替曲卡星a的生物合成基因簇及其應用的製作方法

2023-07-07 10:11:21 2

專利名稱：：替曲卡星a的生物合成基因簇及其應用的製作方法
技術領域：
：本發明屬於微生物基因工程領域，具體涉及抗生素替曲卡星A(TetrocarcinA)的生物合成基因簇的克隆、分析、功能研究及其應用。
背景技術：
：Tetrocarcins是一類新型的螺環乙醯乙酸內酯類抗生素，首次分離自青褐色小單孢菌KY11091(Mfcwwo"os/orac/ia/ceaKY11091)的發酵產物[乂爿""'6/oA(1980)33，668-670]。替曲卡星A(如圖1所示)是其中的一個組分，其分子中含有苷元和糖基兩部分苷元Tetronolide結構非常獨特，其中含有一個反式萘環及一個螺-4-羥基乙醯乙酸內酯(Spirotetronate)單元；苷元的C9位連有由兩個L-阿米西糖和兩個L-毛地黃毒糖交替連接而成的四糖邊鏈，且一個L-毛地黃毒糖的4位羥基被乙醯化修飾;苷元的C17位則連接了一個罕見的，高度修飾的硝基脫氧糖Tetronitrose。替曲卡星A是螺環乙醯乙酸內酯類抗生素中生物活性最好的一個化合物。它對部分革蘭氏陽性菌具有較強的抑制活性，比如對枯草桿菌5ac77/MS仰Z^'feNo.10707的最低抑制濃度(MIC)低至O.l嗎/ml[J爿油'6W.(1980)33,244-246]。對替曲卡星A的構效關係研究表明，隨著寡糖側鏈中糖基的逐個被去掉，替曲卡星A的抑菌活性逐漸降低，這一結果顯示出糖基基團在抗菌過程中的重要作用[歷oow.Afec/.C/ie附.￡飢(2001)11,887-890]。替曲卡星A的抗菌機制可能是抑制細菌RNA的合成，並對蛋白的合成有部分影響，但不影響細菌DNA的合成。在對替曲卡星A抗腫瘤活性的研究中發現其對部分腫瘤，包括白血病細胞P388、Ehrlish腫瘤細胞、MH134肝腫瘤細胞、B16黑色素腫瘤細胞等，均具有強烈的抑制效果[乂^""'6/W.(1980)33，946-950]，同時沒有明顯的骨髓抑制和腎毒性等毒副作用[乂J""6/oA(1982)35，1033-1037]。因此，其良好的生物活性促使人們對其抗腫瘤作用機制進行了深入研究。1983年以來，對替曲卡星A抗腫瘤機制研究的結果表明，它能夠拮抗膜整合蛋白Bcl-2抑制細胞凋亡的作用，從而增加癌細胞對誘導其凋亡信號的敏感性和弱化癌細胞對於物理或化學藥物治療的抗性。Kaneko小組以替曲卡星A為基礎進行化學結構衍生得到了一系列替曲卡星A結構類似物，活性測試結果表明，一些保留抑制Bcl-2活性的結構類似物並不具備抗菌的能力，這一結果暗示了替曲卡星A可能通過不同於抗菌機制的新作用機制來體現其抗腫瘤活性[歷00②MedOe附.￡飢(2001)11,887-890]。值得注意的是，分別以T-急性淋巴細胞白血病(T-ALL)和B-慢性淋巴細胞白血病(B-CLL)腫瘤細胞為模型的細胞凋亡實驗結果表明，替曲卡星A可能是通過激活一條內質網應激通路(ER-stresspathway)而誘導細胞凋亡的發生[F五S5(2002)16，1295-1297]。也有研究者認為，替曲卡星A誘導細胞凋亡的機制是因為它能夠降低線粒體跨膜電位，導致細胞色素C的釋放和半胱天冬酶-9前體的活化而誘導細胞凋亡。由於替曲卡星A誘導細胞凋亡的過程不受Bcl-2、HSP70等抗凋亡因子的影響——這些蛋白的過量表達將鈍化化療藥物Prednisolone、Chlorambucil或Fludarabine的作用，這一現象提示我們可以將替曲卡星A用於對現有臨床化療藥物產生抗性的B-CLL腫瘤病人的治療。同時，B-淋巴細胞對於替曲卡星A的敏感性遠遠高於內源性的T-淋巴細胞，顯示替曲卡星A對治療B-CLL腫瘤可能具有較好的特異性[說ood(2003)101,4561-4568]。另外，替曲卡星A通過對人乳腺癌細胞中的PBK/Akt信號通路中一些因子磷酸化的抑制作用而達到對該腫瘤細胞生長的抑制[5/ocAe附.歷op/^.Cowwm汰(2007)356,260-265],可以通過進一步的研究將其發展成為治療乳腺癌的有效藥物。替曲卡星A獨特的化學結構也吸引了許多有機化學家從事其化學合成研究[J.org.Chem.(1985)50,4673-4681;J.org.Chem.(1988)53,1092-1095;TetrahedronLett.(1991)32,4925-4928;J.Am.Chem.Soc.(1994)116,6457-6458;J.Am.Chem.(1998)120,7411-7419;Bioorg.Med.Chem.Soc.(2001)11,887-890;J.Am.Chem.Chem.Soc.(2006)128，10572-10558]。由於替曲卡星A分子結構的複雜性，其化學半合成路線長，產率低，而且至今尚無關於該分子全合成研究的報導。為了更好的展開對替曲卡星A的研究和開發，我們以微生物來源的替曲卡星A為目標分子，從克隆其生物合成基因簇出發，採用微生物學、分子生物學、生物化學及有機化學相結合的方法研究其生物合成，通過對其生物合成機制的研究揭示包括形成螺-4-羥基乙醯乙酸內酯等化學結構的獨特酶學機理，在此基礎上運用代謝工程和組合生物合成的原理，合理修飾替曲卡星A的生物合成途徑，發展結構多樣的替曲卡星A結構類似物，為深入研究其構效關係提供更多的化合物支持，並通過微生物發酵大量生產新型藥物。
發明內容本發明涉及一種具有獨特聚酮結構的抗生素——替曲卡星A的生物合成基因簇的克隆、分析、功能及其應用。本發明中整個替曲卡星A的生物合成基因簇共36個基因的核苷酸序列或互補序列(序列1)，其中有5個基因(fc"7，fc"2，fc"3，fc"4，fco^:J)用於編碼I型聚酮合成酶(PKS)，共包含12個模塊，57個功能域，負責催化替曲卡星A大環骨架部分聚酮鏈的生物合成；4個基因(/oZ>/，fcfl/)2，Za^3，編碼的蛋白負責三碳單元的生物合成，並進一步與聚酮鏈縮合、環化形成大環骨架的[6，6]並環和[6,5]螺環結構；11個基因(fca5/，fca52，fca53，fca54，fcaB5，fca86，化aB7,fcaS&fcaB9,&a570,&a51/)編碼的蛋白負責阿米西糖、毛地黃毒糖和Tetronitrose的生物合成；9個基因(fcaC，fca￡/，fca￡2，fcaF，^aM，^a77,ra^2，fcaD，fca7V)編碼後修飾酶，催化替曲卡星A大環骨架的氧化和還原及分子中左側四糖側鏈和糖苷鍵的形成；2個調節基因(&ai/，to/及2);1個抗性基因及4個功能不十分確定的基因(fcaC/7，fcaC/2，ZcaCT3，fcaC/4)。本發明還提供了一個編碼糖基轉移酶的核苷酸序列，由序列2中的胺基酸序列組成，命名為tcaTl，其基因的核苷酸序列位於序列1中第8022-9134鹼基處。本發明還提供了一個編碼黃素蛋白氧化還原酶輔因子的核苷酸序列，由序列3中的胺基酸序列組成，命名為tcaC，其基因的核苷酸序列位於序列1中第9250-9810鹼基處。本發明還提供了一個編碼未知蛋白的核苷酸序列，由序列4中的胺基酸序列組成，命名為tcaUl，其基因的核苷酸序列位於序列l中第10171-9842鹼基處。本發明還提供了一個編碼未知蛋白的核苷酸序列，由序列5中的胺基酸序列組成，命名為tcaU2，其基因的核苷酸序列位於序列1中第10440-10880鹼基處。本發明還提供了一個編碼未知蛋白的核苷酸序列，由序列6中的胺基酸序列組成，命名為tcaU3，其基因的核苷酸序列位於序列1中第10691-11629鹼基處。本發明還提供了一個編碼雙組分反饋調節因子的核苷酸序列，由序列7中的胺基酸序列組成，命名為tcaRl，其基因的核苷酸序列位於序列1中第11988-12791鹼基處。本發明還提供了一個編碼NDP-己糖-3，5(或5)異構酶的核苷酸序列，由序列8中的胺基酸序列組成，命名為tcaB5，其基因的核苷酸序列位於序列1中第12849-13442鹼基處。本發明還提供了一個編碼3-酮基還原酶的核苷酸序列，由序列9中的胺基酸序列組成，命名為tcaB4，其基因的核苷酸序列位於序列1中第13499-14497鹼基處。本發明還提供了一個編碼糖基轉移酶的核苷酸序列，由序列10中的胺基酸序列組成，命名為tcaT2，其基因的核苷酸序列位於序列1中第15731-14553鹼基處。本發明還提供了一個編碼甲基轉移酶的核苷酸序列，由序列11中的胺基酸序列組成，命名為tcaBll，其基因的核苷酸序列位於序列1中第16681-15890鹼基處。本發明還提供了一個編碼氨基轉移酶的核苷酸序列，由序列12中的胺基酸序列組成，命名為tcaB7，其基因的核苷酸序列位於序列1中第16895-18037鹼基處。本發明還提供了一個編碼氧-醯基轉移酶的核苷酸序列，由序列13中的胺基酸序列組成，命名為tcaM，其基因的核苷酸序列位於序列1中第18152-19294鹼基處。本發明還提供了一個編碼葡萄糖-l-磷酸TDP轉移酶的核苷酸序列，由序列14中的胺基酸序列組成，命名為tcaBl，其基因的核苷酸序列位於序列1中第19343-20230鹼基處。本發明還提供了一個編碼dNTP-D-葡萄糖-4，6-脫水酶的核苷酸序列，由序列15中的胺基酸序列組成，命名為tcaB2，其基因的核苷酸序列位於序列1中第20227-21225鹼基處。本發明還提供了一個編碼醯基輔酶A脫氫酶的核苷酸序列，由序列16中的胺基酸序列組成，命名為tcaB10，其基因的核苷酸序列位於序列1中第21290-22594鹼基處。本發明還提供了一個編碼NDP-脫氧己糖-3-氨基轉移酶的核苷酸序列，由序列17中的胺基酸序列組成，命名為tcaB8，其基因的核苷酸序列位於序列1中第22600-23721鹼基處。本發明還提供了一個編碼甲基轉移酶的核苷酸序列，由序列18中的胺基酸序列組成，命名為tcaB9，其基因的核苷酸序列位於序列1中第23743-24987鹼基處。本發明還提供了一個編碼未知蛋白的核苷酸序列，由序列19中的胺基酸序列組成，命名為tcaU4，其基因的核苷酸序列位於序列1中第25068-25562鹼基處。本發明還提供了一個編碼含有KS^，ATL，ACPL，KS1，AT1，DH1，KR1，ACP1，KS2，AT2，DH2,KR2，ACP2，KS3，AT3，DH3，KR3，ACP3結構域的非重複使用的I型聚酮合成酶的核苷酸序列，由序列20中的胺基酸序列組成，命名為tcaAl，其基因的核苷酸序列位於序列1中第25588-44580鹼基處。本發明還提供了一個編碼含有KS4，AT4，DH4，KR*4，ACP4，KS5，AT5,DH5，KR5，ACP5，KS6，AT6，DH6，KR6,ACP6，KS7，AT7，DH7，KR7，ACP7結構域的非重複使用的I型聚酮合成酶的核苷酸序列，由序列21中的胺基酸序列組成，命名為tcaA2，其基因的核苷酸序列位於序列1中第44582-65605鹼基處。本發明還提供了一個編碼含有KSIO，ATIO，DHIO，KRIO，ACP10結構域的非重複使用的I型聚酮合成酶的核苷酸序列，由序列22中的胺基酸序列組成，命名為tcaA4，其基因的核苷酸序列位於序列1中第65565-71087鹼基處。本發明還提供了一個編碼含有KSll，ATll，DHll，KR'll，ACP11結構域的非重複使用的I型聚酮合成酶的核苷酸序列，由序列23中的胺基酸序列組成，命名為tcaA5，其基因的核苷酸序列位於序列1中第71162-75775鹼基處。本發明還提供了一個編碼依賴FAD的氧化酶的核苷酸序列，由序列24中的胺基酸序列組成，命名為tcaEl，其基因的核苷酸序列位於序列1中第75796-77271鹼基處。本發明還提供了一個編碼III型3-氧醯基載體蛋白合成酶的核苷酸序列，由序列25中的胺基酸序列組成，命名為tcaD4，其基因的核苷酸序列位於序列1中第77303-78355鹼基處。本發明還提供了一個編碼甲氧基-丙二醯基載體蛋白合成酶的核苷酸序列，由序列26中的胺基酸序列組成，命名為tcaDl，其基因的核苷酸序列位於序列1中第78352-80253鹼基處。本發明還提供了一個編碼獨立存在的醯基載體蛋白的核苷酸序列，由序列27中的胺基酸序列組成，命名為teaD2，其基因的核苷酸序列位於序列1中第80250-80477鹼基處。本發明還提供了一個編碼丙酮酸/2-氧代戊二酸脫氫酶(N端結構域)和水解酶/乙醯基轉移酶(C端結構域)的核苷酸序列，由序列28中的胺基酸序列組成，命名為tcaD3，其基因的核苷酸序列位於序列1中第80474-82324鹼基處。本發明還提供了一個編碼TetR家族轉錄調節因子的核苷酸序列，由序列29中的胺基酸序列組成，命名為tcaR2,其基因的核苷酸序列位於序列1中第83045-82467鹼基處。本發明還提供了一個編碼糖基轉移酶的核苷酸序列，由序列30中的胺基酸序列組成，命名為tcaT3，其基因的核苷酸序列位於序列1中第83216-84410鹼基處。本發明還提供了一個編碼糖基轉移酶的核苷酸序列，由序列31中的胺基酸序列組成，命名為tcaT4，其基因的核苷酸序列位於序列1中第84455-85594鹼基處。本發明還提供了一個編碼包含FAD/FMN的脫氫酶的核苷酸序列，由序列32中的胺基酸序列組成，命名為tcaE2,其基因的核苷酸序列位於序列1中第97242-85225鹼基處。本發明還提供了一個編碼硫酯酶的核苷酸序列，由序列33中的胺基酸序列組成，命名為tcaF，其基因的核苷酸序列位於序列1中第88026-87268鹼基處。本發明還提供了一個編碼2，3-己糖脫水酶的核苷酸序列，由序列34中的胺基酸序列組成，命名為tcaB3，其基因的核苷酸序列位於序列1中第89533-88076鹼基處。本發明還提供了一個編碼含有KS8，AT8，DH'8，ER8，KR8，ACP8，KS9，AT9，DH9，ER9，KR9，ACP9結構域的非重複使用的I型聚酮合成酶的核苷酸序列，由序列35中的胺基酸序列組成，命名為tcaA3，其基因的核苷酸序列位於序列1中第89806-101700鹼基處。本發明還提供了一個編碼氧化還原酶的核苷酸序列，由序列36中的胺基酸序列組成，命名為tcaB6，其基因的核苷酸序列位於序列1中第102587-101715鹼基處。本發明還提供了一個編碼藥物排出蛋白的核苷酸序列，由序列37中的胺基酸序列組成，命名為tcaG，其基因的核苷酸序列位於序列1中第104125-102653鹼基處。