CN111615555B - 生产包含高组成比率的3hh单体单元的共聚pha的转化微生物、以及基于该转化微生物的pha的制造方法 - Google Patents
生产包含高组成比率的3hh单体单元的共聚pha的转化微生物、以及基于该转化微生物的pha的制造方法 Download PDFInfo
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- CN111615555B CN111615555B CN201980008997.6A CN201980008997A CN111615555B CN 111615555 B CN111615555 B CN 111615555B CN 201980008997 A CN201980008997 A CN 201980008997A CN 111615555 B CN111615555 B CN 111615555B
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Abstract
本申请提供一种转化微生物、以及包括培养该转化微生物的工序的包含3HH单体单元的共聚PHA的制造方法,所述转化微生物是生产以更高组成比率包含3HH单体单元的共聚PHA的转化微生物,具体而言,所述转化微生物具有能够合成包含3HH单体单元的共聚PHA的PHA合成酶基因、和编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因,所述转化微生物抑制编码对碳原子数6的β‑酮脂酰辅酶A(即,β‑酮己酰辅酶A)具有硫解活性的至少1种β‑酮硫解酶的基因的表达,使该酶活性消失或降低。
Description
技术领域
本发明涉及以油脂或脂肪酸作为原料生产包含高组成比率的3-羟基己酸(以下有时也称为“3HH”)单体单元的共聚聚羟基烷酸酯(以下有时也称为“共聚PHA”或简称为“PHA”)的转化微生物、以及基于该转化微生物的共聚PHA的制造方法。
背景技术
聚羟基烷酸酯(PHA)是由广泛的微生物生成的聚酯型有机聚合物。PHA是具有生物降解性的热塑性高分子,可以以可再生资源作为原料进行生产。鉴于这些情况,正在进行在工业上生产PHA作为环保型材料或生物适应型材料并在多种产业中加以利用的尝试。
目前为止,已知大量微生物在菌体内蓄积PHA作为储能物质。作为PHA的代表例,可列举出作为3-羟基丁酸(以下有时也称为“3HB”)的均聚物的聚-3-羟基丁酸酯(以下有时也称为“P(3HB)”)。P(3HB)为热塑性高分子,且在自然环境中可被生物降解,因此作为环保的塑料而备受关注。然而,由于P(3HB)的结晶性高,因此具有硬且脆的性质,实际上应用范围受到限制。为了扩大应用范围,需要对P(3HB)赋予柔软性。
因此,开发出了由3HB和3-羟基戊酸(以下记为“3HV”)形成的共聚PHA(以下记为“P(3HB-共-3HV)”)及其制造方法(例如,专利文献1及专利文献2)。与P(3HB)相比,P(3HB-共-3HV)更富有柔软性,因此可以认为能够用于广泛的用途。然而,实际上即使增加P(3HB-共-3HV)中的3HV摩尔分数,与此相伴的物性变化也很小,且特别是柔软性不会提高至用于加工成膜、片、软质包装容器等所需的程度,因此仅在洗发水瓶、一次性剃须刀的手柄等限于硬质成型体的领域中得以利用。
为了进一步提高PHA的柔软性,对由3HB和3HH形成的共聚PHA(以下有时也称为“P(3HB-共-3HH)”)及其制造方法进行了研究(专利文献3及专利文献4)。在这些报告中,P(3HB-共-3HH)是使用从土壤中分离得到的豚鼠气单胞菌(Aeromonas caviae)的野生株并以油酸、棕榈酸等脂肪酸作为碳源进行发酵生产的。
