeuLeu130135140GluMetSerGluProAspArgAlaIleArgGluIleLeuArgValLeu145150155160LysProGlyGlyIleLeuGlyValThrGluValValLysArgGluAla165170175GlyGlyGlyMetProValSerGlyAspArgTrpProThrGlyLeuArg180185190IleCysLeuAlaGluGlnLeuLeuGluSerLeuArgAlaAlaGlyPhe195200205GluIleLeuAspTrpGluAspValSerSerArgThrArgTyrPheMet210215220ProGlnPheAlaGluGluLeuAlaAlaHisGlnHisGlyIleAlaAsp225230235240ArgTyrGlyProAlaValAlaGlyTrpAlaAlaAlaValCysAspTyr245250255GluLysTyrAlaHisAspMetGlyTyrAlaIleLeuThrAlaArgLys260265270ProValGly275&lt;210&gt;8&lt;211&gt;390&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;8MetArgValLeuValValProLeuProTyrProThrHisLeuMetAla151015MetValProLeuCysTrpAlaLeuGlnAlaSerGlyHisGluValLeu202530IleAlaAlaProProGluLeuGlnAlaThrAlaHisGlyAlaGlyLeu354045ThrThrAlaGlyIleArgGlyAsnAspArgThrGlyAspThrGlyGly505560ThrThrGlnLeuArgPheProAsnProAlaPheGlyGlnArgAspThr65707580GluAlaGlyArgGlnLeuTrpGluGlnThrAlaSerAsnValAlaGln859095SerSerLeuAspGlnLeuProGluTyrLeuArgLeuAlaGluAlaTrp100105110ArgProSerValLeuLeuValAspValCysAlaLeuIleGlyArgVal115120125LeuGlyGlyLeuLeuAspLeuProValValLeuHisArgTrpGlyVal130135140AspProThrAlaGlyProPheSerAspArgAlaHisGluLeuLeuAsp145150155160ProValCysArgHisHisGlyLeuThrGlyLeuProThrProGluLeu165170175IleLeuAspProCysProProSerLeuGlnAlaSerAspAlaProGln180185190GlyAlaProValGlnTyrValProTyrAsnGlySerGlyAlaPhePro195200205AlaTrpGlyAlaAlaArgThrSerAlaArgArgValCysIleCysMet210215220GlyArgMetValLeuAsnAlaThrGlyProAlaProLeuLeuArgAla225230235240ValAlaAlaAlaThrGluLeuProGlyValGluAlaValIleAlaVal245250255ProProGluHisArgAlaLeuLeuThrAspLeuProAspAsnAlaArg260265270IleAlaGluSerValProLeuAsnLeuPheLeuArgThrCysGluLeu275280285ValIleCysAlaGlyGlySerGlyThrAlaPheThrAlaThrArgLeu290295300GlyIleProGlnLeuValLeuProGlnTyrPheAspGlnPheAspTyr305310315320AlaArgAsnLeuAlaAlaAlaGlyAlaGlyIleCysLeuProAspGlu325330335GlnAlaGlnSerAspHisGluGlnPheThrAspSerIleAlaThrVal340345350LeuGlyAspThrGlyPheAlaSerAlaAlaIleLysLeuSerAspGlu355360365IleThrAlaMetProHisProAlaAlaLeuValArgThrLeuGluAsn370375380ThrAlaAlaIleArgAla385390&lt;210&gt;9&lt;211&gt;250&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;9MetProSerGlnAsnAlaLeuTyrLeuAspLeuLeuLysLysValLeu151015ThrAsnThrIleTyrSerAspArgProHisProAsnAlaTrpGlnAsp202530AsnThrAspTyrArgGlnAlaAlaArgAlaLysGlyThrAspTrpPro354045ThrValAlaHisThrMetIleGlyLeuGluArgLeuAspAsnLeuGln505560HisCysValGluAlaValLeuAlaAspGlyValProGlyAspPheAla65707580GluThrGlyValTrpArgGlyGlyAlaCysIlePheMetArgAlaVal859095LeuGlnAlaPheGlyAspThrGlyArgThrValTrpValValAspSer100105110PheGlnGlyMetProGluSerSerAlaGlnAspHisGlnAlaAspGln115120125AlaMetAlaLeuHisGluTyrAsnAspValLeuGlyValSerLeuGlu130135140ThrValArgGlnAsnPheAlaArgTyrGlyLeuLeuAspGluGlnVal145150155160ArgPheLeuProGlyTrpPheArgAspThrLeuProThrAlaProIle165170175GlnGluLeuAlaValLeuArgLeuAspGlyAspLeuTyrGluSerThr180185190MetAspSerLeuArgAsnLeuTyrProLysLeuSerProGlyGlyPhe195200205ValIleIleAspAspTyrPheLeuProSerCysGlnAspAlaValLys210215220GlyPheArgAlaGluLeuGlyIleThrGluProIleHisAspIleAsp225230235240GlyThrGlyAlaTyrTrpArgArgSerTrp245250&lt;210&gt;10&lt;211&gt;395&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;10MetSerGluIleAlaValAlaProTrpSerValValGluArgLeuLeu151015LeuAlaAlaGlyAlaGlyProAlaLysLeuGlnGluAlaValGlnVal202530AlaGlyLeuAspAlaValAlaAspAlaIleValAspGluLeuValVal354045ArgCysAspProLeuSerLeuAspGluSerValArgIleGlyLeuGlu505560IleThrSerGlyAlaGlnLeuValArgArgThrValGluLeuAspHis65707580AlaGlyLeuArgLeuAlaAlaValAlaGluAlaAlaAlaValLeuArg859095PheAspAlaValAspLeuLeuGluGlyLeuPheGlyProValAspGly100105110ArgArgHisAsnSerArgGluValArgTrpSerAspSerMetThrGln115120125PheSerProAspGlnGlyLeuAlaGlyAlaGlnArgLeuLeuAlaPhe130135140ArgAsnArgValSerThrAlaValHisAlaValLeuAlaAlaAlaAla145150155160ThrArgArgAlaAspLeuGlyAlaLeuAlaValArgTyrGlySerAsp165170175LysTrpAlaAspLeuHisTrpTyrThrGluHisTyrGluHisHisPhe180185190SerArgPheGlnAspAlaProValArgValLeuGluIleGlyIleGly195200205GlyTyrHisAlaProGluLeuGlyGlyAlaSerLeuArgMetTrpGln210215220ArgTyrPheArgArgGlyLeuValTyrGlyLeuAspIlePheGluLys225230235240AlaGlyAsnGluGlyHisArgValArgLysLeuArgGlyAspGlnSer245250255AspAlaGluPheLeuGluAspMetValAlaLysIleGlyProPheAsp260265270IleValIleAspAspGlySerHisValAsnAspHisValLysLysSer275280285PheGlnSerLeuPheProHisValArgProGlyGlyLeuTyrValIle290295300GluAspLeuGlnThrAlaTyrTrpProGlyTyrGlyGlyArgAspGly305310315320GluProAlaAlaGlnArgThrSerIleAspMetLeuLysGluLeuIle325330335AspGlyLeuHisTyrGlnGluArgGluSerArgCysGlyThrGluPro340345350SerTyrThrGluArgAsnValAlaAlaLeuHisPheTyrHisAsnLeu355360365ValPheValGluLysGlyLeuAsnAlaGluThrAlaAlaProGlyPhe370375380ValProArgGlnAlaLeuGlyValGluGlyGly385390395&lt;210&gt;11&lt;211&gt;539&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;11MetIleSerAlaAlaGlyGluGlnSerGlyProValArgLysGlyGly151015AlaValProGluPheHisAspProAlaProMetASnArgArgThrPro202530GlyThrGluIleThrValGluProAspAspProArgTyrProAspLeu354045ValValGlyHisAsnProArgPheThrGlyLysProGluArgIleHis505560IleAlaSerSerAlaGluAspValValHisAlaValAlaAspAlaVal65707580ArgThrGlyArgArgValGlyValArgSerGlyGlyHisCysPheGlu859095AsnLeuValAlaAspProAlaIleArgValLeuValAspLeuSerGlu100105110LeuAsnArgValTyrTyrAspSerThrArgGlyAlaPheAlaIleGlu115120125AlaGlyAlaAlaLeuGlyGlnValTyrArgThrLeuPheLysAsnTrp130135140GlyValThrIleProThrGlyAlaCysProGlyValGlyAlaGlyGly145150155160HisIleLeuGlyGlyGlyTyrGlyProLeuSerArgArgPheGlySer165170175ValValAspTyrLeuGlnGlyValGluValValValValAspGlnAlal80185190GlyGluValHisIleValGluAlaAspArgAsnSerThrGlyAlaGly195200205HisAspLeuTrpTrpAlaHisThrGlyGlyGlyGlyGlyAsnPheGly210215220IleValThrArgPheTrpLeuArgThrProAspValValSerThrAsp225230235240AlaAlaGluLeuLeuProArgProProAlaThrValLeuLeuArgSer245250255PheHisTrpProTrpHisGluLeuThrGluGlnSerPheAlaValLeu260265270LeuGlnAsnPheGlyAsnTrpTyrGluGlnHisSerAlaProGluSer275280285ThrGlnLeuGlyLeuPheSerThrLeuValCysAlaHisArgGlnAla290295300GlyTyrValThrLauAsnValHisLeuAspGlyThrAspProAsnAla305310315320GluArgThrLeuAlaGluHisLeuSerAlaIleAsnAlaGlnValGly325330335ValThrProAlaGluGlyLeuArgGluThrLeuProTrpLeuArgSer340345350ThrGlnValAlaGlyAlaIleAlaGluGlyGlyGluProGlyMetGln355360365ArgThrLysValLysAlaAlaTyrLeuArgThrGlyLeuSerGluAla570375380GlnLeuAlaThrValTyrArgArgLeuThrValTyrGlyTyrAspAsn385390395400ProAlaAlaAlaLeuLeuLeuLeuGlyTyrGlyGlyMetAlaAsnAla405410415ValAlaProSerAlaThrAlaLeuAlaGlnArgAspSerValLeuLys420425430AlaLeuPheValThrAsnTrpSerGluProAlaGluAspGluArgHis435440445LeuThrTrpIleArgGlyPheTyrArgGluMetTyrAlaGluThrGly450455460GlyValProValProGlyThrArgValAspGlySerTyrIleAsnTyr465470475480ProAspThrAspLeuAlaAspProLeuTrpAsnThrSerGlyValAla485490495TrpHisAspLeuTyrTyrLysAspAsnTyrProArgLeuGlnArgAla500505510LysAlaArgTrpAspProGlnAsnIlePheGlnHisGlyLeuSerIle515520525LysProProAlaArgLeuSerProGlyGlnPro530535&lt;210&gt;12&lt;211&gt;397&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;12MetSerThrThrHisGluIleGluThrValGluArgIleIleLeuAla151015AlaGlySerSerAlaAlaSerLeuAlaAspLeuThrThrGluLeuGly202530LeuAlaArgIleAlaProValLeuIleAspGluIleLeuPheArgAla354045GluProAlaProAspIleGluArgThrGluValAlaValGlnIleThr505560HisArgGlyGluThrValAspPheValLeuThrLeuGlnSerGlyGlu65707580LeuIleLysAlaGluGlnArgProValGlyAspValProLeuArgIle859095GlyTyrGluLeuThrAspLeuIleAlaGluLeuPheGlyProGlyAla100105110ProArgAlaValGlyAlaArgSerThrAsnPheLeuArgThrThrThr115120125SerGlySerIleProGlyProSerGluLeuSarAspGlyPheGlnAla130135140IleSerAlaValValAlaGlyCysGlyHisArgArgProAspLeuAsn145150155160LeuLeuAlaSerHisTyrArgThrAspLysTrpGlyGlyLeuHisTrp165170175PheThrProLeuTyrGluArgHisLeuGlyGluPheArgAspArgPro180185190ValArgIleLeuGluIleGlyValGlyGlyTyrAsnPheAspGlyGly195200205GlyGlyGluSerLeuLysMetTrpLysArgTyrPheHisArgGlyLeu210215220ValPheGlyMetAspValPheAspLysSerPheLeuAspGlnGlnArg225230235240LeuCysThrValArgAlaAspGlnSerLysProGluGluLeuAlaAla245250255ValAspAspLysTyrGlyProPheAspIleIleIleAspAspGlySer260265270HisIleAshGlyHisValArgThrSerLeuGluThrLeuPheProArg275280285LeuArgSerGlyGlyValTyrValIleGluAspLeuTrpThrThrTyr290295300AlaProGlyPheGlyGlyGlnAlaGlnCysProAlaAlaProGlyThr305310315320ThrValSerLeuLeuLysAsnLeuLeuGluGlyValGlnHisGluGlu325330335GlnProHisAlaGlySerTyrGluProSerTyrLeuGluArgAsnLeu340345350ValGlyLeuHisThrTyrHisAsnIleAlaPheLeuGluLysGlyVal355360365AsnAlaGluGlyGlyValProAlaTrpValProArgSerLeuAspAsp370375380IleLeuHisLeuAlaAspValAsnSerAlaGluAspGlu38539395&lt;210&gt;13&lt;211&gt;283&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;13ValGluSerIlePheAspAlaLeuAlaHisGlyArgProLeuHisHis151015GlyTyrTrpAlaGlyGlyTyrArgGluAspAlaGlyAlaThrProTrp202530SerAspAlaAlaAspGlnLeuThrAspLeuPheIleAspLysAlaAla354045LeuArgProGlyAlaHisLeuPheAspLeuGlyCysGlyAsnGlyGln505560ProValValArgAlaAlaCysAlaSerGlyValArgValThrGlyIle65707580ThrValAsnAlaGlnHisLeuAlaAlaAlaThrArgLeuAlaAsnGlu859095ThrGlyLeuAlaGlySerLeuGluPheAspLeuValAspGlyAlaGln100105110LeuProTyrProAspGlyPhePheGlnAlaAlaTrpAlaMetGlnSer115120125ValValGlnIleValAspGlnAlaAlaAlaIleArgGluValHisArg130135140IleLeuGluProGlyGlyArgPheValLeuGlyAspIleIleThrArg145150155160ValArgLeuProGluGluTyrAlaAlaValTrpThrGlyThrThrAla165170175HisThrLeuAsnSerPheThrAlaLeuValSerGluAlaGlyPheGlu180185190IleLeuGluValThrAspLeuThrAlaGlnThrArgCysMetValSer195200205TrpTyrValAspGluLeuLeuArgLysLeuAspGluLeuAlaGlyVal210215220GluProAlaAlaValGlyThrTyrGlnGlnArgTyrLeuGlyAspIle225230235240AlaAlaLysHisGlyProGlyProAlaGlnLeuIleAlaAlaValAla245250255GluTyrArgLysHisProAspTyrAlaArgAsnGluGluSerMetGly260265270PheMetLeuLeuGlnAlaArgLysLysGlnSer275280&lt;210&gt;14&lt;211&gt;320&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;14MetProAsnAlaValSerGlyThrValLeuValProAsnIleProTrp151015ProArgGluAspArgProIleIleThrPheAlaValGlyThrHisGly202530LeuGlySerGlnValAlaProSerTyrLeuLeuArgThrGlyThrGlu354045ProGluThrGluLeuIleAlaValAlaLeuAspArgGlyTrpAlaVal505560ValIleThrAspTyrGluGlyLeuGlyThrProGlyThrHisThrTyr65707580ThrValGlyArgAlaGlnGlyHisAlaMetLeuAspAlaAlaArgAla859095AlaGlnArgLeuProGlySerGlyLeuThrThrAspCysProValGly100105110IleTrpGlyTyrAlaGlnGlyGlyGlnAlaSerAlaPheAlaGlyGlu115120125LeuHisProThrTyrAlaProGluLeuArgIleArgAlaAlaAlaAla130135140GlyAlaValProIleAspLeuLeuAspIleIleHisArgAsnAspGly145150155160ValPheThrGlyProValLeuAlaGlyLeuValGlyHisAlaAlaAla165170175TyrProAspLeuProPheAspGluLeuLeuThrGluAlaGlyArgThr180185190AlaValAspGlnValArgGluLeuGlyAlaProGluLeuValThrArg195200205PheLeuGlyArgGluLeuSerAspPheLeuAspThrSerGlyLeuPhe210215220GluGlnProArgTrpArgAlaArgLeuAlaGluSerValAlaGlyArg225230225240AsnGlyGlyProValValProThrLeuValTyrHisSerThrAspAsp245250255GluIleValProPheAlaPheGlyGluArgLeuArgAspSerTyrArg260265270AlaAlaGlyThrProValArgTrpHisProLeuSerGlyLeuAlaHis275280285PheProAlaAlaLeuAlaSerSerArgValValValSerTrpPheAsp290295300GluHisPheSerGluProSerAlaIleSerGlyProArgAspAlaArg305310315320&lt;210&gt;15&lt;211&gt;332&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;15MetArgLysProValArgIleGlyValLeuGlyCysAlaSerPheAla151015TrpArgArgMetLeuProAlaMetCysAspValAlaGluThrGluVal202530ValAlaValAlaSerArgAspProAlaLysAlaGluArgPheAlaAla354045ArgPheGluCysGluAlaValLeuGlyTyrGlnArgLeuLeuGluArg505560ProAspIleAspAlaValTyrValProLeuProProGlyMetHisAla65707580GluTrpIleGlyLysAlaLeuGluAlaAspLysHisValLeuAlaGlu859095LysProLeuThrThrThrAlaSerAspThrAlaArgLeuValGlyLeu100105110AlaArgArgLysAsnLeuLeuLeuArgGluAsnTyrLeuPheLeuHis115120125HisGlyArgHisAspValValArgAspLeuLeuGlnSerGlyGluIle130135140GlyGluLeuArgGluPheThrAlaValPheGlyIleProProLeuPro145150155160AspThrAspIleArgTyrArgThrGluLeuGlyGlyGlyAlaLeuLeu165170175AspIleGlyValTyrProAlaArgAlaAlaArgHisPheLeuLeuGly180185190ProLeuThrValLeuGlyAlaSerSerHisGluAlaGlnGluSerGly195200205ValAspLeuSerGlySerValLeuLeuGlnSerGluGlyGlyThrVal210215220AlaHisLeuGlyTyrGlyPheValHisHisTyrArgSerAlaTyrGlu225230235240LeuTrpGlySerArgGlyArgIleValValAspArgAlaPheThrPro245250255ProAlaGluTrpGlnAlaValIleArgIleGluArgLysGlyValVal260265270AspGluLeuSerLeuProAlaGluAspGlnValArgLysAlaValThr275280285AlaPheAlaArgAspIleArgAlaGlyThrGlyValAspAspProAla290295300ValAlaGlyAspSerGlyGluSerMetIleGlnGlnAlaAlaLeuVal305310315320GluAlaIleGlyGlnAlaArgArgCysGlySerThr325330&lt;210&gt;16&lt;211&gt;486&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;16MetSerSerSerValGluAlaGluAlaSerAlaAlaAlaProLeuGly151015SerAsnAsnThrArgArgPheValAspSerAlaLeuSerAlaCysAsn202530GlyMetIleProThrThrGluPheHisCysTrpLeuAlaAspArgLeu354045GlyGluAsnSerPheGluThrAsnArgIleProPheAspArgLeuSer505560LysTrpLysPheAspAlaSerThrGluAsnLeuValHisAlaAspGly65707580ArgPhePheThrValGluGlyLeuGlnValGluThrAsnTyrGlyAla859095AlaProSerTrpHisGlnProIleIleAsnGlnAlaGluValGlyIle100105110LeuGlyIleLeuValLysGluIleAspGlyValLeuHisCysLeuMet115120125SerAlaLysMetGluProGlyAsnValAsnValLeuGlnLeuSerPro130135140ThrValGlnAlaThrArgSerAsnTyrThrGlnAlaHisArgGlySer145150155160ValProProTyrValAspTyrPheLeuGlyArgGlyArgGlyArgVal165170175LeuValAspValLeuGlnSerGluGlnGlySerTrpPheTyrArgLys180185190ArgAsnArgAsnMetValValGluValGlnGluGluValProValLeu195200205ProAspPheCysTrpLeuThrLeuGlyGlnValLeuAlaLeuLeuArg210215220GlnAspAsnIleValAsnMetAspThrArgThrValLeuSerCysIle225230235240ProPheHisAspSerAlaThrGlyProGluLeuAlaAlaSerGluGlu245250255ProPheArgGlnAlaValAlaArgSerLeuSerHisGlyIleAspSer260265270SerSerIleSerGluAlaValGlyTrpPheGluGluAlaLysAlaArg275280285TyrArgLeuArgAlaThrArgValProLeuSerArgValAspLysTrp290295300TyrArgThrAspThrGluIleAlaHisGlnAspGlyLysTyrPheAla305310315320ValIleAlaValSerValSerAlaThrAsnArgGluValAlaSerTrp325330335ThrGlnProMetIleGluProArgGluGlnGlyGluIleAlaLeuLeu340345350ValLysArgIleGlyGlyValLeuHisGlyLeuValHisAlaArgVal355360365GluAlaGlyTyrLysTrpThrAlaGluIleAlaProThrValGlnCys370375380SerValAlaAsnTyrGlnSerThrProSerAsnAspTrpProProPhe385390395400LeuAspAspValLeuThrAlaAspProGluThrValArgTyrGluSer405410415IleLeuSerGluGluGlyGlyArgPheTyrGlnAlaGlnAsnArgTyr420425430ArgIleIleGluValHisGluAspPheAlaAlaArgProProSerAsp435440445PheArgTrpMetThrLeuGlyGlnLeuGlyGluLeuLeuArgSerThr450455460HisPheLeuAsnIleGlnAlaArgSerLeuValAlaSerLeuHisSer465470475480LeuTrpAlaLeuGlyArg485&lt;210&gt;17&lt;211&gt;455&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;17ValIleLeuGlyMetLeuProGlyCysSerIleAlaIleGlyGluPhe151015MetArgValLeuPheThrProLeuProAlaSerSerHisPhePheAsn202530LeuValProLeuAlaTrpAlaLeuArgAlaAlaGlyHisGluValArg354045ValAlaIleCysProAsnMetValSerMetValThrGlyAlaGlyLeu505560ThrAlaValProValGlyAspGluLeuAspLeuIleSerLeuAlaAla65707580LysAsnGluLeuValLeuGlySerGlyValSerPheAspGluLysGly859095ArgHisProGluLeuPheAspGluLeuLeuSerIleAsnSerGlyArg100105110AspThrAspAlaValGluGlnLeuHisLeuValAspAspArgSerLeu115120125AspAspLeuMetGlyPheAlaGluLysTrpGlnProAspLeuValVal130135140TrpAspAlaMetValCysSerGlyProValValAlaArgAlaLeuGly145150155160AlaArgHisValArgMetLeuValAlaLeuAspValSerGlyTrpLeu165170175ArgSerGlyPheLeuGluTyrGlnGluSerLysProProGluGlnArg180185190ValAspProLeuGlyThrTrpLeuGlyAlaLysLeuAlaLysPheGly195200205AlaThrPheAspGluGluIleValThrGlyGlnAlaThrIleAspPro210215220IleProSerTrpMetArgLeuProValAspLeuAspTyrIleSerMet225230235240ArgPheValProTyrAsnGlyProAlaValLeuProGluTrpLeuArg245250255GluArgProThrLysProArgValCysIleThrArgGlyLeuThrLys260265270ArgArgLeuSerArgValThrGluGlnTyrGlyGluGlnSerAspGln275280285GluGlnAlaMetValGluArgLeuLeuArgGlyAlaAlaArgLeuAsp290295300ValGluValIleAlaThrLeuSerAspAspGluValArgGluMetGly305310315320GluLeuProSerAsnValArgValHisGluTyrValProLeuAsnGlu325330335LeuLeuGluSerCysSerValIleIleHisHisGlySerThrThrThr340345350GlnGluThrAlaThrValAsnGlyValProGlnLeuIleLeuProGly355360365ThrPheTrpAspGluSerArgArgAlaGluLeuLeuAlaAspArgGly370375380AlaGlyLeuValLeuAspProAlaThrPheThrGluAspAspValArg385390395400GIyGlnLeuAlaArgLeuLeuAspGluProSerPheAlaAlaAsnAla405410415AlaLeuIleArgArgGluIleGluGluSerProSerProHisAspIle420425430ValProArgLeuGluLysLeuValAlaGluArgGluAsnArgArgThr435440445GlyGlnSerAspGlyHisPro450455&lt;210&gt;18&lt;211&gt;462&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;18MetGlnSerArgLysThrArgAlaLeuGlyLysGlyArgAlaArgVal151015ThrSerCysAspAspThrCysAlaThrAlaThrGluMetValProAsp202530AlaLysAspArgIleLeuAlaSerValArgAspTyrHisArgGluGln354045GluSerProThrPheValAlaGlySerThrProIleArgProSerGly505560AlaValLeuAspGluAspAspArgValAlaLeuValGluAlaAlaLeu65707580GluLeuArgIleAlaAlaGlyGlyAsnAlaArgArgPheGluSerGlu859095PheAlaArgPhePheGlyLeuArgLysAlaHisLeuValAsnSerGly100105110SerSerAlaAsnLeuLeuAlaLeuSerSerLeuThrSerProLysLeu115120125GlyGluAlaArgLeuArgProGlyAsPGluValIleThrAlaAlaVal130135140GlyPheProThrThrIleAsnProAlaValGlnAsnGlyLeuValPro145150155160ValPheValAspValGluLeuGlyThrTyrAsnAlaThrProAspArg165170175IleLysAlaAlaValThrGluArgThrArgAlaIleMetLeuAlaHis180185190ThrLeuGlyAsnProPheAlaAlaAspGluIleAlaGluIleAlaLys195200205GluHisGluLeuPheLeuValGluAspAsnCysAspAlaValGlySer210215220ThrTyrArgGlyArgLeuThrGlyThrPheGlyAspLeuThrThrVal225230235240SerPheTyrProAlaHisHisIleThrSerGlyGluGlyGlyCysVal245250255LeuThrGlySerLeuGluLeuAlaArgIleIleGluSerLeuArgAsp260265270TrpGlyArgAspCysTrpCysGluProGlyValAspAsnThrCysArg275280285LysArgPheAspTyrHisLeuGlyThrLeuProProGlyTyrAspHis290295300LysTyrThrPheSerHisValGlyTyrAsnLeuLysThrThrAspLeu305310315320GlnAlaAlaLeuAlaLeuSerGlnLeuSerLysIleSerAlaPheGly325330335SerAlaArgArgArgAsnTrpArgArgLeuArgGluGlyLeuSerGly340345350LeuProGlyLeuLeuLeuProValAlaThrProHisSerAspProSer355360365TrpPheGlyPheAlaIleThrIleSerAlaAspAlaGlyPheThrArg370375380AlaAlaLeuValAsnPheLeuGluSerArgAsnIleGlyThrArgLeu385390395400LeuPheGlyGlyAsnIleThrArgHisProAlaPheGluGlnValArg405410415TyrArgIleAlaAspAlaLeuThrAsnSerAspIleValThrAspArg420425430ThrPheTrpValGlyValTyrProGlyIleThrAspGlnMetIleAsp435440445TyrValValGluSerIleAlaGluPheValAlaLysSerSer450455460&lt;210&gt;19&lt;211&gt;385&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;19ValIleAsnLeuHisGlnProIleLeuGlyThrGluGluLeuAspAla151015IleAlaGluValPheAlaSerAshTrpIleGlyLeuGlyProArgThr202530ArgThrPheGluAlaGluPheAlaHisHisLeuGlyValAspProGlu354045GlnValValPheLeuAsnSerGlyThrAlaAlaLeuPheLeuThrVal505560GlnValLeuAspLeuGlyProGlyAspAspValValLeuProSerIle65707580SerPheValAlaAlaAlaAsnAlaIleAlaSerSerGlyAlaArgPro859095ValPheCysAspValAspProArgThrLeuAsnProThrLeuAspAsp100105110ValAlaArgAlaIleThrProAlaThrLysAlaValLeuLeuLeuHis115120125TyrGlyGlySerProGlyGluValThrAlaIleAlaAspPheCysArg130135140GluLysGlyLeuMetLeuIleGluAspSerAlaCysAlaValAlaSer145150155160SerValHisGlyThrAlaCysGlyThrPheG1yAspLeuAlaThrTrp165170175SerPheAspAlaMetLysIleLeuValThrGlyAspGlyGlyMetPhe180185190TyrAlaAlaAspProGluLeuAlaHisArgAlaArgArgLeuAlaTyr195200205HisGlyLeuGluGlnMetSerGlyPheAspSerAlaLysSerSerAsn210215220ArgTrpTrpAspIleArgValGluAspIleGlyGlnArgLeuIleGly225230235240AsnAspMetThrAlaAlaLeuGlySerValGlnLeuArgLysLeuPro245250255GluPheIlaAsnArgArgArgGluIleAlaThrGlnTyrAspArgLeu260265270LeuSerAspValProGlyValLeuLeuProProThrLeuProAspGly275280285HisValSerSerHisTyrPheTyrTrpValGlnLeuAlaProGluIle290295300ArgAspGlnValAlaGlnGlnMetLeuGluArgGlyIleTyrThrSer305310315320TyrArgTyrProProLeuHisLysValProIleTyrArgAlaAspCys325330335LysLeuProSerAlaGluAspAlaCysArgArgThrLeuLeuLeuPro340345350LeuHisProSerLeuAspAspAlaGluValArgThrValAlaAspGlu355360365PheGlnLysAlaValGluHisHisIleSerGlnArgSerProLeuArg370375380Lys385&lt;210&gt;20&lt;211&gt;249&lt;212&gt;PRT&lt;213&gt;糖多孢菌&lt;400&gt;20MetSerArgValSerAspThrPheAlaGluThrSerSerValTyrSer151015ProAspHisAlaAspIleTyrAspAlaIleHisSerAlaArgGlyArg202530AspTrpAlaAlaGluAlaGlyGluValValGlnLeuValArgThrArg354045LeuProGluAlaGlnSerLeuLeuAspValAlaCysGlyThrGlyAla505560HisLeuGluArgPheArgAlaGluTyrAlaLysValAlaGlyLeuGlu65707580LeuSerAspAlaMetArgGluIleAlaIleArgArgValProGluVal859095ProIleHisIleGlyAspIleArgAspPheAspLeuGlyGluProPhe100105110AspValIleThrCysLeuCysPheThrAlaAlaTyrMetArgThrVal115120125AspAspLeuArgArgValThrArgAsnMetAlaArgHisLeuAlaPro130135140GlyGlyValAlaValIleGluProTrpTrpPheProAspLysPheIle145150155160AspGlyPheValThrGlyAlaValAlaHisHisGlyGluArgValIle165170175SerArgLeuSerHisSerValLeuGluGlyArgThrSerArgMetThr180185190ValArgTyrThrValAlaGluProThrGlyIleArgAspPheThrGlu195200205PheGluIleLeuSerLeuPheThrGluAspGluTyrThrAlaAlaLeu210215220GluAspAlaGlyIleArgAlaGluTyrLeuProGlyAlaProAsnGly225230235240ArgGlyLeuPheValGlyIleArgAsn245&lt;210&gt;21&lt;211&gt;255&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;21MetValLeuValProArgArgPheArgAlaThrLeuGluSerMetSer151015GluGlnThrIleAlaLeuValThrGlyAlaAsnLysGlyIleGlyTyr202530GluIleAlaAlaGlyLeuGlyAlaLeuGlyTrpSerValGlyIleGly354045AlaArgAspHisGlnArgGlyGluAspAlaValAlaLysLeuArgAla505560AspGlyValAspAlaPheAlaValSerLeuAspValThrAspAspAla65707580SerValAlaAlaAlaAlaAlaLeuLeuGluGluArgAlaGlyArgLeu859095AspValLeuValAsnAsnAlaGlyIleAlaGlyAlaTrpProGluGlu100105110ProSerThrValThrProAlaSerLeuArgAlaValValGluThrAsn115120125ValIleGlyValValArgValThrAsnAlaMetLeuProLeuLeuArg130135140ArgSerGluArgProArgIleValAsnGlnSerSerHisValAlaSer145150155160LeuThrLeuGlnThrThrProGlyValAspLeuGlyGlyIleSerGly165170175AlaTyrSerProSerLysThrPheLeuAsnAlaIleThrIleGlnTyr180185190AlaLysGluLeuSerAspThrAsnIleLysIleAsnAsnAlaCysPro195200205GlyTyrValAlaThrAspLeuAsnGlyPheEisGlyThrSerThrPro210215220AlaAspGlyAlaArgIleAlaIleArgLeuAlaThrLeuProAspAsp225230235240GlyProThrGlyGlyMetPheAspAspAlaGlyAsnValProTrp245250255&lt;210&gt;22&lt;211&gt;278&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;22MetGluThrArgGluLeuArgTyrPheValAlaValAlaGluGluLeu151015HisPheGlyArgAlaAlaGlnArgLeuGlyIleAlaGlnProProLeu202530SerArgThrIleAlaGlnLeuGluGlnArgLeuGlyValValLeuLeu354045GlnArgThrSerArgLysValSerLeuThrGluAlaGlyAlaMetLeu505560LeuThrGluGlyArgAlaIleLeuGlyAlaLeuAlaAlaAlaGluArg65707580ArgThrGlnArgAlaAlaThrSerGlnProSerLeuValLeuAlaAla859095LysAlaGlyAlaSerGlyGluLeuLeuAlaLysLeuLeuAspAlaTyr100105110AlaAlaGluProGlyAlaValAlaValAspLeuLeuLeuCysGluSer115120125GlnProGlnLysThrLeuHisAspGlyArgAlaAspValAlaLeuLeu130135140HisGlnProPheAspProThrAlaGluLeuAspIleGluIleLeuAsn145150155160ThrGluGlnGlnValAlaIleLeuProThrSarHisProLeuAlaSer165170175GluProHisValArgMetAlaAspValSerSerLeuProAspLeuPro180185190LeuAlaArgTrpProGlyProAspGlyValTyrProAspGlyProGly195200205ValGluValArgAsnGlnThrGlnLeuPheGlnMetIleAlaLeuGly210215220ArgThrThrValValMetProGluSerSerArgValAsnLeuLeuGlu225230235240GlyLeuAlaAlaValProValLeuAspAlaProAspValThrThrVal245250255IleAlaTrpProProHisSerArgSerArgAlaLeuAlaGlyLeuVal260265270ArgValAlaThrLeuLeu275&lt;210&gt;23&lt;211&gt;198&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;23MetMetLeuLysArgHisArgLeuThrThrAlaIleThrGlyLeuLeu151015GlyGlyValLeuLeuValSerGlyCysGlyThrAlaAlaAlaLeuGln202530SerSerProAlaProGlyHisAspAlaArgAsnValGlyMetAlaSer354045GlyGlyGlyGlyGlyAspIleGlyThrSerAsnCysSerGluAlaAsp505560PheLeuAlaThrAlaThrProValLysGlyAspProGlySerPheIle65707580ValAlaTyrGlyAsnArgSerAspLysThrCysThrIleAsnGlyGly859095ValProAsnLeuLysGlyValAspMetSerAsnSerProIleGluAsp100105110LeuProValGluAspValArgLeuProAspAlaProLysGluPheThr115120125LeuGlnProGlyGlnSerAlaTyrAlaGlyIleGlyMetValLeuAla130135140AspSerGlyAspProAsnAlaHisValLeuThrGlyPheGlnSerSer145150155160LeuProAspMetSerGluAlaGlnProValAsnValLeuGlyAspGly165170175AsnValLysPheAlaAlaLysTyrLeuArgValSerSerLeuValSer180185190ThrAlaAspGluLeuAtg195&lt;210&gt;24&lt;211&gt;751&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;24ValLeuSerValGluLysGlyArgGIuSerAlaThrTrpThrAlaVal151015LeuGluGlyThrLeuGluArgIleThrPheAlaASnGluGluSerGly202530TyrThrValAlaArgIleAspThrGlyArgGlyGlyAspLeuValThr354045ValValGlyAlaLeuLeuGlyAlaGlnProGlyGluAlaLeuArgMet505560ArgGlyArgTrpGlySerHisProGlnTyrGlyArgGlnPheHisVal65707580AspAspTyrThrThrValLeuProAlaThrValGlnGlyIleArgArg859095TyrLeuGlySerGlyLeuIleLysGlyIleGlyProLysLeuAlaGlu100105110LysIleValAspHisPheGlyValAlaAlaLeuAspValIleGluGln115120125GluProAlaArgLeuIleGluValProLysLeuGlyProLysArgThr130135140LysLeuIleAlaAspAlaTrpGluGluGlnLysAlaIleLysGluVal145150155160MetIlePheLeuGlnGlyValGlyValSerThrSerLeuAlaValLys165170175IleTyrLysGlnTyrHisAspAspAlaIleArgThrValLysGluGlu180185190ProTyrArgLeuAlaGlyAspValTrpGlyIleGlyPheLysThrAla195200205AspThrIleAlaLysAlaValGlyIleProHisAspSerProGlnArg210215220ValLysAlaGlyLeuGlnPheThrLeuSerGluSerThrGlyAspGly225230235240AsnCysTyrLeuProGluAsnGluLeuIleAlaGluAlaValLysIle245250255LeuAlaValAspThrGlyLeuValIleGluCysLeuAlaGluLeuVal260265270ThrGluGluGlyValValArgGluGluIleProThrAspAspAspGlu275280285ValProThrValAlaIleTyrLeuValProPheHisArgAlaGluVal290295300AlaLeuAlaAsnGlnLeuSerArgLeuLeuAsnThrSerAlaAspArg305310315320MetProValPheAlaAspValAspTrpHisLysAlaLeuAspTrpLeu325330335ArgArgAlaThrGlyAlaGluLeuAlaGluAlaGlnGluArgAlaVal340345350LysLeuAlaLeuThrGluLysValAlaValLeuThrGlyGlyProGly355360365CysGlyLysSerPheThrValArgSerIleIleAlaLeuAlaGlnAla370375380LysLysAlaLysValIleLeuAlaAlaProThrGlyArgAlaAlaLys385390395400ArgLeuThrGluLeuThrGlyHisAspAlaAlaThrValHisArgLeu405410415LeuGlnLeuGlnProGlyGlyAspAlaAlaTyrAspArgAspAsnPro420425430LeuAspAlaAspLeuValValValAspGluAlaSerMetLeuAspLeu435440445LeuLeuAlaAsnLysLeuAlaLysAlaIleAlaProGlyAlaHisLeu450455460LeuLeuValGlyAspValAspGlnLeuProSerValGlyAlaGlyGlu465470475480ValLeuArgAspLeuLeuAlaProGlyThrProIleProHisValArg485490495LeuAsnGluValPheArgGlnAlaAlaGluSerGlyValValThrAsn500505510AlaHisArgIleAsnAlaGlyAspTyrProLeuThrHisGlyLeuThr515520525AspPhePheLeuPheHisValGluGluSerGluProThrAlaGluLeu530535540ThrValAspValValAlaArgArgIleProArgLysPheArgPheAsn545550555560ProArgThrAspValGlnValLeuAlaProMetHisArgGlyProAla565570575GlyAlaGlyAlaLeuAsnGlnLeuLeuGlnGluAlaIleThrProAla580585590ArgGluGlyLeuProGluArgArgPheGlyGlyArgIlePheArgVal595600605GlyAspLysValThrGlnIleArgAsnAsnTyrAspLysGlyAlaAsn610615620GlyValPheAsnGlyThrGlnGlyValValSerAlaLeuAspAsnGlu625630635640AlaGlnThrMetThrValArgThrAspGluAspGluAspIleAspTyr645650655AspPheThrGluLeuAspGluLeuValHisAlaTyrAlaValThrIle660665670HisArgSerGlnGlySerGluTyrProCysValValIleProLeuThr675680685ThrSerAlaTrpMetMetLeuGlnArgAsnLeuLeuTyrThrAlaVal690695700ThrArgAlaLysLysValValValLeuValGlySerLysLysAlaLeu705710715720GlyGlnAlaValArgThrValGlySerGlyArgArgHisThrAlaLeu725730735AspHisArgLeuArgArgGlyGlyThrGlySerArgProAlaAla740745750&lt;210&gt;25&lt;211&gt;2310&lt;212&gt;DNA&lt;213&gt;刺糖多孢菌&lt;220&gt;&lt;221&gt;CDS&lt;222&gt;(88)..(1077)&lt;220&gt;&lt;221&gt;CDS&lt;222&gt;(1165)..(1992)&lt;400&gt;25ggatcctgcttcgtagctcggtgtgtcatgccagactgcgcacgcggacctgcagcgggc60cgcgaaatcccggcgaggaagggcgcgatgcggattctggtcaccggcggagcc114MetArgIleLeuValThrGlyGlyAla15ggtttcatcggctcgcactacgttcggcagttgctcggtggtgcgtac162GlyPheIleGlySerHisTyrValArgGlnLeuLeuGlyGlyAlaTyr10152025cccgcattcgccgacgccgacgtggtcgtgctcgacaagctcacctac210ProAlaPheAlaAspAlaAspValValValLeuAspLysLeuThrTyr303540gccggcaacgaggcgaacctggcgccggtcgcggacaacccccggctg258AlaGlyAsnGluAlaAsnLeuAlaProValAlaAspAsnProArgLeu455055aagttcgtctgcggcgacatctgcgaccgcgaactggttggcggcctg306LysPheValCysGlyAspIleCysAspArgGluLeuValGlyGlyLeu606570atgtccggcgtggacgtggtggtgcacttcgccgccgaaacccacgtc354MetSerGlyValAspValValValHisPheAlaAlaGluThrHisVal758085gaccgctcgatcaccggctcggacgccttcgtgatcaccaacgtggtc402AspArgSerIleThrGlySerAspAlaPheValIleThrAsnValVal9095100105ggcaccaacgtgctgctgcaggccgcgctcgacgccgagatcggcaag450GlyThrAsnValLeuLeuGlnAlaAlaLeuAspAlaGluIleGlyLys110115120ttcgtgcacgtttccaccgacgaggtctacggctccatcgaggacggc498PheValHisValSerThrAspGluValTyrGlySerIleGluAspGly125130135tcgtggcccgaagaccacgcgctggagccgaattccccgtactcggcg546SerTrpProGluAspHisAlaLeuGluProAsnSerProTyrSerAla140145150gcgaaagcgggctcggacctgctggcccgcgcctaccaccgcacccac594AlaLysAlaGlySerAspLeuLeuAlaArgAlaTyrHisArgThrHis155160165ggactgccggtgtgcatcacccgctgctccaacaactacgggccctac642GlyLeuProValCysIleThrArgCysSerAsnAsnTyrGlyProTyr170175180185cagttcccggagaaggtgctgccgctgttcatcacgaacctgatggac690GlnPheProGluLysValLeuProLeuPheIleThrAsnLeuMetAsp190195200ggcagccaggtgccgctctacggcgacgggctcaacgtgcgggactgg738GlySerGlnValProLeuTyrGlyAspGlyLeuAsnValArgAspTrp205210215ctgcacgtcagcgaccactgccggggcatccagctggtggccgactcc786LeuHisValSerAspHisCysArgGlyIleGlnLeuValAlaAspSer220225230gggcgcgcgggcgagatctacaacatcggcggcggcaccgagctgacc834GlyArgAlaGlyGluIleTyrAsnIleGlyGlyGlyThrGluLeuThr235240245aacaacgagctgaccgagcggctgctggcagagctgggcctcgactgg882AsnAsnGluLeuThrGluArgLeuLeuAlaGluLeuGlyLeuAspTrp250255260265tcggtggtgcggccggtcaccgaccgcaagggccacgaccgccgctac930SerValValArgProValThrAspArgLysGlyHisAspArgArgTyr270275280tcggtggaccacagcaagatcgtcgaggaactggggtacgcgccgcag978SerValAspHisSerLysIleValGluGluLeuGlyTyrAlaProGln285290295gtcgacttcgagaccgggctgcgcgagacaatccgctggtaccaggac1026ValAspPheGluThrGlyLeuArgGluThrIleArgTrpTyrGlnAsp300305310aaccgggactggtgggagccgctgaaggcccgatcggcggtggctcga1074AsnArgAspTrpTrpGluProLeuLysAlaArgSerAlaValAlaArg315320325tgagtcgcctcgccgtgctggttgcccggcggccgcggccagctgggctcgga1127330gctggcccggatcctcgccgcgcggacgggggcgctggtgcaccggccgggttcc1182ValHisArgProGlySet335ggggaactggacgtcaccgacgccgaggaggtcgccgacgcgttgggt1230GlyGluLeuAspValThrAspAlaGluGluValAlaAspAlaLeuGly340345350tccttcgcggagacggcgaaggacgcggagctgcgaccggtggtgatc1278SerPheAlaGluThrAlaLysAspAlaGluLeuArgPtoValValIle355360365aacgccgcggcgtacacggcggtggacgcggccgagtccgacccggac1326AsnAlaAlaAlaTyrThrAlaValAspAlaAlaGluSerAspProAsp370375380cgcgcggcccggatcaacgccgaaggcgcggcctcgctggcgaaagcg1374ArgAlaAlaArgIleAsnAlaGluGlyAlaAlaSerLeuAlaLysAla385390395400tgccggagcagcggtctgcccctggtgcacgtgtcgacggattacgtg1422CysArgSerSerGlyLeuProLeuValHisValSerThrAspTyrVal405410415ttcccccgtgatggggcccggccgtacgagccgacggacccgaccggg1470PheProArgAspGlyAlaArgProTyrGluProThrAspProThrGly420425430ccgcgatcggtctacgggcgcaccaagctcgaaggcgaacgggccgtg1518ProArgSerValTyrGlyArgThrLysLeuGluGlyGluArgAlaVal435440445ctggagtccggcgcgcgggcctgggtggtgcgcacggcatgggtgtac1566LeuGluSerGlyAlaArgAlaTrpValValArgThrAlaTrpValTyr450455460ggcgcgagcggcaagaacttcctgaaaacgatgatccgcctctcgggg1614GlyAlaSerGlyLysAsnPheLeuLysThrMetIleArgLeuSerGly465470475480gagcgcgacacgctgtccgttgtggacaatcagatcggctcgccgact1662GluArgAspThrLeuSerValValAspAsnGlnIleGlySerProThr485490495tgggcggcggacctggcgagcggcctgctggagctggccgaacgggtc1710TrpAlaAlaAspLeuAlaSerGlyLeuLeuGluLeuAlaGluArgVal500505510gccgaacgccgtggaccggagcagaaggtgctgcactgcaccaattcc1758AlaGluArgArgGlyProGluGlnLysValLeuHisCysThrAsnSer515520525ggccaggtgacctggtacgagttcgcgcgggcgatcttcgcggaattc1806GlyGlnValThrTrpTyrGluPheAlaArgAlaIlePheAlaGluPhe530535540ggcctggacgagaaccgcgtccacccgtgcacgacggcggacttcccc1854GlyLeuAspGluAsnArgValHisProCysThrThrAlaAspPhePro545550555560ctcccggcgcaccgcccggcctactcggtcctgtccgacgtggcgtgg1902LeuProAlaHisArgProAlaTyrSerValLeuSerAspValAlaTrp565570575cgagaggcgggcctgaccccgatgcgcacctggcgggaagccctggcg1950ArgGluAlaGlyLeuThrProMetArgThrTrpArgGluAlaLeuAla580585590gcggccttcgagaaagacggcgaaaccctccgaacccgctga1992AlaAlaPheGluLysAspGlyGluThrLeuArgThrArg595600605ccagtcacccggagggcgcgagtagccccggcagggccgtttcgacgcgatatcggctgg2052cgcggtgcgcacaatgggtgtcgccggggcgaggaaggaaggccaggtgccccgggggca2112tgactgggagcctggcctgatgcctgtccggggcgttcagcctgcggcgaggcggtatgc2172gttcagggttgcttcggcgcaggttcgccaggtgaaggctttagcttgggcacggccctt2232ttccgcgtctgggggactggtcagggcttggtgcagggcttcgttgagggccgtcgggtc2292gccgtgggggaagcggat2310&lt;210&gt;26&lt;211&gt;329&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;26MetArgIleLeuValThrGlyGlyAlaGlyPheIleGlySerHisTyr151015ValArgGlnLeuLeuGlyGlyAlaTyrProAlaPheAlaAspAlaAsp202530ValValValLeuAspLysLeuThrTyrAlaGlyAsnGluAlaAsnLeu354045AlaProValAlaAspAsnProArgLeuLysPheValCysGlyAspIle505560CysAspArgGluLeuValGlyGlyLeuMetSerGlyValAspValVal65707580ValHisPheAlaAlaGluThrHisValAspArgSerIleThrGlySer859095AspAlaPheValIleThrAsnValValGlyThrAsnValLeuLeuGln100105110AlaAlaLeuAspAlaGluIleGlyLysPheValHisValSerThrAsp115120125GluValTyrGlySerIleGluAspGlySerTrpProGluAspHisAla130135140LeuGluProAsnSerProTyrSerAlaAlaLysAlaGlySerAspLeu145150155160LeuAlaArgAlaTyrHisArgThrHisGlyLeuProValCysIleThr165170175ArgCysSerAsnAsnTyrGlyProTyrGlnPheProGluLysValLeu180185190ProLeuPheIleThrAsnLeuMetAspGlySerGlnValProLeuTyr195200205GlyAspGlyLeuAsnValArgAspTrpLeuHisValSerAspHisCys210215220ArgGlyIleGlnLeuValAlaAspSerGlyArgAlaGlyGluIleTyr225230235240AsnIleGlyGlyGlyThrGluLeuThrAsnAsnGluLeuThrGluArg245250255LeuLeuAlaGluLeuGlyLeuAspTrpSerValValArgProValThr260265270AspArgLysGlyHisAspArgArgTyrSerValAspHisSerLysIle275280285ValGluGluLeuGlyTyrAlaProGlnValAspPheGluThrGlyLeu290295300ArgGluThrIleArgTrpTyrGlnAspAsnArgAspTrpTrpGluPro305310315320LeuLysAlaArgSerAlaValAlaArg325&lt;210&gt;27&lt;211&gt;275&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;27ValHisArgProGlySerGlyGluLeuAspValThrAspAlaGluGlu151015ValAlaAspAlaLeuGlySerPheAlaGluThrAlaLysAspAlaGlu202530LeuArgProValValIleAsnAlaAlaAlaTyrThrAlaValAspAla354045AlaGluSerAspProAspArgAlaAlaArgIleAsnAlaGluGlyAla505560AlaSerLeuAlaLysAlaCysArgSerSerGlyLeuProLeuValHis65707580ValSerThrAspTyrValPheProArgAspGlyAlaArgProTyrGlu859095ProThrAspProThrGlyProArgSerValTyrGlyArgThrLysLeu100105110GluGlyGluArgAlaValLeuGluSerGlyAlaArgAlaTrpValVal115120125ArgThrAlaTrpValTyrGlyAlaSerGlyLysAsnPheLeuLysThr130135140MetIleArgLeuSerGlyGluArgAspThrLeuSerValValAspAsn145150155160GlnIleGlySerProThrTrpAlaAlaAspLeuAlaSerGlyLeuLeu165170175GluLeuAlaGluArgValAlaGluArgArgGlyProGluGlnLysVal180185190LeuHisCysThrAsnSerGlyGlnValThrTrpTyrGluPheAlaArg195200205AlaIlePheAlaGluPheGlyLeuAspGluAsnArgValHisProCys210215220ThrThrAlaAspPheProLeuProAlaHisArgProAlaTyrSerVal225230235240LeuSerAspValAlaTrpArgGluAlaGlyLeuThrProMetArgThr245250255TrpArgGluAlaLeuAlaAlaAlaPheGluLysAspGlyGluThrLeu260265270ArgThrArg275&lt;210&gt;28&lt;211&gt;1272&lt;212&gt;DNA&lt;213&gt;刺糖多孢菌&lt;220&gt;&lt;221&gt;CDS&lt;222&gt;(334)..(1119)&lt;400&gt;28aaggccaccggcaaggtcgtgcagggcatctcgcaggacgtcgcgaagaagatctccaag60aagatccgcgacgagggcccgaagggcgttcaggcccagatccagggcgagcagctgcgg120gtgtccggcaagaagaaggacgacctgcaggccgtgatccagttgctgaagtcgagcgac180ttcgacgtcgcgctccagttcgagaatttccggtaatccaccgctggaggtatccgggtg240aaggggatcgtgctggcgggtggcaacgggacccggctgcatccgctgacgcaggccgtg300tccaaacagctacttccggtgtacgacaagccgatgatctactacccgctgtcg354MetIleTyrTyrProLeuSer15gtgctgatgctggccggcatccgggacgtgctgctgatctcgaccccg402ValLeuMetLeuAlaGlyIleArgAspValLeuLeuIleSerThrPro101520gccgacatgccgttgttccagcggctgctcgggaacgggtcgcagttc450AlaAspMetProLeuPheGlnArgLeuLeuGlyAsnGlySerGlnPhe253035ggcattcggatcgagtacgccgagcagtcccagcccaacgggctagcc498GlyIleArgIleGluTyrAlaGluGlnSerGlnProAsnGlyLeuAla40455055gaggcgttcgtgatcggtgccgacttcgtcggcgacgactcggtggcg546GluAlaPheValIleGlyAlaAspPheValGlyAspAspSerValAla606570ttggtgctcggcgacaacatcttttacgggcagggcttttccgggatc594LeuValLeuGlyAspAsnIlePheTyrGlyGlnGlyPheSerGlyIle758085ctccagcagtgcgtccgggagctcgacggctgcacgctgttcggctac642LeuGlnGlnCysValArgGluLeuAspGlyCysThrLeuPheGlyTyr9095100ccggtccgcgacccgcagcgctacggcgtcggtgaggtggacgacgac690ProValArgAspProGlnArgTyrGlyValGlyGluValAspAspAsp105110115ggtcggctgttgtccatcgtggagaagccggagcggccgaagtccaac738GlyArgLeuLeuSerIleValGluLysProGluArgProLysSerAsn120125130135atggccatcaccggcctgtacttctacgacaacgacgtggtgcgcatc786MetAlaIleThrGlyLeuTyrPheTyrAspAsnAspValValArgIle140145150gccaaggggctcacgccgtcggcccgcggcgagctggagatcaccgac834AlaLysGlyLeuThrProSerAlaArgGlyGluLeuGluIleThrAsp155160165gtcaacctggcctacctgcaggagggccgggcgcacctgaccaagctc882ValAsnLeuAlaTyrLeuGlnGluGlyArgAlaHisLeuThrLysLeu170175180ggccgcgggttcgcctggctggacaccgggacccacgactcgctagtg930GlyArgGlyPheAlaTrpLeuAspThrGlyThrHisAspSerLeuVal185190195gaggcctcgcagttcgtgcaggtgctggagcaccggcagggcgtgcgg978GluAlaSerGlnPheValGlnValLeuGluHisArgGlnGlyValArg200205210215atcgcctgcctggaggagatcnccctgcgcatgggctacatctcggcc1026IleAlaCysLeuGluGluIleXaaLeuArgMetGlyTyrIleSerAla220225230gacgactgtttcgcgctgggcgtgaagctggccaagtcgggctacagc1074AspAspCysPheAlaLeuGlyValLysLeuAlaLysSerGlyTyrSer235240245gagtacgtcatggacgtcgcccgcaactccggcgcgcggggctga1119GluTyrValMetAspValAlaArgAsnSerG1yAlaArgGly250255260cccgagctcgtccgatttccattgaaatcgcggaccgtcggcgtgtcgtagtccggtgcg1179ccgatattccgggcggcgtcaccaggccgggggtagttggtggccggccatgccctccag1239gcggcgaaatgcggtcggccatcggcgggttgc1272&lt;210&gt;29&lt;211&gt;261&lt;212&gt;PRT&lt;213&gt;刺糖多孢菌&lt;400&gt;29MetIleTyrTyrProLeuSerValLeuMetLeuAlaGlyIleArgAsp151015ValLeuLeuIleSerThrPrcAlaAspMetProLeuPheGlnArgLeu202530LeuGlyAsnGlySerGlnPheGlyIleArgIleGluTyrAlaGluGln354045SerGlnProAsnGlyLeuAlaGluAlaPheValIleGlyAlaAspPhe505560ValGlyAspAspSerValAlaLeuValLeuGlyAspAsnIlePheTyr65707580GlyGlnGlyPheSerGlyIleLeuGlnGlnCysValArgGluLeuAsp859095GlyCysThrLeuPheGlyTyrProValArgAspProGlnArgTyrGly100105110ValGlyGluValAspAspAspGlyArgLeuLeuSerIleValGluLys115120125ProGluArgProLysSerAsnMetAlaIleThrGlyLeuTyrPheTyr130135140AspAsnAspValValArgIleAlaLysGlyLeuThrProSerAlaArg145150155160GlyGluLeuGluIleThrAspValAsnLeuAlaTyrLeuGlnGluGly165170175ArgAlaHisLeuThrLysLeuGlyArgGlyPheAlaTrpLeuAspThr180185190GlyThrHisAspSerLeuValGluAlaSerGlnPheValGlnValLeu195200205GluHisArgGlnGlyValArgIleAlaCysLeuGluGluIleXaaLeu210215220ArgMetGlyTyrIleSerAlaAspAspCysPheAlaLeuGlyValLys225230235240LeuAlaLysSerGlyTyrSerGluTyrValMetAspValAlaArgAsn245250255SerGlyAlaArgGly260&lt;210&gt;30&lt;211&gt;23&lt;212&gt;DNA&lt;213&gt;人工序列&lt;220&gt;&lt;223&gt;人工序列描述引物&lt;220&gt;&lt;221&gt;不確定&lt;222&gt;(1)&lt;223&gt;n為a,t,c或g&lt;220&gt;&lt;221&gt;不確定&lt;222&gt;(10)&lt;223&gt;n為a,t,c或g&lt;400&gt;30ngsgtsggsnssccaccttccgg23&lt;210&gt;31&lt;211&gt;33&lt;212&gt;DNA&lt;213&gt;人工序列&lt;220&gt;&lt;223&gt;人工序列描述引物&lt;220&gt;&lt;221&gt;不確定&lt;222&gt;(6)&lt;223&gt;n為a,t,c或g&lt;220&gt;&lt;221&gt;不確定&lt;222&gt;(18)&lt;223&gt;n為a,t,c或g&lt;400&gt;31catsangtcgtcytcsansgcsacgaacgcgtg33&lt;210&gt;32&lt;211&gt;1165&lt;212&gt;DNA&lt;213&gt;人工序列&lt;220&gt;&lt;221&gt;CDS&lt;222&gt;(226)..(834)&lt;220&gt;&lt;223&gt;人工序列描述Pdab1622&lt;400&gt;32gggatcaacaacaacttcaccagcaggttcaacaatttgtcaatcccacttggcagtacg60cgcgtcctttttggatcgggattgcggcagtacgtgcacccggtttcagtgccccatttc120gcagtacgtacgtccgttttgaatatggcgatcaatggctcgcatgacccatatcaactc180cgccccaccgaaccgcattccaaccaacgtcataggctttcggccgtgcaggtacgt237ValGlnValArg1cgacttgacatcacgggtgcatacgagttcaccccgaaggccttcccc285ArgLeuAspIleThrGlyAlaTyrGluPheThrProLysAlaPhePro5101520gaccaccggggcctgttcgtggccccgttccaggaggcggcgttcarc333AspHisArgGlyLeuPheValAlaProPheGlnGluAlaAlaPheIle253035gacgccacggggcacccgctgcgagtcgcgcagaccaaccacagcgtc381AspAlaThrGlyHisProLeuArgValAlaGlnThrAsnHisSerVal404550tcggcgcgcaacgtcatccgcggcgtgcacttctcggacgtgccgccg429SerAlaArgAsnValIleArgGlyValHisPheSerAspValProPro556065ggccaagcgaagtacgtgtactgcccgcagggcgcgctgctcgacgtg477GlyGlnAlaLysTyrValTyrCysProGlnGlyAlaLeuLeuAspVal707580gtcatcgacatccgggtcggttccccgaccttcggccgctgggaggcg525ValIleAspIleArgValGlySerProThrPheGlyArgTrpGluAla859095100gtccggctcgacgacaccgagtaccgggccgtctacctagccgaagga573ValArgLeuAspAspThrGluTyrArgAlaValTyrLeuAlaGluGly105110115ctcgggcacgcgttcgccgcgctgaccgacgacaccgtgatgacctac621LeuGlyHisAlaPheAlaAlaLeuThrAspAspThrValMetThrTyr120125130ctctgctcgacgccctacaccccgggcgccgagcacggcatcgacccg669LeuCysSerThrProTyrThrProGlyAlaGluHisGlyIleAspPro135140145ttcgacccggaactcgcgttgccgtggtccgacctcgacggtgaaccg717PheAspProGluLeuAlaLeuProTrpSerAspLeuAspGlyGluPro150155160gtcctgtccgaaaaggaccggaccgccccgagcctcgcggaagccgcc765ValLeuSerGluLysAspArgThrAlaProSerLeuAlaGluAlaAla165170175180gacaacggcctgcttccggactacgaaacatgcctcgcccactacgaa813AspAsnGlyLeuLeuProAspTyrGluThrCysLeuAlaHisTyrGlu185190195ggcctgcgcagccccggctgaacggtcaccgcaagcggcccggcttcggcc864GlyLeuArgSerProGly200agaggcgccaccggataatgccgagcacctcggccgggccgagctcccgcgagtccgtcg924agccgaagttgttgtcgccctcgacgtaccagccatcgccctcgcggcgcagcgcgcgct984tcaccgacaactgccccgggcgctgggcccaacgcaccagcacgacgtttccccggccgg1044gcggaaccccgaagccgcagcagcaccacttcgcgatcccgcagggtgggaaccataaac1104ggcccgcgcaccaccaaccgccgccagggccagcgcccgagggatttcacatccacctcc1164a1165&lt;210&gt;33&lt;211&gt;202&lt;212&gt;PRT&lt;213&gt;人工序列&lt;400&gt;33ValGlnValArgArgLeuAspIleThrGlyAlaTyrGluPheThrPro151015LysAlaPheProAspHisArgGlyLeuPheValAlaProPheGlnGlu202530AlaAlaPheIleAspAlaThrGlyHisProLeuArgValAlaGlnThr354045AsnHisSerValSerAlaArgAsnValIleArgGlyValHisPheSer505560AspValProProGlyGlnAlaLysTyrValTyrCysProGlnGlyAla65707580LeuLeuAspValValIleAspIleArgValGlySerProThrPheGly859095ArgTrpGluAlaValArgLeuAspAspThrGluTyrArgAlaValTyr100105110LeuAlaGluGlyLeuGlyHisAlaPheAlaAlaLeuThrAspAspThr115120125ValMetThrTyrLeuCysSerThrProTyrThrProGlyAlaGluHis130135140GlyIleAspProPheAspProGluLeuAlaLeuProTrpSerAspLeu145150155160AspGlyGluProValLeuSerGluLysAspArgThrAlaProSerLeu165170175AlaGluAlaAlaAspAsnGlyLeuLeuProAspTyrGluThrCysLeu180185190AlaHisTyrGluGlyLeuArgSerProGly195200&lt;210&gt;34&lt;211&gt;28&lt;212&gt;DNA&lt;213&gt;人工序列&lt;220&gt;&lt;223&gt;人工序列描述引物&lt;400&gt;34cccgaattcgagctgctgtcaatcaact28&lt;210&gt;35&lt;211&gt;29&lt;212&gt;DNA&lt;213&gt;人工序列&lt;220&gt;&lt;223&gt;人工序列描述引物&lt;400&gt;35gggaagcttgttgaccgtggcggtttcct29&lt;210&gt;36&lt;211&gt;42&lt;212&gt;DNA&lt;213&gt;人工序列&lt;220&gt;&lt;223&gt;人工序列描述誘變引物&lt;400&gt;36ctggttcattcggccgcctcaccggtggggatggccgcgatc42&lt;210&gt;37&lt;211&gt;42&lt;212&gt;DNA&lt;213&gt;人工序列&lt;220&gt;&lt;223&gt;人工序列描述誘變引物&lt;400&gt;37gatcgcggccatccccaccggtgaggcggccgaatgaaccag42&lt;210&gt;38&lt;211&gt;20&lt;212&gt;DNA&lt;213&gt;人工序列&lt;220&gt;&lt;223&gt;人工序列描述側(cè)翼引物&lt;400&gt;38gctgctcgaaatcgcacgtc20&lt;210&gt;39&lt;211&gt;19&lt;212&gt;DNA&lt;213&gt;人工序列&lt;220&gt;&lt;223&gt;人工序列描述側(cè)翼引物&lt;400&gt;39gcatcgctgggcagtgagg19權(quán)利要求1．