序列1的互補序列可根據DNA鹼基互補原則隨時得到。序列1的核苷酸序列或部分核苷酸序列可以通過聚合酶鏈式反應(PCR)或用合適的限制性內切酶酶切相應的DNA或使用其他合適的技術得到。本發明提供了得到至少包含部分序列1中DNA序列的重組DNA質粒的途徑。本發明還提供了產生替曲卡星A生物合成基因被中斷或加倍的微生物體的途徑，至少其中之一的基因包含有序列l中的核苷酸序列。本發明所提供的核苷酸序列或部分核苷酸序列，可利用聚合酶鏈式反應(PCR)的方法或包含本發明序列的DNA作為探針以Southern雜交等方法從其他生物體中得到與替曲卡星A生物合成基因相似的基因。包含本發明所提供的核苷酸序列或至少部分核苷酸序列的克隆DNA可用於從青褐色小單孢菌Mc/w/ce"NRRL11289基因組文庫中定位更多的文庫質粒。這些文庫質粒至少包含本發明中的部分序列，也包含有青褐色小單孢菌MWa/CMNRRL11289基因組中以前鄰近區域未克隆的DNA。包含本發明所提供的核苷酸序列或至少部分核苷酸序列可以被修飾或突變。這些途徑包括插入、置換或缺失，聚合酶鏈式反應，錯誤介導聚合酶鏈式反應，位點特異性突變，不同序列的重新連接，序列的不同部分或與其他來源的同源序列進行定向進化(DNAshuffling)，或通過紫外線或化學試劑誘變等。包含本發明所提供的核苷酸序列或至少部分核苷酸序列的克隆基因可以通過合適的表達體系在外源宿主中表達以得到相應的酶或其他更高的生物活性或產量。這些外源宿主包括鏈黴菌、假單孢菌、大腸桿菌、芽孢桿菌、酵母、植物和動物等。本發明所提供的胺基酸序列可以用來分離所需要的蛋白並可用於抗體的製備。包含本發明所提供的胺基酸序列或至少部分序列的多肽可能在去除或替代某些胺基酸之後仍有生物活性甚至有新的生物學活性，或者提高了產量或優化了蛋白動力學特徵或其他致力於得到的性質。包含本發明所提供的核苷酸序列或至少部分核苷酸序列的基因或基因簇可以在異源宿主中表達並通過DNA晶片技術了解它們在宿主代謝鏈中的功能。包含本發明所提供的核苷酸序列編碼的蛋白可以催化合成阿米西糖、毛地黃毒糖、硝基脫氧糖Tetronitrose及替曲卡星A聚酮大環骨架，進一步催化合成抗生素替曲卡星A。包含本發明所提供的核苷酸序列或至少部分核苷酸序列的基因或基因簇可以通過遺傳重組來構建重組載體以獲得新型生物合成途徑，也可以通過插入、置換、缺失或失活進而獲得新型生物合成途徑。包含本發明所提供的核苷酸序列或至少部分核苷酸序列的克隆基因或DNA片段可以通過中斷替曲卡星A生物合成的一個或幾個步驟而得到新的替曲卡星A結構類似物或前體。包含DNA片段或基因可以用來提高替曲卡星A或其衍生物的產量，本發明提供了在基因工程微生物中提高產量的途徑。包含本發明所提供的聚酮合成酶可以通過缺失、插入或失活來自於相同或不同的聚酮合成酶系統的一個或多個聚酮合成酶結構域、模塊或基因而產生新的聚酮化合物。包含本發明所提供的核苷酸序列或至少部分核苷酸序列的片段或基因可以用來構建聚酮合成酶庫或聚酮合成酶衍生庫或組合庫。本發明所提供的三碳單位的生物合成基因及其他相關基因與聚酮合成藕聯可用於合成替曲卡星A家族獨特的[6，5]螺環及螺-4-羥基乙醯乙酸內酯結構極其類似物。本發明所提供的替曲卡星A大環骨架的後修飾基因提供了通過遺傳修飾得到類似物的途徑，所包含的催化大環內酯生成的氧化反應亦可有其他應用。總之，本發明所提供的包含替曲卡星A生物合成相關的所有基因和蛋白信息可以幫助人們理解替曲卡星A家族天然產物的生物合成機制，為進一步遺傳改造提供了材料和知識。本發明所提供的基因及其蛋白質也可以用來尋找和發現可用於醫藥、工業或農業的化合物或基因、蛋白。圖l:替曲卡星A的化學結構圖2:替曲卡星A生物合成基因簇的限制性內切酶譜和基因結構。(A)7個交疊的粘粒代表了青褐色小單孢菌基因組中約110kb的DNA區域,B代表限制性內切酶5。mHI，N代表限制性內切酶NcoI，粗體線表示已被DNA測序的部分，P5、P6代表標記的探針部分；(B)替曲卡星A生物合成基因簇的基因組成。圖3:提出的替曲卡星A糖基單元阿米西糖、毛地黃毒糖和硝基脫氧糖Tetronitrose的生物合成途徑。圖4:提出的替曲卡星A大環骨架的生物合成途徑及各單元組裝成完整的替曲卡星A分子。圖5:青褐色小單孢菌發酵產物的高效液相色譜(HPLC)分析。(I)替曲卡星A標準品；(II)野生型青褐色小單孢菌NRRL11298;(III)fc"7，^"2，fco^/和&"基因中斷的突變株。圖6:I型聚酮合成酶PKStcaAl-A5的功能分析。(A)醯基轉移酶結構域AT保守區域的分析；(B)脫水酶結構域DH保守區域的分析；(C)酮基還原酶結構域KR保守區域的分析。符號說明圖hTetrocarcin:替曲卡星A。圖2:(A)pTL3001，pTL3002，pTL3003，pTL3004，pTL3005，pTL3006和pTL3007表示篩選青褐色小單孢菌NRRL11289基因文庫得到的粘粒；(B)P:探針；Sugar:糖基合成基因；PKSSkeleton:形成聚酮骨架的基因；3-CUnit:三碳單元合成基因；Glycosyltransferase:糖基化基因；Tailoring:後修飾基因；Regulation:調節基因；Resistance:抗性基因；Unknown:未知功能；BeyondtheCluster:基因簇之外。圖3:TDP-L-amicetose:胸腺嘧啶核苷二磷酸-L-阿米西糖；TDP-L-digitoxose:胸腺嘧啶核苷二磷酸-L-毛地黃毒糖；TDP-L-tetronitrose:胸腺嘧啶核苷二磷酸-L-tetronitrose。圖4:KS:酮基合成酶；AT:醯基轉移酶；DH:脫氫酶；ER:烯醇還原酶；KR:酮基還原酶；ACP:醯基載體蛋白。圖5:黑色三角替曲卡星A標準品；數字16:野生型青褐色小單孢菌NRRL11298發酵液中新發現的可能的替曲卡星結構類似物。圖6:(A)方框內表示決定底物特異性的保守胺基酸，星號表示活化丙二酸單醯輔酶A的AT;(B)方框內表示催化活性區域保守的酸性胺基酸，星號表示模塊4和8中的DH因保守胺基酸的突變可能失去功能；(C)方框內表示催化活性保守的胺基酸，星號表示模塊11中的KR因保守胺基酸的突變可能失去功能。具體實施例方式以下結合圖l、圖2、圖3、圖4、圖5、及圖6對本發明進一步詳細說明。1.克隆、分析替曲卡星A的生物合成基因簇我們首先構建了以pOJ446為載體的青褐色小單孢菌NRRL11289總基因組文庫。由於氯絲菌素和替曲卡星A在苷元結構上具有很高的相似性，這也暗示了這兩個化合物苷元的生物合成基因簇也具有一定的同源性。以本課題組於2006年報導的氯絲菌素的生物合成基因簇為參照，我們將其中位於聚酮合成酶基因AM2，和c/"5內部的一些DNA片段標記為異源探針，在青褐色小單孢菌NRRL11289總基因組文庫中大約6000個克隆中進行篩選，分離得到的30個粘粒涵蓋了染色體約70kb的區域。為獲得完整的替曲卡星A生物合成基因簇，我們又構建了以pCClFOS為載體的，隨機性和效價都更高的青褐色小單孢菌NRRL11289總基因組文庫。將已獲得的與替曲卡星A生物合成相關的DNA區域左右末端的DNA片段標記為探針P5和P6，進行基因文庫篩選和染色體步移，獲得的18個粘粒分別向左右兩側擴展了15kb和22kb的DNA區域。經DNA測序和序列分析，發現該110kb的DNA區域已包含了完整的替曲卡星A生物合成基因簇。進一步經聚酮合成酶基因中斷發現相應基因失活的突變菌株完全喪失了產生替曲卡星A的能力(圖5，III),證明克隆了負責替曲卡星A生物合成的基因簇。綜上所述，我們通過對青褐色小單孢菌NRRL11289的基因文庫篩選和染色體步移獲得了一系列相互交疊的粘粒，其中的pTL3001,pTL3002,pTL3003,pTL3004,pTL3005,pTL3006禾卩pTL3007涵蓋了染色體約110kb的區域(圖2A)。DNA順序分析了108，236bp的染色體區域，GC含量72.9%。生物信息學分析包含了47個開放讀碼框(圖2B)。o;/f-力至詳細的分析結果列於表l。表1替曲卡星A的生物合成基因簇中各基因及編碼蛋白的功能分析基因胺基酸數目相似蛋白"相同粉相似性o/c推測功能134CBG1971(CAE72536.1)36/47未知蛋白296CitA(ZP一00616833.1)52/63ATP結合蛋白l貼Ci氾(NP一629572.1)58/67雙組分調節因子1031DnaE(ZP—01650120.1)87/93HI型DNA聚合酶，a單元105未知蛋白加77370STIAU—3104(ZP—01461407)30/42糖基轉移酶186RHAl_ro09012(YP—708214)55/68黃素氧化還原酶輔因子加W109Strop—3510(505卿4;i65/69未知蛋白fC146CLOL250—02534(ED056846)32/56未知蛋白312未知蛋白267ChlF2(AAZ77687)44/59雙組分調節因子197TylCVII(AAD41825)60/73NDP-己糖-3,5-(or5-)異構酶加醜4332PlaA5(ABB69760)5詣NDP-己糖-3-酮基還原酶加72392ChlC7(AAZ77672)37/53糖基轉移酶263SareDRAFT—209538/53甲基轉移酶(ZP_01650637)380SpnR(AAG23279)55/71氨基轉移酶380Srm6(CM96572)40/56氧-醯基轉移酶295AclY(AAK83289)62/75dNDP-l-葡萄糖合成酶加￡2332AprE(AAG18457)74/83dNDP-葡萄糖-4，6-脫水酶434RubN8(CAI94696)61/74醯基輔酶A脫氫酶fca朋373Med-ORF20(BAC79028)80/86NDP-脫氧己糖-3-氨基轉移酶414PCZA361.22(CAA11777)69/79甲基轉移酶164YDrepeat(ZP—00573146)41/52未知蛋白6330FRAAL4072(YP—714269)44/55聚酮合成酶7007FscC(AAQ82564)49/61聚酮合成酶1840HbmAII(AAY28226)49/62聚酮合成酶1537ChlA6(AAZ77699)51/62聚酮合成酶491ChlE3(AAZ77700)48/61依賴FAD的氧化還原酶350C固(AAZ77702)65/76III型3-氧乙醯基-ACP合成酶633ChlDl(AAZ77703)60〃0FKbH-likeprotein75ChlD2(AAZ77704)57〃2醯基載體蛋白616ChlD3(AAZ77705)58〃4N-端結構域ChlD4(AAZ77706)55/71c-端結構域192SACE—3583(YP—001105782)40/56TetR家族轉錄調節因子加73398ChlC7(AAZ77672)41/55糖基轉移酶加7V379ChlC7(AAZ77672)42/57糖基轉移酶505M欣(AAD28454)楊5氧化還原酶254SAV407(AAD28454)54〃0硫酯酶487ORF26(AAP85341)53/642，3-己糖脫水酶fc"33964CMA5(AAZ77698)55/66聚酮合成酶289SCO3730(NP—627921)59/71氧化還原酶490FRAAL1973(YP—712205)45/63藥物排出蛋白275STIAU_2740(ZP_01466190.1)39/53M23肽酶o一222CHAP(ZP—00532045.1)32/52整聯蛋白132m115401(NP—106072.1)40/52醛酮變位酶106ArsR(YP一OOl135161,1)78/84調節蛋白。y"243MMT1(YP_001135160.1)76/83金屬離子轉運蛋白，26148PldB(YP—286985.1)41/57水解酶a/p摺疊區域a括號中提供NCBI登記號b替曲卡星A生物合成基因簇之外的開放閱讀框2.替曲卡星A的生物合成基因簇邊界的確定根據基因編碼蛋白的功能分析，替曲卡星A的生物合成基因簇被確定為從基因fca77到fcoG(圖2B)，涵蓋染色體94.6kb的區域，包含36個開放讀碼框。通過生物信息學分析，確定替曲卡星A的生物合成基因簇的邊界在替曲卡星A生物合成相關DNA區域左側末端，or/(W)，or/T-"，or/r-"，or/f力和分別編碼了未知蛋白、ATP-結合區域(ATP酶)、雙組分調節因子、III型DNA聚合酶和未知蛋白。這些酶往往參與微生物的初級代謝過程而與次級代謝無關；而to77和toC分別編碼了糖基轉移酶和黃素氧化還原酶，我們推測它們都與替曲卡星A的生物合成相關。另外，從以上基因的相對位置來分析，ory0和"fl77方向相反，不在相同啟動子的控制之下。綜合以上分析，我們推測替曲卡星A生物合成基因簇的左側邊界位於o^D和^77之間。在替曲卡星A生物合成相關DNA區域右側末端，和fcaG分別編碼了氧化還原酶和藥物抗性基因，它們分別對替曲卡星A的生物合成以及排出微生物體外起著不可或缺的作用；而w/W、o//"、or/W、o//"、or/46和or/47分別編碼了M23肽酶、整聯蛋白、醛酮變位酶、調節蛋白、金屬離子轉運蛋白和a/p水解酶。以上這些酶均與微生物的初級代謝相關而非次級代謝必需。另外，從以上基因的相對位置來分析，和or/W方向相反，它們處於不同的啟動子控制之下。綜合以上分析，我們推測替曲卡星A生物合成基因簇的右側邊界位於和or/47之間。整個替曲卡星A的生物合成基因簇共36個基因，其中5個(/c"7，fc"2，fc"3，fca/lA^l45)用於編碼非重複使用的I型聚酮合成酶，共包含12個模塊，負責催化替曲卡星A大環骨架部分聚酮鏈的生物合成；4個基因(加￡>7,fcaD3,編碼的蛋白負責三碳單元的生物合成，並進一步與聚酮鏈縮合、環化形成大環骨架的[6，6]並環和[6,5]螺環結構；11個(fca5/，to52，/ca53，fca54，,ca55，toi56，Za^7，fcfl5S，^fl59，fca570，fcaB7/)編碼的蛋白負責阿米西糖、毛地黃毒糖和硝基脫氧糖Tetronitrose的生物合成；9個後修飾基因(fcaC，&a￡3，化flF，fcaM，^a77，fcfl"，to"，fcaT4)編碼的蛋白催化替曲卡星A大環骨架的後修飾和糖基化；還包括2個調節基因(fc"及7，fcfl及2)和1個抗性基因(化aG)及4個功能不十分確定的基因(&aL7，fc"C/2，&flt/3,/caC/4)。