还进行了有关P(3HB-共-3HH)的物性的研究(非专利文献1)。在该报告中,将碳原子数为12个以上的脂肪酸作为唯一碳源对A.caviae进行培养,发酵生产了具有各种3HH组成比的P(3HB-共-3HH)。明确了P(3HB-共-3HH)随3HH组成比的增加,从如P(3HB)那样的硬且脆的性质逐渐显示出柔软的性质,当3HH组成比变得更高时,显示出超过P(3HB-共-3HV)的柔软性。即,对于P(3HB-共-3HH)而言,通过改变3HH组成比,可以使其具有能够应用于从硬质聚合物至软质聚合物的广泛的物性,因此可以期待用于广泛的领域。
另外,研究了以杀虫贪铜菌(Cupriavidus necator)作为宿主、并通过在质粒pJRD215(ATCC37533)中导入了聚酯合成酶基因、R体特异性烯酰辅酶A水合酶基因等而成的pJRDEE32、pJRDEE32d13等PHA合成酶表达质粒进行转化而得到的微生物的PHA生产性(专利文献5及非专利文献2)。已知该菌株培养后的菌体量原本低至4g/L,但通过改善以植物油脂作为碳源的相同菌株的培养条件,使聚合物生产性提高至菌体量为45g/L、聚合物含量为62.5%,而且3HH组成比提高至8.1mol%。这样,尝试了通过培养条件来改善P(3HB-共-3HH)的3HH组成比、聚合物生产性(专利文献6)。
还报道了通过增强R体特异性烯酰辅酶A水合酶基因的表达而使3HH组成比提高(专利文献7、专利文献8及非专利文献3)。在这些报告中,对于具有源自豚鼠气单胞菌的PHA合成酶的杀虫贪铜菌,通过导入R体特异性烯酰辅酶A水合酶基因、或者通过增加宿主染色体上的R体特异性烯酰辅酶A水合酶基因的表达量,从而使以植物油脂作为原料所生产的P(3HB-共-3HH)的3HH组成比率提高至最大14mol%左右。
另外,还报道了利用增强了编码β-酮硫解酶的bktB基因的表达的C.necator菌株、并使用植物油和丁酸作为碳源来生产3HH组成比率提高至13mol%的P(3HB-共-3HH)的例子(参照非专利文献4)。已知由bktB基因编码的β-酮硫解酶具有使碳原子数4的丁酰辅酶A与碳原子数2的乙酰辅酶A缩合而生成作为3HH单体的前体的碳原子数6的β-酮己酰辅酶A的活性,着眼于该缩合活性,还报道了通过增强β-酮硫解酶基因来提高P(3HB-共-3HH)的3HH组成比率的尝试(非专利文献5及非专利文献6)。
现有技术文献
专利文献
专利文献1:日本特开昭57-150393号公报
专利文献2:日本特开昭59-220192号公报
专利文献3:日本特开平5-93049号公报
专利文献4:日本特开平7-265065号公报
专利文献5:日本特开平10-108682号公报
专利文献6:日本特开2001-340078号公报
专利文献7:PCT国际公开第2011/105379号
专利文献8:PCT国际公开第2015/115619号
非专利文献
非专利文献1:Y.Doi,S.Kitamura,H.Abe,Macromolecules,28,pp.4822-4823(1995)
非专利文献2:T.Fukui,Y.Doi,J.Bacteriol,179,15,pp.4821-4830(1997)
非专利文献3:H.Arikawa,K.Matsumoto,Microb.Cell.Fact.,15,pp.184(2016)
非专利文献4:S.Satoetal.,J.Biosci.Bioeng.,120,pp.246-251(2015)
非专利文献5:T.Fukui,H.Abe,Y.Doi,Biomacromolecules,3,pp.618-624(2002)
非专利文献6:Q.Wangetal.,Appl.Microbiol.Biotechnol.,99,pp.2593-2602(2015)
发明内容
发明所要解决的课题
本发明的目的在于提供生产以更高的组成比率包含3HH单体单元的共聚PHA的转化微生物、以及使用了以油脂或脂肪酸(优选为植物来源的油脂或脂肪酸)作为原料的该转化微生物的共聚PHA的制造方法。
用于解决课题的方法