分離的DNA分子，其含有編碼刺糖噻生物合成酶的DNA序列，其中所述酶由選自SEQIDNO2-5,7-24,26,27,29和33的氨基酸序列限定，或者所述酶由選自SEQIDNO2-5,7-24,26,27,29和33的氨基酸序列限定，但該氨基酸序列中進(jìn)行了一個或多個不會影響到酶的功能特性的氨基酸取代。2．權(quán)利要求1的分離的DNA分子，其中所述DNA序列選自基因spnA,spnB,spnC,spnD,spnE,spnF,spnG,spnH,spnI,spnJ,spnK,spnL,spnM,spnN,spnO,spnP,spnQ,spnR,spnS,ORFL15,ORFL16,ORFR1,ORFR2，刺糖多孢菌gtt，刺糖多孢菌gdh，刺糖多孢菌epi和刺糖多孢菌kre，所述基因分別描述于SEQIDNO1的堿基21111-28898,28916-35374,35419-44931,44966-59752,59803-76569,20168-20995,18541-19713,17749-18501,16556-17743,14799-16418,13592-14785,12696-13547,11530-12492,10436-11434,8967-10427,7083-8450,5363-6751,4168-5325,3416-4165,2024-2791,1135-1971,76932-77528和77729-79984,SEQIDNO27的堿基334-1119,SEQIDNO24的堿基88-1077,SEQIDNO31的堿基226-834,和SEQIDNO24的堿基1165-1992。3．分離的DNA分子,其含有編碼選自KSi,ATi,ACPi,KS1,AT1，KR1和ACP1的刺糖噻PKS結(jié)構(gòu)域的DNA序列，所述結(jié)構(gòu)域分別對應(yīng)于SEQIDNO2的氨基酸6-423,528-853,895-977,998-1413,1525-1858,2158-2337和2432-2513，或者所述結(jié)構(gòu)域是進(jìn)行了一個或多個不會影響到結(jié)構(gòu)域的功能特性的氨基酸取代的所述氨基酸序列之一。4．權(quán)利要求3的分離的DNA分子，其中所述DNA序列選自SEQIDNO1的堿基21126-22379,22692-23669,23793-24041,24102-25349,25683-26684,27582-28121和28404-28649。5．分離的DNA分子，其含有編碼選自KS2,AT2,DH2,ER2,KR2和ACP2的刺糖噻PKS結(jié)構(gòu)域的DNA序列，所述結(jié)構(gòu)域分別對應(yīng)于SEQIDNO3的氨基酸1-424,536-866,892-1077,1338-1683,1687-1866和1955-2034，或者所述結(jié)構(gòu)域是具有一個或多個不會影響到結(jié)構(gòu)域的功能特性的氨基酸取代的所述氨基酸序列之一。6．權(quán)利要求5的分離的DNA分子，其中所述DNA序列選自SEQIDNO1的堿基29024-30295,30629-31621,31697-32254,33035-34072,34082-34621,34886-35125。7．分離的DNA分子，其含有編碼選自KS3,AT3,KR3,ACP3,KS4,AT4,KR4和ACP4的刺糖噻PKS結(jié)構(gòu)域的DNA序列，所述結(jié)構(gòu)域分別對應(yīng)于SEQIDNO4的氨基酸1-423,531-280,1159-1337,1425-1506,1529-1952,2066-2396,2700-2880和2972-3053，或者所述結(jié)構(gòu)域是進(jìn)行了一個或多個不會影響到結(jié)構(gòu)域的功能特性的氨基酸取代的所述氨基酸序列之一。8．權(quán)利要求7的分離的DNA分子，其中所述DNA序列選自SEQIDNO1的堿基35518-36786,37108-38097,38992-39528,39790-40035,40102-41373,41713-42705,43615-44157和44431-44676。9．分離的DNA分子，其含有編碼選自KS5,AT5,DH5,KR5,ACP5,KS6,AT6,KR6,ACP6,KS7,AT7,KR7和ACP7的刺糖噻PKS結(jié)構(gòu)域的DNA序列，所述結(jié)構(gòu)域分別對應(yīng)于SEQIDNO5的氨基酸1-424,539-866,893-1078,1384-1565,1645-1726,1748-2172,2283-2613,2916-3095,3188-3269,3291-3713,3825-4153，4344-4638和4725-4806，或者所述結(jié)構(gòu)域是進(jìn)行了一個或多個不會影響到結(jié)構(gòu)域的功能特性的氨基酸取代的所述氨基酸序列之一。10．權(quán)利要求9的分離的DNA分子，其中所述DNA序列選自SEQIDNO1的堿基45077-46348,46691-47674,47753-48310,49226-49771,50009-50254,50318-51592,51923-52915,53822-54361,54638-54883,54947-56215,56549-57535,58106-58990和59249-59494。11．分離的DNA分子，其含有編碼選自KS8,AT8,DH8,KR8,ACP8,KS9,AT9,DH9,KR9,ACP9,KS10,AT10,DH10,KR10,ACP10和TE10的刺糖噻PKS結(jié)構(gòu)域的DNA序列，所述結(jié)構(gòu)域分別對應(yīng)于SEQIDNO6的氨基酸1-424,530-848,883-1070,1369-1552,1648-1726,1749-2173,2287-2614,2640-2800,3157-3341,3422-3500,3534-3948,4060-4390,4413-4597,4900-5078,5172-5253和5302-5555，或者所述結(jié)構(gòu)域是進(jìn)行了一個或多個不會影響到結(jié)構(gòu)域的功能特性的氨基酸取代的所述氨基酸序列之一。12．權(quán)利要求11的分離的DNA分子，其中所述DNA序列選自SEQIDNO1的堿基59902-61173,61489-62445,62548-63111,64006-64557,64843-65079,65146-66420,66760-67743,67819-68301,69370-69924,70165-70401,70471-71745,72079-73071,73138-73692,74599-75135,75415-75660和75805-76566。13．分離的DNA分子，其含有編碼刺糖噻PKS組件的DNA序列，所述組件選自SEQIDNO2的氨基酸6-1413,SEQIDNO2的1525-2513,SEQIDNO3的1-2034,SEQIDNO4的1-1506,SEQIDNO4的1529-3053,SEQIDNO5的1-1726,SEQIDNO5的1748-3269,SEQIDNO5的3291-4806,SEQIDNO5的1-1726,SEQIDNO6的1-1726,SEQIDNO6的1749-3500和SEQIDNO6的35434-5555，或者所述組件是進(jìn)行了一個或多個不會影響到結(jié)構(gòu)域的功能特性的氨基酸取代的所述氨基酸序列之一。14．權(quán)利要求13的分離的DNA分子，其中所述DNA序列選自SEQIDNO1的堿基21126-24041,24102-28649,29024-35125,35518-40035,40102-44676,45077-50254,50318-54883,54947-59494,59902-65079,65146-70401和70471-76566。15．重組DNA載體，其含有如權(quán)利要求1所述的DNA序列。16．被權(quán)利要求15所述的重組載體轉(zhuǎn)化的宿主細(xì)胞。17．提高刺糖噻之產(chǎn)量的方法，所述方法包括下列步驟1)用重組DNA載體或其部分轉(zhuǎn)化利用生物合成途徑生產(chǎn)刺糖噻或刺糖噻前體的微生物，所述載體或其部分含有權(quán)利要求1所述的DNA序列，所述DNA序列編碼所述途徑中限速活性的表達(dá)，和2)在適于細(xì)胞生長和分裂、表達(dá)所述DNA序列和生產(chǎn)刺糖噻的條件下培養(yǎng)被所述載體轉(zhuǎn)化的所述微生物。18．權(quán)利要求17的方法，其中步驟1)包括用含有編碼刺糖多孢菌gtt和刺糖多孢菌gdh的DNA序列的載體或其部分轉(zhuǎn)化所述微生物。19．經(jīng)轉(zhuǎn)化的生產(chǎn)刺糖噻的微生物，其基因組中含有刺糖噻生物合成基因，其中至少一個選自spnA,spnB,spnC,spnD,spnE,sppnF,spnG,spnH,spnI,spnJ,spnK,spnL,spnM,spnN,spnO,spnP,spnQ,spnR,spnS，刺糖多孢菌gtt，刺糖多孢菌gdh，刺糖多孢菌epi或刺糖多孢菌kre的刺糖噻生物合成基因已被復(fù)制。20．權(quán)利要求19的經(jīng)轉(zhuǎn)化的生產(chǎn)刺糖噻的微生物，其中刺糖多孢菌gtt和刺糖多孢菌gdh被復(fù)制。21．生產(chǎn)刺糖噻化合物的方法，所述方法包括培養(yǎng)權(quán)利要求20的經(jīng)轉(zhuǎn)化的生產(chǎn)刺糖噻的微生物。22．權(quán)利要求19的經(jīng)轉(zhuǎn)化的生產(chǎn)刺糖噻的微生物，其中刺糖多孢菌gtt，刺糖多孢菌gdh和刺糖多孢菌kre被復(fù)制。23．生產(chǎn)刺糖噻化合物的方法，所述方法包括培養(yǎng)權(quán)利要求22的經(jīng)轉(zhuǎn)化的生產(chǎn)刺糖噻的微生物。24．生產(chǎn)刺糖噻化合物的方法，所述方法包括培養(yǎng)權(quán)利要求19的經(jīng)轉(zhuǎn)化的生產(chǎn)刺糖噻的微生物。25．經(jīng)轉(zhuǎn)化的生產(chǎn)刺糖噻的微生物，其基因組中含有刺糖噻生物合成基因，其中所述基因中的至少一個基因已通過與該基因的內(nèi)部片段重組而被破壞，其余所述基因可有效產(chǎn)生刺糖噻，而不是被破壞的基因有效時產(chǎn)生的產(chǎn)物。26．生產(chǎn)刺糖噻化合物的方法，所述方法包括培養(yǎng)權(quán)利要求25的經(jīng)轉(zhuǎn)化的生產(chǎn)刺糖噻的微生物。27．經(jīng)轉(zhuǎn)化的生產(chǎn)刺糖噻的微生物，所述微生物的基因組中含有可操作的包括多個PKS組件的刺糖噻生物合成基因，其中所述基因a)包括至少一個可操作的PKS組件，所述組件比SEQIDNO1中所述組件少一個以上或至少少一個；或b)包括通過缺失，失活或添加KR,DH或ER結(jié)構(gòu)域，或通過取代針對不同羧酸的AT結(jié)構(gòu)域而與SEQIDNO1所述的相應(yīng)組件有所不同的PKS組件。28．生產(chǎn)刺糖噻化合物的方法，所述方法包括培養(yǎng)權(quán)利要求27的經(jīng)轉(zhuǎn)化的生產(chǎn)刺糖噻的微生物。29．分離大環(huán)內(nèi)酯生物合成基因的方法，所述方法包括制備大環(huán)內(nèi)酯生產(chǎn)微生物的基因組文庫，并將長度至少為20個堿基的經(jīng)標(biāo)記的SEQIDNO1,SEQIDNO25,SEQIDNO28或SEQIDNO32片段用作雜交探針。30．權(quán)利要求29的方法，其中微生物是生產(chǎn)刺糖噻的微生物。全文摘要本發(fā)明涉及刺糖噻生物合成基團(tuán),用該生物合成基因轉(zhuǎn)化的產(chǎn)刺糖噻微生物,用生物合成基因增加刺糖噻殺蟲大環(huán)內(nèi)酯類化合物的產(chǎn)生的方法,以及用所述基因或其片段改變由產(chǎn)刺糖噻微生物產(chǎn)生的產(chǎn)物的方法。文檔編號C12N1/21GK1298447SQ99805146公開日2001年6月6日申請日期1999年2月16日優(yōu)先權(quán)日1998年3月9日發(fā)明者R·H·巴爾茨,M·C·布勞頓,K·P·克勞福德,K·馬杜里,D·J·默洛,P·J·特雷德韋,J·R·特納,C·沃爾德倫申請人:道農(nóng)業(yè)科學(xué)公司