3.阿米西糖、毛地黃毒糖和硝基脫氧糖Tetronitrose的生物合成阿米西糖、毛地黃毒糖和硝基脫氧糖Tetronitrose的生物合成如圖3A所示:1編碼的dNDP-D-葡萄糖合成酶催化dNDP-D-葡萄糖(2)的合成，然後在to^2編碼的dNDP-D-葡萄糖-4，6-脫水酶的催化下發生6位脫水，生成化合物(3)，接著在編碼的2,3-脫水酶的催化下發生2位脫水生成化合物(4)。以此化合物為第一個分支點，分別合成脫氧糖和硝基脫氧糖。在Zm54編碼的3-酮基還原酶的作用下3位酮基還原為羥基，生成化合物(5)，接著在fc"A5編碼的5位異構酶的催化下生成NDP-4-酮-2，6-二脫氧阿洛糖(6)，以此化合物為第二個分支點分別在進行3位脫氧和4位還原分別形成化合物(7)和毛地黃毒糖，前者再經&fl56編碼的氧化還原酶催化反應生成阿米西糖。從化合物(4)出發，經/a75S編碼的氨基轉移酶在其3位轉上氨基，生成化合物(8)，然後再經fc"59編碼的碳甲基轉移酶在其3位轉上甲基，生成化合物(9)，to^70編碼的氧化還原酶將其3位氨基氧化成為硝基，再經&"57編碼的氨基轉移酶在化合物(10)的4位轉上氨基，生成化合物(11)，fca5W編碼的氮甲基轉移酶在4位氨基上轉上甲基，之後，可能由一些位於已發現基因簇外側的氧化酶和C-甲基轉移酶的催化下，對化合物(11)再進行一系列氧化、甲基化進而生成硝基脫氧糖Tetronitrose，從而完成替曲卡星A中各個糖基單元的生物合成。4.替曲卡星A聚酮大環骨架的合成及各單元組裝成完整的替曲卡星A分子替曲卡星A大環骨架聚酮鏈部分是由典型的I型聚酮合成酶PKS催化合成的(圖4)。其中編碼的PKS包含四個模塊，起始模塊包含KS^，ATL,ACPL三個結構域，KSQL中因KS催化縮合關鍵的活性位點由半胱氨酸C突變為穀氨醯胺Q而僅具有脫羧活性。延伸模塊1包含KS1，ATI,DH1，KR1，ACPI結構域；延伸模塊2包含KS2，AT2，DH2，KR2,ACP2結構域；延伸模塊3包含KS3，AT3，DH3，KR3，ACP3結構域。fcd2編碼的PKS包含四個延伸模塊，延伸模塊4包含KS4，AT4，DH'4，KR4，ACP4結構域，其中的DH結構域因關鍵的保守胺基酸突變而不具有活性(圖6B);延伸模塊5包含KS5，AT5，DH5，KR5，ACP5結構域結構域；延伸模塊6包含KS6，AT6，DH6,KR6,ACP6;延伸模塊7包含KS7，AT7,DH7，KR7，ACP7結構域。/c"3編碼的PKS包含延伸模塊8，9，其中延伸模塊8由KS8，AT8，DH'8，ER8，KR8，ACP8結構域組成，其中的DH結構域因關鍵的保守胺基酸突變而不具有活性(圖6B);延伸模塊9由KS9，AT9，DH9，KR9，ACP9結構域組成。fc"4編碼PKS只包含一個延伸模塊10，由KSIO，ATIO，DHIO，KRIO，ACP10結構域組成，/c"5編碼的PKS包含最後一個模塊11，由由KSll，ATll，DHIO，KR*10，ACP11結構域組成，其中的KR結構域因關鍵的保守胺基酸突變而不具有活性(圖6C)。分析所有模塊中的AT結構域發現只有模塊4、模塊6和模塊10中的AT識別甲基丙二酸單醯輔酶A，而其他模塊的AT均識別丙二酸單醯輔酶A為底物(圖6A)，但根據替曲卡星A的分子結構，其中的起始模塊、模塊1和模塊2中的AT也均應識別丙二酸單醯輔酶A，可能現有的推測AT底物的模型還不能準確推測其識別的真正底物。在上述PKS的催化下7分子丙二酸單醯輔酶A與5分子甲基丙二酸單醯輔酶A依此經活化、脫羧縮合生成聚酮長鏈，其經第一次分子內[4+2]環加成反應形成中間體14;同時由甘油代謝的三碳單元中間體經^"D7編碼的甲氧基-丙二醯基載體蛋白合成酶活化，連接到fcfl/^編碼的醯基載體蛋白上，然後經/CfliW編碼的丙酮酸/2-氧代戊二酸脫氫酶的催化，從TcaD2蛋白上解離的同時被連接於輔酶A上，形成活性形式的甘油醯輔酶A(16);然後該化合物在tcaD4編碼的III型酮基合成酶催化下，將聚酮長鏈從TcaA5的最後一個醯基載體蛋白ACP上解離下來，形成中間體(17)，其在fcaZ)3編碼的水解酶/乙醯基轉移酶的催化下形成五元內酯環，經一步可能自發進行也可能是由未知蛋白催化的脫水反應後形成化合物(19)，其再經歷一次分子內的[4+2]環加成反應生成化合物(20);fcfl五7，/cfl五2，fcflM,fc77，to/",rca73,編碼的氧化酶、糖基轉移酶和醯基轉移酶對化合物(20)進行一系列的氧化、糖基化、醯基化等後修飾反應後，最終完成替曲卡星A的生物合成(圖4)。5.替曲卡星A生物合成基因簇的應用——以生物合成基因簇中聚酮合成酶基因的中斷突變株發酵產物作為對照，從野生型菌株發酵產物中新發現一系列可能的替曲卡星A結構類似物在克隆、分析了完整替曲卡星A生物合成基因簇，研究了各基因編碼蛋白可能的功能的基礎上，本發明對替曲卡星A的生物合成機制進行了初步探討，這有助於理解替曲卡星A的生物合成機制，同時也為進一步通過對生物合成基因簇進行遺傳修飾獲得替曲卡星A機構類似物提供了可能。如本發明通過對(編碼糖基轉移酶)基因進行基因中斷獲得的突變菌株不再產生替曲卡星A，但可以產生幾個新的替曲卡星A結構類似物(圖5)。以下進一步提供實施實例，這些實施實例有助於理解本發明，僅用作說明而不限制本發明的應用範圍。實施例1替曲卡星A產生菌青褐色小單孢菌NRRL11289總DNA的提取吸取100pl-80°0凍存的青褐色小單孢菌菌絲懸液接種到含有3mlTSB(30g/LIryptone旦oya旦roth)培養基的試管中，30'C，振蕩培養約36小時，取2.5ml菌液接種至50mlTSB(含0.5%甘氨酸，25mM氯化鎂)培養基中，30'C，振蕩培養約36個小時至菌液顯新鮮橙色，3500rpm離心收集菌體，用裂解液(150f蔗糖，25mMTris-Cl，25mMEDTA)洗兩次，存於-20。C供提取基因組DNA用。向收集的菌絲中加入10ml裂解液(含溶菌酶5mg/ml，消色肽酶1mg/ml)，渦旋至均一，37°。溫浴30分鐘，加入O.lml蛋白酶K(4mg/ml)，1ml10。/。SDS，混勻迅速放入70°C水浴15分鐘，待溶液澄清。置於冰上冷卻，加入2.5ml5M醋酸鉀，冰上冷卻15分鐘。加入10mlTris飽和酚，混勻，10ml氯仿，混勻，12000-15000rpm，4。C離心20分鐘。用平口的槍頭將水相吸出轉移至新的離心管，加等量的氯仿/異戊醇(24:1)抽提，12000rpm，4'C離心10分鐘，用平口的槍頭將水相吸出置於新的離心管，加入0.1體積的3M醋酸鈉，2倍體積的乙醇，混勻，有大團的DNA出現。將其勾出置於新的離心管，力B5ml70%乙醇洗滌，將液體傾出，用槍吸淨，加5mlTE溶解，加32plRNA酶(終濃度為50pg/ml)，37'C溫浴0.5小時。依次用等體積的飽和酚抽提兩次，氯仿/異戊醇抽提兩次，向水相中加入0.1體積的3M醋酸鈉，2倍體積的無水乙醇,輕輕的混合充分，有絮狀DNA出現。將四管DNA合併到兩管(每管中有lml70。/。乙醇)，將乙醇吸出，再加lml無水乙醇洗滌，吸出，超淨臺中吹乾，溶於1mlTE(50ml菌液收集的菌絲體提出的總DNA溶於1mlTE緩衝液)中。實施例2替曲卡星A產生菌青褐色小單孢菌NRRL11289基因組Cosmid文庫的建立首先通過一系列的稀釋實驗來確定Saw3AI的用量，在此基礎上大量酶切得到的DNA片段略大於40kb，脫磷。pOJ446先用5gfll從兩個cos序列中間切開並脫磷，然後再從多克隆位點處用5"wHI切開，獲得兩個臂，與製備的40kb的DNA片段連接過夜。從-80'C冰箱中取出包裝混合物置於乾冰桶中，將包裝混合物在指間迅速融化，在剛剛開始融化時加入4jiL的連接產物，用槍混勻，22'C水浴2小時。加入500SM緩衝液[(L"):5.8gNaCl，2.0gMgS04，50.0ml1MTris.HCl(pH=7.5)，5.0ml2%(w/v)瓊脂]和50^L氯仿，輕輕混勻，3000rpm離心4秒，上下界面出現沉澱，轉移上清至新管中，於4'C保存。將凍存於-8(TC的菌株五.②//vcs257塗布在LB培養基上復甦。挑取單克隆接種於50mlLB培養基中(含0.2%麥芽糖和10mMMgS04),37°C,220rpm振蕩6.5小時，測得其OD6QQ=0.8時，取用100mL的包裝上清和100od600=0.83的菌液，輕彈管壁使其混勻，平行操作5份。22'C水浴30分鐘，加入800nL的LB培養基，37'C水浴1.5小時，每15分鐘倒轉一次。每一份塗布一塊LB瓊脂培養基(含lOOpg/ml氨苄西林)(15mmxl5mm)，每一份用20(HiL的LB培養基涮洗，37'C培養18個小時。測定噬菌斑形成單位(pfU)以估算文庫的校價。然後用LB培養基涮洗，加入氨苄西林和甘油，使氨節西林的終濃度為50pg/ml，甘油的終濃度為18%。分裝成1mix12，0.5mlx48，025mlx24。保存於-80。C。替曲卡星A產生菌青褐色小單孢菌NRRL11289基因組Fosmid文庫的建立用注射器對提取的青褐色小單孢菌NRRL11289總DNA(2.5嗎以上)反覆的吹吸來使其被機械剪切力隨機打斷，吹吸次數根據片段原始的大小來決定，一般每50次用電泳檢查一次效果，直至10%左右的片段在36kb的controlDNA附近。用蔗糖密度梯度離心的方法分離36-40kb大小的DNA進行補平且5'端被磷酸化。將DNA片段以10:1(載體:片段)的比例連至試劑盒提供的pCClFOS載體，包裝入CopyControl(Epicentre,Aus.)試劑盒中提供的MaxPlaxLambdaPackagingExtracts噬菌體蛋白。將試劑盒中提供的宿主菌EPI300—T^取出，塗布或者畫線於不含任何抗生素的LB瓊脂培養基上，37'C過夜培養，以10%的接種量，接入50mlLB(含10mMMgSO4)中，37。C培養至ODeo(r0.81.0，將包裝好的噬菌體蛋白轉染該宿主菌並進行效價測定，並將轉染後得到的克隆用合適體積的LB洗下後加入甘油(終濃度20%)，凍存於—7(TC。實施例3核酸分子雜交1)DIGDNA標記將待標記的DNA用無菌水稀釋至總體積15nL，沸水浴中加熱變性10分鐘，立即置於冰鹽浴中冷卻。接著加入2^L引物混合物，2jiLdNTP混合物，lpL酶，混合均勻後，37'C水浴約16小時。加入0.8^L0.8MEDTA(pH8.0)以終止反應，加入2.5nL4MLiCl混合均勻，再加入75^L預冷的無水乙醇沉澱標記後的DNA，置於一80。C沉降40分鐘。4°C，12000rpm離心20分鐘收集DNA，用預冷的70。/。乙醇洗滌DNA沉澱，真空乾燥後重新溶於50nLTE((pH8.0)中。2)DIGDNA探針標記後的質量檢測稀釋標記的DNA探針，至以下六個梯度，1、10"、l(T2、l(T3、l(T4、l(T5。稀釋標記的對照DNA至濃度分別為以下濃度ljig/ml,100ng/ml,10ng/ml，lng/ml，0.1ng/ml，0.01ng/ml。分別取ljiL上述梯度的DNA樣品點在雜交用的尼龍膜上，根據7)所述步驟進行顯色反應，對比標記的DNA探針和DIG標記的對照DNA的顯色強度以決定標記的DNA探針濃度。3)菌落雜交(文庫篩選)的膜轉移將保存於-8(TC的基因文庫稍融，取50pL，用450jiLLB稀釋得到10"的稀釋倍數，倍比稀釋得到1(T2，l(T3，IO"4，l(T5，l(T6。30(HiL塗培養基(15cmxl5cm，培養基為LB/50ng/ml卡那黴素)。選取合適的比例，使每塊培養基約1200—1500個克隆。照選定的比例均勻塗布四塊培養基，37'C培養過夜。根據培養基的大小剪取尼龍膜，小心地覆蓋於培養基表面不要產生氣泡，做好位置標記，1分鐘後取下尼龍膜置於乾燥濾紙上，乾燥10分鐘直至菌落結合在尼龍膜上。原始的培養基置於培養箱中4一5hr，使克隆重新生長作為原培養基。將尼龍膜置於變性液(0.25MNaOH，1.5MNaCl)飽和的濾紙上15分鐘(不要浸過膜)，轉移至中和液(1.0MTris.HCl，1.5MNaCl,pH7.5)飽和的濾紙上5分鐘。轉移至2xSSC(20XSSC儲備液(L"):NaCl，350.6g，檸檬酸鈉，176.4g，pH=7.0)飽和的濾紙上自然風乾。取下尼龍膜置於烘箱中，120。C固定45分鐘。常溫下於3xSSC/0.1%SDS溶液中振蕩洗滌3小時，以除去細胞碎片。4)Southern雜交的膜轉移DNA樣品在適當濃度的瓊脂糖凝膠上電泳至適當距離，做好標記。浸泡於40011110.25\111(:1中脫嘌呤20分鐘，使溴酚藍變黃，用去離子水洗數次。室溫下浸入鹼性緩衝液(0.5MNaOH，1MNaCl)15分鐘並輕輕振蕩。換液一次繼續浸泡凝膠20分鐘，並輕輕振蕩，去離子水洗三次。取一張每邊都比凝膠大lmm的尼龍膜，用去離子水完全浸溼，做好標記。採用向上毛細管轉移方法，用10xSSC轉移緩衝液轉移8—24hr。用2xSSC略微洗膜，120'C烘烤30分鐘。5)預雜交和雜交預熱雜交液(20ml/100cm2)至雜交溫度68。C，放入雜交尼龍膜，輕輕振蕩並保溫30分鐘。將DIG標記的DNA探針在沸水浴中變性5分鐘，立即置於冰鹽浴中冷卻。冷卻後，將DNA探針與合適體積的DIG雜交液(2.5ml/100cm2)混合均勻。去除預雜交液並立即把DNA探針/DIG雜交液加入，輕輕振蕩保持雜交溫度64'C或68'C約16小時。6)雜交後嚴緊洗脫室溫下用2xSSC/0.1%SDS漂洗兩次，每次5分鐘。68°C，用0.1xSSC/0.P/。SDS振蕩漂洗兩次，每次15分鐘。7)顯色反應和檢測嚴緊洗脫後的尼龍膜在洗滌緩衝液(0.1M馬來酸，0.15MNaCl，pH=7.5，0.3%(v/v)Tween20)中平衡1-5分鐘，接著在封閉緩衝液(封閉試劑以10。/。的濃度溶於0.1M馬來酸，0.15MNaCl，pH=7.5)中封閉30分鐘，然後在抗體中浸泡30分鐘。