本发明人等为了解决上述课题而进行了深入研究,结果发现,通过抑制编码对碳原子数6的β-酮脂酰辅酶A(即,β-酮己酰辅酶A)具有硫解活性的至少1种、或至少2种的β-酮硫解酶的基因的表达,使该酶活性消失或降低,能够进行以更高的组成比率包含3HH单体单元的共聚PHA的发酵生产,从而完成了本发明。
即,本发明涉及一种转化微生物,其包含能够合成包含3HH单体单元的共聚PHA的PHA合成酶基因、和编码具有R体特异性烯酰辅酶A水合酶(烯酰CoA水合酶)活性的蛋白质的基因,所述转化微生物抑制编码对作为碳原子数6的β-酮脂酰辅酶A的β-酮己酰辅酶A具有硫解活性的至少1种或至少2种β-酮硫解酶的基因的表达,使该酶活性消失或降低。
根据本发明的实施方式,本发明的转化微生物进一步使编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因的表达增强。
根据本发明的实施方式,本发明的转化微生物进一步使能够合成包含3HH单体单元的共聚PHA的PHA合成酶基因的表达增强。
本说明书中的基因的“表达抑制”是指,使上述β-酮硫解酶的活性消失或降低,表达抑制包括使编码该酶的基因的功能消失。用于抑制表达的方法没有特别限定,例如可列举出如下方法:编码上述β-酮硫解酶的基因的全部或部分的破坏(例如,利用基因组编集技术(例如,CRISPR/Cas(例如,Cas9)***、TALEN等)的基因的敲除、利用同源重组技术的基因破坏、利用转位子的基因破坏等)、该基因的转录或翻译的效率的降低、与该基因转录相关的启动子区域的修饰或与翻译相关的核糖体结合序列的修饰、使mRNA不稳定化的转录区域碱基序列的修饰、RNA干扰导致的mRNA的降解或切断、该酶的底物特异性的改变等。另外,还可以使用抑制该酶的活性的试剂、蛋白质等。
只要没有特别声明,本说明书中的基因的“破坏”是指,通过编码β-酮硫解酶的基因的碱基序列的去除(或缺失)、切断、该碱基序列的缺失、置换、添加、***等突变,而使由该基因编码的酶蛋白本身被破坏的状态。
本说明书中的上述酶蛋白的活性的“降低”是指活性降低,使得共聚PHA的3HH单体单元的组成比率高于酶活性未降低的对照。或者,优选上述酶蛋白的活性消失,作为相对于完整的蛋白质的活性(100%)的相对活性,例如可以残留20%以下、10%以下、5%以下、2%以下或1%以下的弱活性,但并不限定于此。
本说明书中的基因表达的“强化”或“增强”是指该基因的表达量增加或提高。
根据本发明的实施方式,上述微生物优选为细菌(也称为bacteria),更优选为属于贪铜菌(Cupriavidus)属的细菌,进一步优选为杀虫贪铜菌(例如,杀虫贪铜菌(Cupriavidus necator)H16株)。
根据本发明的实施方式,编码上述β-酮硫解酶的基因是选自源***虫贪铜菌H16株的bktB基因或其同源物、以及源***虫贪铜菌H16株的A1528基因(基因编号“H16_A1528”)或其同源物中的至少1种基因。
本说明书中使用的“同源物(homolog)”是指包括直向同源物(ortholog)及横向同源物(paralog)中的任意一者,是编码具有同种或异种微生物所具有的β-酮硫解酶活性的蛋白质的基因组。直向同源物及横向同源物具有学术上通常使用的含义,直向同源物是在物种分化时分支的同源物(相同体),是指存在于不同微生物中的具有相同功能的基因组。另一方面,横向同源物是由基因重复而产生的同源物。
根据本发明的实施方式,编码上述β-酮硫解酶的基因为源***虫贪铜菌H16株的bktB基因或源自贪铜菌属细菌(例如杀虫贪铜菌)的该bktB基因的同源物、源***虫贪铜菌H16株的A1528基因或源自贪铜菌属细菌(例如杀虫贪铜菌)的该A1528基因的同源物,或者为这两者。
根据本发明的实施方式,上述bktB基因包含序列号7所示的碱基序列或与该碱基序列具有85%以上的序列同一性的碱基序列,并且上述A1528基因包含序列号8所示的碱基序列或与该碱基序列具有85%以上的序列同一性的碱基序列。