用洗滌緩衝液漂洗尼龍膜兩次後，用檢測緩衝液(0.1MTris-HCl，O.IMNaCl,pH=9.5)中平衡2-5分鐘，最後將尼龍膜置於10ml新配製的顯色溶液[NBT(nitrobluetetrazoliumtcaoride)溶於70%DMF，濃度為70mg/ml，BCIP(5-bromo-4-tcaoro-3-indolyl-phosphate)溶於水，濃度為50mg/ml。用時10ml顯色溶液中加45^iLNBT，35^LBCIP]中，置於黑暗中顯色。顯色合適後用去離子水漂洗以終止反應。實施例4替曲卡星A產生菌青褐色小單孢菌NRRL11289遺傳轉移系統的建立取1ml-80匯凍存的青褐色小單孢菌^(111^11289菌絲懸液接種到TSB培養基(含3%甘露糖)，28。C，250rpm振搖培養3036小時至菌絲的對數生長期中期，即菌絲大量增殖，且顯新鮮橙色。3000rpm離心IO分鐘收集菌絲。用15mlLB(10g/L蛋白腖，5g/L酵母提取物，10g/ml氯化鈉)洗兩次，懸浮菌絲於5mlLB中，取lml轉移入勻漿器中勻漿1520分鐘使菌絲變細，待用。將構建好的重組質粒轉化五.CO//S17-1,從轉化的培養基上挑取單克隆菌落入3mlLB(含相應抗生素)中於37'C，220rpm振搖培養12~15小時，取500菌液接種入50mlLB(含相應抗生素)，於37。C，220rpm振搖培養4~5小時至OD600至0.3-0.4。將菌液倒入50ml離心管中，於2500rpm離心10分鐘，傾去上清，用15mlLB洗滌菌體兩次。向其中加入5mlLB培養液重懸菌體細胞，待用。將青褐色小單孢菌NRRL11289的菌液和五.CO//S17-1(含重組質粒)菌體細胞按照1:10體積混合，取200pL塗在As-l(含10mMMgCl2)培養基上，同時做陰性對照和陽性對照，其中，用做陽性對照和陰性對照的培養基上只塗200小單孢菌菌液。將塗好菌液的培養基放入30'C培養箱中培養16~20小時後，用8~10ml無菌水輕輕洗去每塊培養基上的大腸桿菌，用槍吸走菌液，再向接合轉移培養基上和陰性對照的培養基上塗布相應抗生素。然後將培養基置於超淨臺中吹34小時。將培養基放於30'C培養箱中倒置培養，約6天後長出淺橙色的接合子單菌落。實施例5替曲卡星A產生菌青褐色小單孢菌NRRL11289基因中斷突變菌株的獲得將含有相應重組質粒的青褐色小單孢菌NRRL11289的接合子單菌落接種入4mlTSB培養液(含相應抗生素)中於30'C，250rpm培養7天，待菌液長濃，顯新鮮橙紅色。取50pL單交換突變株的菌液接種入4mlTSB培養液(不含抗生素)中，於30°C,220rpm振搖培養並在無抗生素的TSB培養液中傳代3~4次誘導基因雙交換突變株的產生。之後，取2nL菌液塗於IWL-4瓊脂培養基上，挑取對相應抗生素抗性正確的菌落即可能為基因雙交換突變株。抽提突變株的總DNA進行Southern雜交驗證，同時進行發酵進行表型驗證。實施例6替曲卡星A生物發酵、產物分離純化與鑑定接種1ml-80°<:凍存的青褐色小單孢菌\皿11289到50ml種子培養基(10g/L葡萄糖，24g/L可溶性澱粉，3g/L牛肉浸膏，5g/L蛋白腖，5g/L酵母提取物，20g/L碳酸鈣，pH7.2)中，220rpm，28。C培養36小時。取10ml種子發酵液接種入100ml二級發酵液(60g/L可溶性澱粉，10g/L乾酵母，10g/Lp-環糊精，2g/L碳酸鈣，pH6.8)中，220rpm，28。C培養72小時後，3800rpm離心10分鐘收集上清，用1MHCl調pH至2.0，用等體積乙酸乙酯萃取3次，合併有機相，無水硫酸鈉乾燥，減壓濃縮至幹，然後將濃縮物溶於1ml甲醇中，用HPLC(AngilentTM1100)方法檢測，HPLC的條件如表2。將發酵產物的乙酸乙酯提取液以同樣條件進行LC隱MS檢測(ThermoFisherLTQFleet)。表2HPLC條件和洗脫程序tableseeoriginaldocumentpage26實施例7替曲卡星A生物合成基因簇的應用——以聚酮合成酶合成基因中斷突變株為對照，在青褐色小單孢菌NRRL11289的發酵液中發現新的替曲卡星結構類似物在替曲卡星A生物合成基因簇中，fc"7，toj^4，fc"5是一組同順反子的編碼聚酮合成酶的基因。該基因失活的突變菌株由於喪失了合成替曲卡星大環骨架的能力而不再產生替曲卡星。該結果不僅可以證實我們發現的該段DNA區域的確與替曲卡星的生物合成相關，其發酵液中消失的組分(與野生型發酵液)同時也可以幫助我們重新發現並識別青褐色小單孢菌NRRL11289產生的一系列替曲卡星的結構類似物、衍生物和其生物合成過程中的副產物。本發明首先對粘粒pTL3001和pTL3002進行iVort/5amHI限制性內切酶酶切分別獲得6.0kb和4.5kb的基因片段，連接入質粒載體pANT841的相應酶切位點，得到重組質粒pTL3016和pTL3017;再分別從中酶切回收6.0kb歷w/III/5flAwHI和4.5kb5"wHI/印el片段，將其共同連入pOJ260載體的歷wc/IIMafll位點，構建&"7，fco42,&o^4和/c"5基因中斷突變株的重組質粒。將該質粒以實施例2所示方法導入替曲卡星A的產生菌青褐色小單孢菌NRRL11289中，按實施例5所示方法獲得基因中斷的雙交換突變菌株，按實施例4所示方法發酵、提取產物，HPLC分析發現^"7，^"2，/c"4和/c"5基因中斷的突變菌株的確不再產生替曲卡星，與此同時，與野生型發酵產物相比，該基因突變株中也同時消失了其它很多組分。因此，我們通過HPLC-MS進一步分析青褐色小單孢菌NRRL11289的發酵產物，發現其至少可以產生6個新的替曲卡星A結構類似物。以下根據本
發明內容提供基因和蛋白序列序列列表SEQUENCELISTING中國科學院上海有機化學研究所替曲卡星A(TetrocarcinA)生物合成基因簇Patentlnversion3.31108236DNA青褐色小單孢菌NRRL11289(M/cAWMowo;s/7orac/a/ceaNRRLl1289)1ccatggtcaggtagatggcggtgccgtcgaggttgaacgagtagccggtgggcacggtga60tcccgatcgscgggcttgctgscgccgscgtgctccstcttggcgstgsgccggggcsgcg120ccgsctccgacgacgaggtggacaggatcagcaggasctc'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,cgc33gcccttgctcgcgcgcctgctgscgccstcgttgs3C3ccscccg1860cgcgcacccg33cgccctggccsgctcgstctgctggccsggcgtcgggt1920'ctggt33cgatcsccsctgt3g3cstgtcggcctstggcc1980gc3tccgcsctggtsgggcgttC3CC3CC3ccsscgtcgg3sccctcggcgsgtcggtgc2040gggcggtggtgccggtccgggccgtcgscgggcggstcgtcgggctggtctccgtcggcs2100tcscc^cccgcgcgstcssccgtcgcctgctggcccaggcccccgtgctg3tcgccgccg2160ccsccccggcgctcgcggtcgcggcggccgggtcgtggctgctgsgccggcggctgcgcc2220ggcsgscccscggcctgggccccgcccsgstggcgaccgtgg3ccgccgggtggccctgg2280tcsscgscgaggcgcggcggctgctggggctcsccg3cgscgcggcggtggtggsccggc2340cggccggccaggtcgscctgccgccggccgtggcggagctgctgscctcggggcgggscg2400cgcscgscgagccggtcgtggcgggcg3ccgggtgctggtggtcssccsgcgcgcggcgc2460tgttcgsggggcsccgcctcggcsccgtgctgaccctgcgggsccsgscggsgctgcgcs2520cgctcsccsgcgsgctggsctcggtgcgggscg3gtcggccssccggctgcacsccgtgcsggcggtccggctggccsccgaiggscctggtcggcgcggtg3gg3ggcg3tggcggcgctcgtcctgctcgacttccggctgcccgscctcgccgccggcsgcgcggtgg3cgtgctggcgcgcsccgccgtgtcgctcggcgtgsccc3gttccgcgsc33gctgc3ccgctscgccgsggtggccgcccsgcscgsggtgg3ccgg3tcscgct3ccg33ggggctcgscgsgcsgsccgscgccggccggtccgcgtccgsggtggcccggcggtscctgg3gt3tctggtggccgccsccccgggccgccccgsggtggsgtsccgggcccgggtc3gctcscgttggccgggccggtggtggccgcgscccggsscgggccgsgg3gcttg3cgtggscctcggtgtcgccggggaccagcggcggggtgcagcggtgcacggggttgctggtgscgtcgggcsgctgcatgtcccggtcgscccggcccttgsccscgscg3tgtcgtsggtgttgggg33g33cagggcctccgscgcccscgcgcggccctgcttggtgscg3gggtgsccsccgcgccgtcggggscggtgtcggccgccgcgccgsggscgtgttcg3ggccg3gcatctcgcgttcgaaggcgsgcttggtcggc3tg3cggtggtgttgccgccgscg3ggtcgtsctggccgaicggcctccttgcgcgcgtgcscggcgsgcsgccccttgcggctg3tc3gcg3ttcgstggtcttcttgttgcsgtsg33gtcggcgtsctcgcccttctcctgggccccgacgttgcggstcgccgcgaggccgggcccggccgacgtgttcacgtcgggcggggaca'ggtacaacgccatcttgtccttgtcgtactcggccgggtagtgcgccttcaggtacgccgsgtgcgccttgttgsscgcgtscccgtgg3tcgcctcgtcggsgtsgccgcgctcgttgtcgsggatctccttcttcttcttgcccagcgtgtagccggcgaggatctgcgcggcgccgtgggtgggggcgsggstctcccgcsgccgctgsccgscgcgctgcsggcgcagsccc2580tgscgctggtggsgttgggccggsccg3cg2640cggtggcccsgcsgctcsccgaccgggtgg2700gcggcsgcgcgcggsgcsccccgtcgscct2760gcscgggctggsggtgtgccgggcgctgcg2820cgtgscgtcggcccgggscctggcggtggt2880ctscctgctcS3gccgttcscgttcgcggc2940gtsccgccgccaggtgctggccg3cggcg33000gttcgccsccctgcggggcccggctgcgcs3060gctgcgggcggtgctcggctcgctcggcgg3120ggggctggccggcstctcccgggtcsccgc3180cgsgcgggtggtgcgggcaccccgctscgg3240cccggcctgsccgcccccgcccgccggccc33003gg3cgctcttgaggtcacccatgagggcg3360cgcsgggtggtggtcttgccgccgttgsgg3420tgc3gs3cg3gggtctccttgsggcgttcg34803tggtgsgggtgsccggtttgctgcccggg35403tcgccaitgatgcggggggtgtcgtcgcgg3600gcgtcctcggcgstgtsctggccgstcscc3660scgccgccggcgsggtcctccsgggtggcc3720cggcgctgcsccccggsgsggstgccggcg3780ccctcctcgg3g3gggcggcgstggtgc3g3謹ccgwcsgggggtggtcggag3cgt3g3gg3900tcgcgcttgtcccsctcggcctcgccg3tg3960gtctcggtgtcgccg33gccggcgccgssc4020ttgacgtcggcgtacgcgtcgstcgcgtcg4080tggcccatgscgtcg33cgcgccggccttg41403cc3ccgcgtcgsccttggccsgg33gtcg4200cggcsccgcstg3tcgsggcC3cc3cgttc426033tcggatgtccttcccgsccggggtgssc4320sggaicctggstgcccstccgccggcsctcc4380tcgccgscggsggtcsgcsgcccggcc3t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cgcctggt106080tcgccctgaccccagggtctgcgtgtgcgscsgtggtccstgccgctgasC3cgt3tc3C106140ctcsgsgcttcgatcgccgtgtccg3cst3cascgggcggtcgcgttctacg33ggccgs106200ctgggcctscggccgctgcggtcgggccccsgcgccg3C3tcgccggcggcsgccgcgtc106260t3tggttccggcggcgtggcggcgctgsscgtctaccagtcggtc3ccgccgggssgsgc106320ccggcgscgctggcgsc3tggt3tgtcgscgacaitcgsgcgg3tcgtcgscgsgctcgcc106380tcggccggcgtcgggttcstccggtscgsccagctcgscc3cg3cgccsgagg33tcacc106440gcccgggccggcggtggscgt3tcgcctggttccaggatccggscggcaacaccttcgcc106500gtcgs3tccgacgtctgscgccccgsgcc3gggccccggcggcgtcggsccgccttgctt106560cgg3tgtsctaitccgggstgtggsgscgttgsccc3cgggC3ggtgctgg106620cccggttcggccacgccctgtccg3cccc3cccgggcccgcctgctgctggcgctgcgcg1066803cggccccggctacccggcgcsgctcgccgacctgctcggc3cc3cccggc3g33cctgt106740CC33CC3CCtgscctgcctgcgcggctgcggcctcgtcgtggccgcccccg33ggccgcc106,gcacccgctacgsgctcgccgscccgcgcctcgcccscgccctcggcgscctgctcggcc106860tcgtgctcgccgtcgaccccgccgcctgccccgacgccgcC3cgs3gggttgctgctgat106920ggccctgcccctggtccsggccccggccggcccgacgccggcccgccgggc3gtcctcgc106980ccggcgggtscgcctgctggtcgccgcc3cC3tC3CCt3C33cgtcgtcgsggcggtcgt107040ggccstcsgcgccggc3cc3tcgcctcgtccaccgcgctgstcggcttcggcctcgsctc107100cgccstcg3ggtctcctccgccgccgccgtggcctggcsgttcgccggccgcgsccccgs107160ggcccgggsgsggaccgccctgcgcgtcstcgcggtctcgttcttcgccctcgccgcgts107220cgtcsccgtcgagtccgtccgcgccctgctcggcggcgccgscgccgsccsttcccccgt107280cggcctcgtcctcgccgcgctgtccctggccgtcstgcccggsctgtcgt3cgcccsgcg107340ccgcgccggccgggaactcggctcccgcsccgcggtggccgsctccsggcsgsccctgct107400ctgcgcctacctgtcggcggtcctgctcgtcggcctcggcctc33c3gcctgttcggctg107460gtcctgggccgscccgctcgccgcgctcgtcstcgccgccgtcgccgtcs3gg33ggccg107520cgaiggcctggcgcggcgscgcctgctgcgcggccccggccgccggtacgcccsccgccgc107580csccccgggcggggsggscg3ctgcgg3tgccagcctggctgctcctgctgctccggcgs107640cgsccggtgagcsggcccggccctgcttcccgctgsgctgcctg3gcgcgggccgcggsc107700ctggcgcsgc3gtc3gtggcggctgtcccggcgg3gg33gcccg3C3gcsgttgccagaa107760ctcgtgcgggtgctcgstcgccggcscgtgcccgcstcggccgsgcscgtgcsgccggsc107820stcggccsggtgttcgagcaggggcagggtcgacgtcgcgsgcggggtgscccggtcatc107880ggcgccgtgccgggcgcgcggstcgcggccsgcgtctgcgtcgsgagggt107940gsggtcgtcggcccsgcgtgccctgggtggcggccgcscc108000cgcccgcstcgcggcggc3cgggcctcgscggccgcgtcggtcscgsgcgcctggtcgsg108060gscgsgtcgsctcsgcstgtcccgggccccgggcgggccggcgggggcggcccsgatcgc108120gtcgsggtcggcggscsgcggcgccccgggggcgcccstcgtcg3g3ccgcc3cg3C3cg108180gctgscctgctcagggcgcgcggccgcc33cgccsgcgcg3cggcgccgc■ccatgg108236<210〉2370PRT〈213〉Wc葡o應;固cvWceaNRRL112891VallieValAlaCysAlaThrGinProAlaProGlyHisPheLeuLeu151015MetThrGlyLeuLeuArgAlaLeuArgAspArgGlyHisGinValThr202530ValLeuSerSerProAlaPheGlyGlyPheValAlaSerArgGlyPhe354045AlaPheArgGlyValGlySerProTrpLeuAlaAlaGinArgAlaPro505560LeuProPheThrValGlyGluSerProThrAlaGinSerThrAspHis65707580SerPheAlaGluAlaAlalieArgAspSerPheArgAlaAlaAlaGly.85ValLeuAspAspLeuSerProAspLeu100105PheGlyValThrPheAlaAlaGluArg115120lieGlyPheLeuArgThrGly90LeuLeuArgGluValGly130GlySerLeuLeuLeu145ProAspAspLeuArg135ArgLeuArgAla150AlaLeuSerArgAlaGlyAspArglie95ProThrGlu110AlaValAlaThr125MetAlaAspGlyLeu140GlyLeuProAsp165ProProSerPheGluGinValPro180AspProGlyHisGluAla155ArgArgTyrValGin170AlaLeuThrThrValAspPro195ValThrLeuGlyThrLeu210LeuAlaGluLeuAla225AspArgAlaAlaGin185AlaProHisAlaAlaThr160ThrThr175ArgAlaAla200AsnArgLysGluMet190ProArgLeuLeu205LeuThrArgValGinProPheAla260GlyGlu245AspGlyGlyPheGlyValAsnArgLysGluLeu215220ArglieProValAspCysValLeuAlaAlaGly230235240lieAlaAlaHisAlaProAlaHisValGinVal250255AlaAlaSerCysThrAlaLeuLeuGlyArglieCysHis275ValThrValLeuLeuPro290GluArgMetArgVallieGlyAlaGlyPro295GlySer280TyrLeu265lieLeuHisAlaThr270ValHisGlyAsnVal285AlaAspGinGluTrpAsnAla300ArgArgValGlyTrpAspGlu305310315320LeuGlyAspGlyAlaLeuAlaAlaAlaValGluGluMetHisSerPro325330335ProProLeuArgAlaAlaArgLeuLeuAlaAlaGluLeuGlyGlyMet340345350ProSerProAspGinValAlaAspLeuLeuThrAlaGlulieGlyAla355360365ThrHis370〈210〉3186〈212>PRT〈213>Wc_rcwo/3os/arac力s7ceaNRRL11289〈400〉1MetArgArg1SerGluLeuArgGlyVal35ValAspAla50ValSerLeu65ThrSerTrpGlyArg5ProAla20LeuGlyGlyThrAspProSerArglieGlyMetValProHisProPro70LeuValProAla25PheAlaThr40ValGlyLeu55LeuValAlaArgArgGlyGluSerArgValGluProVal1015SerlieAspProLeuGluPhe30GlyValAlaAlaValThrGly45LeuValAsnSerPheThrSer60PheCysValAlaHisThrSer7580GluArgHisCyslieCysPhe859095LeuAlaAlaAspGinGinGluGinGlyLeuArgLeuAlaGlyArgGly100105110ValAspLysPheArgAspValAspTrpSerProSerProSerGlyLeu115120125ProValLeuAspGlyAlaLeuAlaTrpLeuGluCysAlaValGluAla130135140GluHisProAlaGlyAspHisVallieValValAlaArgValHisHis145150155160LeuAlaArgSerGlyAspAspAlaArgThrGluProLeuLeuPheTyr165170175ArgGlyArgTrpThrArgLeuProGlyAla1801854109〈212〉PRT<213〉Wcro/Bcwosjoorac力a7ceaNRRL112891ValGlyArgProGlySerPheAsn15lielieProValArgSerArgThr20lieArgTyrLeuAlaGluLeuGly3540ValProLeuProProLeuGluArg5055ProAlaLeuAlaProAlaAlaArg1015GinAsnThr.lieCysProLeuLeu2530TyrAlaCysTrpThrMetSerGly45SerGinPheArgAspGluVallie60GluValGlyProProProGlyHisProGluArgLeuSerThrAlaPro65707580ProThrArgValGluArgArgLeuTrpArgGinLeuArgLysAsnArg859095ThrAlaArgSerTrpSerArgPheAlaPhePheArgGly100105〈210〉5〈211>146〈212〉PRT〈213〉WcrcwKwasporacA37ceaNRRL11289〈400〉1MetThrArgSerAlaThrAsnArgArgAlaLysThrLysGinArgArg151015AspHisArgValGlyProLeuArgPheAsnAspAspGluLeuArglie202530ValGinMetAlaAlaAspLysAlaGlyLeuSerLeuGlyAlaTyrVal354045ThrAlaAlaAlaValArgSerAlaArgThrGluLeuHisLeuGlyLeu505560ProGluCysGluSerProThrGluLeuHisAsplieArgThrlieLeu65、707580ThrLeuLeuArgTrpArgLeuAspMetAlaGlyGlyAspSerArgArg859095AlaAspLeuLeuAsnAspLeuLeuThrGluAlalieAsnAlaThrLeu100105110HisGinGinAlaGluAlaThrAlaGinAlaGlyAlaProAlaSerArg115120125ProAlaProProHisGlyProAspSerAlaGluProProProProPro130135140ProGly145<210〉61263〈212〉PRT〈213〉Wcrawcwos^orac力a7ceaNRRL11289〈400〉1MetAlaAlaGlyHisGlyArgArgArgGinGinThrGlyGlyProAla151015GinArgProAlaHisArgGlyHisGinArgAspProAlaProAlaGly202530ArgGlyAsnGlyThrGlyArgSerAlaGlyLeuAlaProArgThrAla354045AlaArgAlaArgGinArgArgAlaAlaAlaProAlaSerArgLeuAla505560GlyArgSerArgLeuProGlyArgThrLeuArgGlyAspAlaProAla65707580AlaProProThrArgSerProAsnSerTrpSerAlaAla''ArgValGly859095TrpSerSerTrpSerLeuAspProProAlaThrGlyAlaGlyArgAla100105110ArgProSerProGlyLysThrArgProArgProValGlyProLeuAla115120125AlaGlyHisProAspGinGlyAspArgArgLeuValArgProArgSer130135140ArgArgProArgGinArgSerGlyArgSerThrAlaAlaThrGlyArg145150155160ArgAlaAlaGlyValGluProGlyAlaPheGinAspProThrAlaArg165170175ThrArgArgAlaArgAlaAsplieAspThrAlaSerAlaThrThrAsp180185190HisAspAlaGlyThrAsnAlaThrAlaAlaProProArgArgProGly195200205SerSerAlaThrArgAlaGlyArgArgHisGlyGluHisSerTrpSer210215220ArgHisArgAlaProHisArgArgProProProLeuArgGluHisVal225230235240SerSerLeuSerValAspAlaCysArgGlulieAlaGlyAlaValAla245250255GlyGinArgAlaAlaArgArgArgThrProAlaProAlaProThrPro260265270ProGlyThrGlyHisGluProGinHisArgAlaProlieAsnAlaGly275280285AlaGlyCysGlyGlyProAlaAlaGlyValAlaAlaProArgProPro290295300ThrProAspLeuThrArgValGin305310〈210〉7267PRT1LeuArgTyrGlulieLeuGlyProValArglieThrAlaGlyLysAsp151015ThrProSerValGlyThrHisLysMetGluValLeuLeuArgThrLeu202530LeulieArgAsnGlyHislieLeuSerLeuAspGinLeuAlaThrGlu354045LeuTrpGlyAspLysProProlieArgAlaArgAlaSerlieHisVal505560TyrValSerGinLeuArgLysValLeuAsnArgPheSerArgAsnThr65707580GlyVallieThrThrArgAlaProGlyTyrlieLeuGluLeuGlyGly859095AspGluLeuAspLeuGluLeuPheLeuAlaLeuValGluLysAlaArg100105110LeuGinArgSerValHisArgHisAspLeuAlaValGluThrLeuThr115120125GluAlaLeuArgTyrTrpArgGluProValGinAlaSerSerTyrGlu130135140GlyProlielieArgGluPheAlaAsnTrpAlaGluGluLeuArgVal145150155160GluCysThrGluLeuLeuAlaArgSerLeuLeuAlaSerAspGinSer165170175SerLysAlaValArglieLeuTyrGlyLeulieAlaGluPheProLeu180185190ArgGluLysLeuTyrAlaPheLeuMetGluAlaLeuSerGinSerGly195200205ArgArgAlaAspAlaLeuGluValTyrGinThrAlaArgArgGinlie210215220ArgGluGluLeuGlyLeuGluProCysArgPheLeuArgGluThrGin225230235240GlulielieLeuLysAspAsnLeuAspGluLeuSerPheArgArgAla245250255ArgHisGluGinArglieGinProTyrAlaVal260265<210〉8〈211〉197PRT臉層o"卿orac力s7ceaNRRL11289〈400>1MetAspPhe1ThrGinHisSerGluLeu35AsnTyrSer50ThrLeuPro65AlaMetAspThrGluThrSerliePro5Ser20LeuAspArgArgGlyGinGinValValSerArgProGlyValAla85Gin70ValLys55SerGly40AsnSer25GinThrLysLeuAspLeuArgGlyAlaTyrArglieThrVal1015PhePheGluAlaTrpArgPhe30ArgPheGlulieArgGinVal45LeuArgGlylieHisGlyThr60ValThrCysValArgGlyAla7580ValGlySerProThrPheGly9095LysPheAspValThrPheGinAspAlaThrSerGlylieGlyValTyr100105110LeuThrGluGlylieGlyHisAlaPheLeuAlaLeuThrAspAspThr115120125CysMetSerTyrLeuCysGlyAlaGluTyrValProGlyThrMetlie130135140AspValAlaAlaLeuAspProAlaLeuGlylieProTrpLysLeuAsp145150155160GlyProProValMetSerAspLysAspAlaAlaAlaProThrLeuAla165170175GluAlaAlaGluSerGlyLeuLeuProThrTyrGluGinValLeuAla180185190ThrThrArgSerAla1959〈211>332PRTWcro/wwos/wrac力a7ceaNRRL112891MetGluHisMetGlyAsnThrArgPro15CysAlaAsplieAlaTrpArgArgThr2025ProLeulieThrLeuThrAlalieAla3540AlaHisPheThrGluArgPheGlyGlylieArgMetGlyVallieGly1015LeuProAlaMetGluAsnGlu30SerArgHisArgAspArgAla45ValProValGluGlyTyrGlu50AlaLeuLeuGluGin65AlaValLeuHis55AsplieAspAlaAspAsplieAspAlaVal7075GluTrplieGluArgAlaAlaGluTrplieGluArg8590HisValLeuAlaGluLysProLeuThrThr100ArgValAlaAla60TyrValProLeuArgAlaHisLeuPhe115PheMetPheLeuHisHis130AlaAspGlyVallie145lieProProLysGlyGlyArgPheAlaLeu180GlyGly150GinAspProAspLeuGlu120HisGinHisGin135GluValArgSerThrThrAspArg105HisArgArgValArgLeuPro80ArgAlaGlyLys95LysGinAlaGlu110LeuValGluAsn125AlaAspMetLeuVal140AlaSerSerPro165LeuGlyAsplielieAspGlyPhe155ArgTyrGinAlaAsp170TyrProlieArgLeu195PheArgAspValVal185ValAlaGlyAlaGluArg210AspGinGlyValThr225ThrAsnThrTyrGin200ValGlyGlySerVal215AlaGinLeuThrPhe230PheArgGlySerPheThr160ValGly175AlaAlaGly190ValPheArgHis205LeuLeuAlaThrAla220MetGluHisPheThr260HisGlu245ProProAlaThrGly235Gly八rgLeuTrpArgValArgGinAspHisPheGluGinPheValLeuProAlaAspAspGinPheHis265ValThr250GinProVallieTyr270AspSerTyr240LeuAsn255lieGlu275280AlaLyslieValArgAlaPheAlaGinAla290295ProProGluTrpThrGluGlySerLeuAla305310AlaVallieAlaValAlaLeuLysPhePro325330285ValLeuAlaGlySerAla300HisAlaSerLeuValAsp315320PheSer10〈211〉392〈212>PRT〈213〉臉層o願poracvWceaNRRL112891MetArgValLeuPheThrSerAlaThrPheArgSerHisLeuPhePro151015LeuValProLeuAlaTrpAlaLeuArgAlaAlaGlyHisAspValArg202530ValAlaValGinProProLeuValArgAspValLeuGlyAlaGlyLeu354045ProAlalieGluAlaGlyAlaGlyProAspPheMetlieGluLeuLys505560LysAlaLeuAlaGlyGlyLeuGluGlyProGlyGlyThrThrProSer65707580lieGluGinlieValValProHisValArglieAlaGluAlaPheAla859095AlaAspLeuValProPheAlaArgArgTrpSerProAspLeuValVal100105110AlaAspProAlaAlaPheValAlaProValValAlaArgAlaValGly115120LeuValLeuHisThrTrpAlaProLeuValLeuHisThr130135AlaAspLeuValThrGluSer145150LeuLeuAlaPheLeuAspArg165AlaAspLeuVallieAspPro180MetAlaSerArgHisAlaThr195ProSerTrpLeuGluTrpCysGlyProValArgMetGin155ProPro140AsnArg125AspGinLeuTrpProTrpLeuGlyProAspVal170ProAspGluLeuLeu185TyrValProTyrLeuThr210lieSer225ThrProArg200GluProAlaGlyLysGlu160AspTyr175AlalieArg190GlySerAlaThr230ValGluAlaTrpGlyThrLeuArglie245ValAlaAlaLeuGlyLyslieAsp260AspAsnValArgValValAsp275AspAlaLeulieAsp215SerAspPheMetAsn205ProArgValCysArg220SerGluValLeuAla250ArgGlyLeuLeu265LeuProLeuSerGly235AspMetAspValAspGlyLeuArg240GluVal255ProArgThrCys290AlaValAlaSerGly305GinProLeuGlyAla325Trp280GinGlyGlyProAsn295ProGinLeuValAla270MetLeuLeuPro285.ThrValLeuAlaVal310GluLeuLeuGly300ProGinlieThrAla330Val315SerGlyAlaGlySerAla320LeuSer335LeuThrProAspGluValThrAlaGluSerlieGluLysThrValSer340345350GluLeuLeuAspGlySerSerValArgAlaAlaAlaGinAlaLeuAla355360365GluArgAsnAlaAlaArgProAspAlaThrGinLeuValProAlaLeu370375380GinAlaLeuAlaAspSerAlaArg385390〈210〉11263〈212〉PRTWcr咖o/305jDoracvWcesNRRL112891ValGlyAsnAlalieGluAsnAlaLeuPheAspGluArgLeuAlaGin151015PheGinGinTrpGinLysThrProTrpGlyArgLeuArgTyrSerVal202530ValGluAlaAsnValAlaArgHisLeuGlyAspArgProLeuArgVal354045LeuAspValAlaGlyGlyAsnGlyArgAspAlaValProlieAlaAla505560ArgGlyHisHisValThrValLeuAspSerAlaProValSerLeuAla65707580MetAlaGinArgLeuAlaAlaAspGluGlyValAlaGluArglieGlu859095lieArgGluGlyAspAlaHisAspValProGluLeuPheAlaGlyGinformulaseeoriginaldocumentpage89lieAsnValThrGinProSerlieGlyAlaGluGluLeuAlaAla15ArgThrMet1lieThrAlaThr5PheAspSerLysVal20GluGluPheGluGlyLeuPhe35LeuPheLeuAsnGly10LeuGlySerGlyAsnVal50GluLeuLeuGlylie65GlyPheValAlaTrp25AlaArgHisLeuGly40AlaThrSerAlaSer55GlyProGlyAspAsp70AlaSerAlaValAsn85ValPheCysAsplieAspGluHis100ValLeuAlaAlaLeuThrProHis115120GlyTyrProGlyAspValLeuGOValValMetPro75AlaAlaGlyGlyPro30ValProAlaGlu45PheLeuAlaValHis105ThrTyrGly130ArgGlu145SerValArgGlySerLeuGlylieAlaArgAspAspValAsp135lieGlu'AspAlaVal90LeuAsnProSerArgAlaValLysLeu150MetCysGly.ThrGin165ArgLysVallielieAla155GlySerAsn80ArgPro95ValGluAsp110MetValLeuHis125AlaLeuCysAlaAla140ValSerlieSer180AspProAlaValTyrAlaArg195HisGlyLeuAspAspArg210Thr185GinPhe170ThrGlyAspGlyAspAspArgAlaArgAlaSer160LeuGlylieTrp175ValLeuSer215Ala200SerPheThrThfAla220Gly190ArgLeuSerTyr205ThrLysSerGinHis225GlyValTrpAspAlaGlyPheAsnAlaLeuGlyAla305ThrHis290lieGly275ArgArgTyrThrAspThrSerLeuLeuAlaGin370Pro355GinTrpSerPheGin230lieThrAlaAla245ValGluArgArg260GlyPheSerGlySerThrHisTyr295AspGlyValSer310ArgTyrTyrPro325ValLeuProVal340AlaHisGinSerValLeuAlaAla375lieGlulieGlyArgAla265lieArg280PheAsplie235ThrVal250lieGlyLeuProGlyArgArgLeuTyrCysValGluAspLeuHisThrLeu360ValAsp345LeuGluLeuLeu315ArgVal330AlaValAspAspAlaArgGinLeuGinArgProPro285ArgPhe300AlaAsnArgArgSerAspGluVal365Leu380GlyLys255TyrAsp270LeuProAspSerGlylieTyrGly335ThrSer350AspLeuVal240LeuLysGluGinTyr320AlaLeulie13<211〉380PRT〈213>J/z.oro/z7o/jasoraa7ceaNRRL11289〈400>1MetValAspGluSerLysValSerArgLeuAspSerLeuThrGlyAla15ArgPhelieAlaAlaAlaSerVal20ArgliePheGinProThrGlyPhe35SerAlaThrSerGlyThr50GlyPhelieLeuThr65PheTyrArgArg10PheliePheHisAla25AspSerAspPhePro40AlaValSerPhe15AlaSerlie30LeuThrliePhe45PheValLeuSerArg85PheLeuLeuSerLeuValValTyr100LeuAsnlieThrMetAlaValSerPhePhe5560TrpSerAlaArgLysTyrAspThrAlaArgGlu707580PhePheLysliePheProAsnHislieValThr9095ThrLeuAlaGlyAlaLeuLeuProAlaLeu115ProTyrPhelieSerPhe130LeuLeuPheTyrAla145lieProValArgAla105LeuHisAlaTrpLeu120HisValThrTrpAla110ValProLysMet125LeuSerCysGluArg165liePheValValProLeuPheAla180LeuLeuThrAspAsnHisValThrTrpSer135140AlaPheProLeuLeuTyrLysLeuAlaGinArg150155160LeuTrpTrpAlaAlaGlyGlyValLeuAlaAla170175LeuLeuProThrGluProArgMetMetLeu195TrpPheValTyrLys185GinThrPheSerlie215AlaAsn200PheProProValGinTyr210ValLeuGlylieLeuMetAlaArglieValLeuAlaGlyArgArg220AlaGlu205LeuGlu190ProlieLeuLeuAspPheTrplie225230AsnLeuArgProLeuProAlaLeuAla245LeuAlaSerPheValProPheLeu260AlaLeulielielie305Arg235ValValValAla250SerLeuAsnAlaValGlyVal275ProTyr265AlaValAla240CysTyrVal255ValThrlie270GluThrAlaGlyArg290SerPheThrPheLeuAla295AlaPheTyrMetValHis310GinGinValGlyTyrArgHisPhe325GlyTrplieLeuLeuMetPhe340AlaValGluArgProAlaValAlaSerAla280285SerArgProMetlieTrpLeuGlyGlu300VallieAlaMetMet315LeuAsnThrThr330ThrLeuValGlyLeuTyrVal355ArgLys370lie345MetMetArgArgArgProAlaVal375Pro360GluThrThrValArgPhe365Ser380LeuTyrGly320GinGlylie335GlyTrpLeu350AlaArgAla〈210>14395<212〉PRT<213〉奶'cro邁o"os/orac力a7ceaNRRL11289<400〉1ValLysGlylieValLeuAlaGlyGlySerGlyThrArgLeuHisPro151015LeuThrValAlaPheSerLysGinLeuLeuProLeuTyr20TyrProLeuSerMetlieTyr35PheLeulielieSerThr50LeuGlyThrGlyAla65GinArgProAlaLeu25LeuMetLeuGlyThr40AlaAspLeuProPro55LeuGlyLeuArgGluLeuGlyLeuArgPhe7075lieAlaGluAlaPheArgValGlyProAsp100LeuGly85ProValSerLeuSerProGin115GlyCysAlaLeuPhe130ValValGluLysAsp145ProAlaProGlyLeuGlyGlyLeu120Thrlie105AlaPhe90LeuGly45PheTyrlieGlyAlaLeu60SerAsp30ValArgAlaArgSerAlaAspProHis135AlaGluGlyArgLeu150SerSerGlulieGlyAspAsnArgGlyMetValAlaAspAla125Arglie110GluProArg165ValGluLeuAlaPro140ValGlylieGlu155ThrGlyLeuTyrVal180GlulieThrAspVal170ArglieArgProGlyGluLeu195ArgLeuHisSerArgAla210GlyThrTyrA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luLeuThrLeuLeuAlaProLeuVal3105311031153120ValProGluGinGlyGlyValArgLeuGinLeuValValAlaAlaGlu312531303135GluAsnGlyThrGinGinLeuThrValHisAlaArgProGluSerGlu314031453150AspAspAspAlaAspTrpThrLeuHisAlaSerGlyThrLeuThrGly315531603165ThrAlaProProAlaAlaGluGlyLeuThrAlaTrpProProProGly317031753180AlaGluArgLeuAspLeuAspAlaValTyrAspArgPheLeuAlaLys3185319031953200GlyGinLeuTyrGlyProAlaPheGinGlyLeuArgAlaAlaTrpArg320532103215HisGlyAspGluUuCysAlaGluValThrLeuProGluAspValAsp322032253230ValGluGlyPheGlyValHisProAlaUuLeuAspAlaAlaLeuHis323532403245ThrLeuMetAlaAspProAlaArgAlaArgGluAlaAlaGlySerAla325032553260AlaLeuLeuProPheSerTrpThrGlyLeuSerLeuGluAlaThrVal3265327032753280GlyArgAlaLeuArgValArglieArgSerSerAlaAspGinAlaVal328532903295SerLeuAspLeuAlaAspAlaGluGlyArgProAlaGlyArglieGly330033053310ArgProLeuArgGlyAspLeuGlyAlaAlaAlaArg33203325ThrLeuArgTrpArgTrpValGluAlaThrAlaGin33353340GinProLeuValPheValGlyAlaThrAlaValAsp335033553360ProArgHisAlaThrLeuAspAspLeuArgAlaAla336533703375AlaLeuArgMet3315AspArgGinPro3330AlaAlaProAla3345GinValSerAlaLeuAlaGlyGlyAlaProValProSerValValValValSerValPro338033853390AspGlyAlaGlyAlaAspProAlaAlaGinAlaHisLeuAlaThrHis339534003405ArgThrLeuHisThrValGinGluTrpLeuAlaAspAspThrPheAla341034153420GlySerSerLeuAlaLeuValThrArgGlyAlaThrGlylieThrGlu3425343034353440GinGluProValProAspLeuAlaAlaAlaAlaValTrpGlyLeuVal344534503455ArgSerAlaGinAlaGluAsnProGlyArgPheGinLeuValAspVal346034653470AspAlaThrAlaThrGluGinAlaValAlaAlaVallieAlaSerGly347534803485GluProGinSerAlaValArgAspGlyArgAlaTyrValProArgLeu349034953500AlaTrpTrpSerAlaThrAspAspAlaSerGlyGlyAlaAspAlaArg3505351035153520ProAlaLeuAlaAlaAlaPheArgProGlyGlyThrValLeulieThr352535303535GlyGlyThrGlyThrLeuGlyGlyLeuValAlaArgHisLeuValThr354035453550AlaHisArgValGlyHisLeuValLeuValSerArgGlyGlyLeuAsp355535603565AlaProGlyAlaProGluLeuAlaThrGluLeuSerAlaLeuGlyAla357035753580SerValThrValAlaAlaCysAspThrThrAspArgAlaAlaLeuThr3585359035953600GlyValLeuSerAlalieProGlyGluHisProLeuThrGlyValVal360536103615HisAlaAlaGlyThrLeuAspAspAlaThrValProSerLeuThrPro362036253630GluArgLeuAspThrValLeuGlyProLysValAspAlaAlaTrpAsn363536403645LeuHisGluLeuThrArgAspLeuAspLeuSerAlaPheValLeuPhe365036553660SerSerAlaAlaGlyValLeuGlyAlaProGlyGinAlaAsnTyrAla3665367036753680AlaAlaAsnSerPheLeuAspGlyLeuAlaArgHisArgHisAlaLeu368536903695GlyLeuProAlaValSerValAlaTrpGlyProTrpGinGinLysSer370037053710AlaLeuThrGlyGlyLeuAspGluGlyArgHisGlyGlyAlaAlaArg371537203725ArgGlyLeuValProLeuProThrAspGluAlaLeuAlaCysPheAsp373037353740GlyValLeuAspAlaAspLeuProThrValValValAlaArgLeuHis3745375037553760LeuArgGluLeuArgAlaGinAlaValAlaAspAlaLeuProProVal376537703775LeuArgAspLeuValArgValProArgArgArgAlaGluSerAlaGlu378037853790ProAspLeuAlaAlaArgLeuValGlyArgAspAspAspGluGinArg379538003805AlaValThrValGluValLeuArgGlyHisLeuAlaAlaValLeuGly381038153820HisGlySerProGlyAsplieAlaThrAspArgProPheGinAspLeu3825383038353840GlyPheAspSerLeuThrAlaLeuGluLeuArgAsnArgLeuArgArg384538503855AlaThrGlyLeuProLeuProAlaThrLeuValPheAspTyrProThr386038653870ValGlyAlaLeuAlaAspHisValArgGinArgLeuValProProGin387538803885ProSerProAlaGluAlaValLeuGluHisLeuAspArgLeuGluAla389038953900AlaLeuAlaAlaLeuProGlyAspAlaThrArgAspLeulieAspHis3905391039153920ArgLeuArgLeuLeuAlaLeuGlyProAspProValAspGluAlaGlu392539303935GinArgAlaAlaGluGlyAlaMetlieGlyAlaAlaSerAlaAspGlu394039453950LeuMetAspLeulieAspArgGluPheArgGinAla39553960〈210>36289〈212〉PRT〈213〉i^'cro邁o/3aporac力a7ceaNRRL11289〈400〉1MetThrAlaAsnSerlieThrAlaGluAlaAlaGlyThrLeuThrLeu151015GlyGlyAspLeuProValArgArgLeuGlyPheGlyAlaMetArgLeuAlaPheGly35Ala20GlySerValArgArgSer50TyrGlyPheGly65SerProValAspSerAspAsp25AspProGluThrAla40ValAsnHislieGly55HisSerHisGlu30AlaThrValLeu45ThrAlaGlyPheTyrlieGluGlyArgGinLeu115AspLeuVal130ValSer145GlyLeuProLeu70AspLeuValAla85GlyValValProThr100ValGluGluAsplieAla90AlaGlu105ArgArgVal75ThrAsp60lieArgGinLeuValTyrLeuArgGlyArglieGlyAspLeu120ValGlyGlyAlaThr135PheAlaAlaLeuLysLysGlyAlaLysProAlaLeu80ValGlyProVal95GinLeuAsp110ValAspArgLeu125AlaProGlyGlyArg150LeuGlyValAla140GinLeuArgAla155ValAspAlaGluAlaGluAlaGin180HisValHisPhe195AspGlylie210Prolie225ThrThrHisLeuGlyValSerAsn165170AlalieAlaProValAlaAlaValGin185GluLeuValAlaHisArgGlyAspTyrAspAlaTyrValSer200PhePheProVal230AlaPro215LeuLysAlaValGin205GlyAsn190CysGlyAspArgGinValAlaLeuAlaTrpLeuLeuAlaValSerAla235LeuGly220GluArgHisGluGlu160GinLeu175GinPheAlaLysGlyAlaGlyAla240ProAla245250255lieLeuAlalieProGlyThrSerValLeuAspHisLeuThrGluAsn260265270lieAlaAlaAlaGlyLeuAlaLeuThrAspGluAspMetAlaAlaLeu275280285SerGlu29037<211〉490PRT〈213〉#/cro/zw/asporac/a7ceaNRRL11289〈400〉1MetLeuArgLysArgSerThrGluProArgAlaAlaGlyGlyAspAla151015ProLeuProLysGluLeuGinLyslieAlaValValValLeuValGly202530LeuLeuLeuMetGinLeuAspGlyThrMetValGlylieAlaLeuAsn354045ThrLeuSerGlyGluLeuSerValSerValSerThrLeuGinTrpVal505560ValThrGlyTyrLeuLeuAlaLeuMetValGlyMetProlieAlaGly65707580TrpAlaAlaAspArgPheGlyThrArgArgMetTrpThrValSerLeu859095ValValPheLeuValGlySerValLeuCysGlylieAlaValAsnlie100105110GluThrLeuliePheAlaArgValValGinGlyLeuGly120125MetLeuMetArgValAlaMetVal130HisArg145ProThrLeu115ProValGlyGinAlaMetLeuMetArgVal135140AlaArgLeuValGlyLeuMetAlaliePro150155GlyProValValGlyGlyVallieGlyGlyMetGlyAlaGluValLeuPro165TrpArgTrpMetPheLeulieAsn180GlyArgAsnLeuVal170ProlieGlyLeuPheLeuAla195AlaLeuAspValLeuGly210ValValPheGlyLeu225LeuValValAlalie185AsnPheLysGluGlyVallieGly160ValAspAspPheSer175AlaPhePro200ValValLeuLeuVal215ArgAlaAlaAlalie190GluAlaArgAla205GlyLeuValAlaSer230LeuValThrGlyPro220GlyLeuGlyPro245lieLeuHisAlaAlaArgProAsn260TyrArgAsnPheLeuPheLys275AlaAlaLeuThrMetGly290GinValHisGlyGlu305PheGlyValGlySer325Gly235ValValLeulieAla250lieGluAlaLeuVal265AlaAlaSerAlaAla280GlylieValGinAla295ProMetGlyAlaSer310AlaLeuThrSerVal330Gly315ValAspPro240GlyPhe255SerMetArg270LeuThrLeuLeu285ProLeuPheLeuGin300LeuLeuLeuValGly320LeuSerArgValPhe335AsnArgLeuGlyAlaArgLeuValGlyThrValGlyLeuAlaLeuThr340345350PheThrGlyThrValAlaPheThrGinPheTyrAlaSerThrGlyArg355360365ValPhelieValLeuAlaMetLeuLeuSerGlyValGlyLeuAlaMet370375380ValThrLeuThrMetSerThrAlaLeuTyrValGlyLeuProProGin385390395400GinlieAlaArgAlaThrGlyAlaSerArglieValGinGinLeuGly405410415LeuSerThrGlyThrAlaVallieSerLeuValLeuGinlieGinLeu420425430ThrLysGinThrAlaGlySerAspLeuAspSerLeuAlaAsnAlaTyr435440445HisHisAlaPheTrpTrpSerAlaGlyPheLeuAlaLeuAlalieVal450455460ProAlaLeuLeuLeuProGlyArglieProAlaThrProGlyThrGin465470475480AspLysLysValAlaGinAlaGinProAla485490權利要求1.一種抗生素——替曲卡星A的生物合成基因簇，其在於編碼替曲卡星A生物合成所涉及的36個基因，具體為1)替曲卡星A非重複使用的I型聚酮合成酶基因，即tcaA1，tcaA2，tcaA3，tcaA4，tcaA5共5個基因tcaA1位於基因簇核苷酸序列第25588-44580個鹼基處，長度為18993個鹼基對，編碼聚酮合成酶，6330個胺基酸；tcaA2位於基因簇核苷酸序列第44582-65605個鹼基處，長度為21024個鹼基對，編碼聚酮合成酶，7007個胺基酸；tcaA3位於基因簇核苷酸序列第89806-101700個鹼基處，長度為11895個鹼基對，編碼聚酮合成酶，3964個胺基酸；tcaA4位於基因簇核苷酸序列第65565-71087個鹼基處，長度為5523個鹼基對，編碼聚酮合成酶，1840個胺基酸；tcaA5位於基因簇核苷酸序列第71162-75775個鹼基處，長度為4614個鹼基對，編碼聚酮合成酶，1537個胺基酸；2)替曲卡星A特殊三碳單元生物合成基因，即tcaD1，tcaD2，tcaD3，tcaD4共4個基因tcaD1位於基因簇核苷酸序列第78352-80253個鹼基處，長度為1902個鹼基對，編碼甲氧基-丙二醯基載體蛋白合成酶，633個胺基酸；tcaD2位於基因簇核苷酸序列第80250-80477個鹼基處，長度為228個鹼基對，編碼獨立存在的醯基載體蛋白，75個胺基酸；tcaD3位於基因簇核苷酸序列第80474-82324個鹼基處，長度為1851個鹼基對，N端結構域編碼丙酮酸/2-氧代戊二酸脫氫酶，C端結構域編碼水解酶/乙醯基轉移酶，616個胺基酸；tcaD4位於基因簇核苷酸序列第77303-78355個鹼基處，長度為1053個鹼基對，編碼III型聚酮合成酶，350個胺基酸；3)替曲卡星A脫氧糖阿米西糖和毛地黃毒糖以及硝基脫氧糖Tetronitrose的生物合成基因，即tcaB1，tcaB2，tcaB3，tcaB4，tcaB5，tcaB6，tcaB7，tcaB8，tcaB9，tcaB10，tcaB11共11個基因tcaB1位於基因簇核苷酸序列第19343-20230個鹼基處，長度為888個鹼基對，編碼dNDP-D-葡萄糖合成酶，295個胺基酸；tcaB2位於基因簇核苷酸序列第20227-21225個鹼基處，長度為999個鹼基對，編碼dNDP-D-葡萄糖-4，6-脫水酶，332個胺基酸；tcaB3位於基因簇核苷酸序列第89533-88076個鹼基處，長度為1464個鹼基對，編碼2，3-脫水酶，487個胺基酸；tcaB4位於基因簇核苷酸序列第13499-14497個鹼基處，長度為999個鹼基對，編碼3-酮基還原酶，332個胺基酸；tcaB5位於基因簇核苷酸序列第12849-13442個鹼基處，長度為603個鹼基對，編碼NDP-己糖-5-異構酶，200個胺基酸；tcaB6位於基因簇核苷酸序列第102587-101715個鹼基處，長度為873個鹼基對，編碼氧化還原酶，290個胺基酸；tcaB7位於基因簇核苷酸序列第16895-18037個鹼基處，長度為1143個鹼基對，編碼氨基轉移酶，380個胺基酸；tcaB8位於基因簇核苷酸序列第22600-23721個鹼基處，長度為1122個鹼基對，編碼氨基轉移酶，373個胺基酸；tcaB9位於基因簇核苷酸序列第23743-24987個鹼基處，長度為1245個鹼基對，編碼甲基轉移酶，414個胺基酸；tcaB10位於基因簇核苷酸序列第21290-22594個鹼基處，長度為1305個鹼基對，編碼醯基輔酶A脫氫酶，434個胺基酸；tcaB11位於基因簇核苷酸序列第16681-15890個鹼基處，長度為792個鹼基對，編碼甲基轉移酶，263個胺基酸；4)替曲卡星A大環骨架的後修飾基因，即tcaC，tcaE1，tcaE2，tcaF，tcaM，tcaT1，tcaT2，tcaT3，tcaT4，共9個基因tcaC位於基因簇核苷酸序列第9250-9810個鹼基處，長度為561個鹼基對，編碼黃素依賴的氧化酶，186個胺基酸；tcaE1位於基因簇核苷酸序列第75796-77271個鹼基處，長度為1476個鹼基對，編碼FAD依賴的氧化酶，491個胺基酸；tcaE2位於基因簇核苷酸序列第87242-85225個鹼基處，長度為1518個鹼基對，編碼FAD-脫氫酶，505個胺基酸；tcaF位於基因簇核苷酸序列第88026-87268個鹼基處，長度為765個鹼基對，編碼硫酯酶，254個胺基酸；tcaM位於基因簇核苷酸序列第18152-19294個鹼基處，長度為1143個鹼基對，編碼O-醯基轉移酶，380個胺基酸；tcaT1位於基因簇核苷酸序列第8022-9134個鹼基處，長度為1113個鹼基對，編碼糖基轉移酶，370個胺基酸；tcaT2位於基因簇核苷酸序列第15731-14553個鹼基處，長度為1179個鹼基對，編碼糖基轉移酶，392個胺基酸；tcaT3位於基因簇核苷酸序列第83216-84410個鹼基處，長度為1197個鹼基對，編碼糖基轉移酶，398個胺基酸；tcaT4位於基因簇核苷酸序列第84455-85594個鹼基處，長度為1140個鹼基對，編碼糖基轉移酶，379個胺基酸；5)替曲卡星A的調節基因，即tcaR1，tcaR2共2個基因tcaR1位於基因簇核苷酸序列第11988-12791個鹼基處，長度為804個鹼基對，編碼特異活化因子，267個胺基酸；tcaR2位於基因簇核苷酸序列第83045-82467個鹼基處，長度為579個鹼基對，編碼TetR家族轉錄調節因子，192個胺基酸；6)替曲卡星A的抗性基因，即tcaG共1個基因tcaG位於基因簇核苷酸序列第104125-102653個鹼基處，長度為1473個鹼基對，編碼藥物排出蛋白，490個胺基酸；7)還包括4個功能不明確的基因，即tcaU1，tcaU2，tcaU3，tcaU4tcaU1位於基因簇核苷酸序列第10171-9842個鹼基處，長度為330個鹼基對，編碼未知功能蛋白，109個胺基酸；tcaU2位於基因簇核苷酸序列第10440-10880個鹼基處，長度為441個鹼基對，編碼未知功能蛋白，146個胺基酸；tcaU3位於基因簇核苷酸序列第10691-11629個鹼基處，長度為939個鹼基對，編碼未知功能蛋白，312個胺基酸；tcaU4位於基因簇核苷酸序列第25068-25562個鹼基處，長度為495個鹼基對，編碼未知功能蛋白，164個胺基酸。2.根據權利要求1所述的替曲卡星A的生物合成基因簇，其特徵在於編碼的聚酮合成酶包含模塊或結構域酮基合成酶結構域KS、醯基轉移酶結構域AT、酮基還原酶結構域KR、脫水酶結構域DH、烯醯基還原酶結構域ER、醯基載體蛋白ACP。3.根據權利要求1所述的替曲卡星A的生物合成基因簇的用途，其編碼蛋白催化合成抗生素替曲卡星A及其結構類似物。4.根據權利要求3所述的替曲卡星A的生物合成基因簇的用途，其編碼蛋白催化合成脫氧糖阿米西糖和毛地黃毒糖極其類似物。5.根據權利要求3所述的替曲卡星A的生物合成基因簇的用途，其編碼蛋白催化合成硝基脫氧糖Tetronitrose及其類似物。6.根據權利要求3所述的替曲卡星A的生物合成基因簇的用途，其編碼蛋白催化合成及替曲卡星A聚酮大環骨架及其類似物。7.根據權利要求3所述的替曲卡星A的生物合成基因簇的用途，對其中的基因進行遺傳改造獲得的突變體經生物發酵得到替曲卡星A的結構類似物。全文摘要本發明是一種由青褐色小單孢菌(MicromonosporachalceaNRRL11289)產生的具有抗腫瘤活性的抗生素——替曲卡星A(TectrocarcinA)的生物合成基因簇的克隆、測序、分析、功能研究及其應用。整個基因簇共包含36個基因5個非重複使用的I型聚酮合成酶基因；4個特殊三碳單元生物合成基因；11個脫氧糖生物合成基因；9個後修飾基因；2個調節基因；1個抗性基因；以及4個功能不確定的基因。通過對上述生物合成基因的遺傳操作可阻斷替曲卡星A的生物合成。本發明所提供的基因及其蛋白也可以用來尋找和發現可用於醫藥、工業或農業的化合物或基因、蛋白。文檔編號C12P17/02GK101363022SQ200810036248公開日2009年2月11日申請日期2008年4月18日優先權日2008年4月18日發明者文劉,潔方申請人:中國科學院上海有機化學研究所