本发明还涉及包含3HH单体单元的共聚PHA的制造方法,该方法包括:使用含有油脂或脂肪酸(优选为植物来源的油脂或脂肪酸)的碳源来培养上述转化微生物的工序、以及对包含3HH单体单元的共聚PHA进行回收的工序。该共聚PHA优选为P(3HB-共-3HH)(别称聚(3-羟基丁酸酯-共-3-羟基己酸酯))。
本说明书包括作为本申请的优先权基础的日本专利申请号2018-005998号的公开内容。
发明的效果
根据本发明,可以提供生产包含更高组成比率的3HH单体单元的共聚PHA的转化微生物,另外,通过培养该转化微生物,能够发酵生产包含更高组成比率的3HH单体单元的共聚PHA。这样的共聚PHA具有柔软性提高的优点。
具体实施方式
以下,对本发明进一步详细地进行说明。
1.生产包含3HH单体单元的共聚PHA的转化微生物
根据本发明的一个方式,提供一种转化微生物,其包含PHA合成酶基因、和编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因,所述PHA合成酶基因能够合成包含3HH单体单元的共聚PHA,所述转化微生物抑制编码对碳原子数6的β-酮脂酰辅酶A(即,β-酮己酰辅酶A)具有硫解活性的至少1种或至少2种β-酮硫解酶的基因的表达,使该酶活性消失或降低。与上述酶活性未消失或未降低的对照微生物相比,该转化微生物能够生产包含高组成比率的3HH单体单元的共聚PHA
在本说明书中,关于3HH单体单元,“高(的)组成比率”是指:与对β-酮己酰辅酶A具有硫解活性的β-酮硫解酶完整(即,自然或天然的状态)的对照微生物、或者与编码该β-酮硫解酶的基因的表达未被抑制的对照微生物相比,生产的共聚PHA的3HH单体单元的组成比率高。
在本说明书中,“β-酮硫解酶”是指,在脂肪酸的β氧化中,对β-酮脂酰辅酶A在辅酶A的存在下引起硫解(硫醇裂解)而生成缩短了2个碳原子的量的脂肪酸酰基辅酶A和乙酰辅酶A的反应进行催化的酶。在本发明中,通过使β-酮硫解酶的活性消失或降低,可以抑制β-酮己酰辅酶A的分解,提高生产的共聚PHA的3HH单体单元的组成比率。
在本说明书中,“PHA合成酶”是生物合成聚羟基烷酸酯的酶,通过使包含(R)-3-羟基己酰辅酶A的2种以上(R)-3-羟基脂酰辅酶A聚合,可以生成包含3HH单体单元的共聚PHA。
本说明书中“具有R体特异性烯酰辅酶A水合酶活性的蛋白质”是指,具有从作为脂肪酸β氧化体系的中间体的烯酰辅酶A转化为作为PHA单体的供给源的(R)-3-羟基脂酰辅酶A的酶活性的蛋白质。
本发明的转化微生物的特征如下所述。
(1)转化微生物包含:能够合成包含3HH单体单元的共聚PHA的PHA合成酶基因、和编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因。
(2)优选编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因的表达得到增强。通过这样的增强,与未进行表达增强的情况相比,包含3HH单体单元的共聚PHA中3HH单体单元的组成比率提高,在本发明中,在这样的性质中追加下述(4)的性质时,令人意外地赋予了可进一步提高该组成比率的特征。
(3)优选能够合成包含3HH单体单元的共聚PHA的PHA合成酶基因的表达得到增强。
(4)具有生产包含高组成比率的3HH单体单元的共聚PHA的能力,其特征在于,抑制编码对碳原子数6的β-酮脂酰辅酶A(即,β-酮己酰辅酶A)具有硫解活性的至少1种或至少2种β-酮硫解酶的基因的表达,使该酶活性消失或降低。这里,上述酶活性的“降低”如上所述,是指与酶活性未降低的对照相比,共聚PHA的3HH单体单元的组成比率进一步提高那样的活性降低。
(5)通过包含上述(1)~(4)的性质,可以使本发明的转化微生物具有生产包含高组成比率的3HH单体单元的共聚PHA的能力。
成为进行上述基因的表达抑制的原始菌株(也称为“亲本菌株”)的微生物如上所述,只要是包含能够合成包含3HH单体单元的共聚PHA的PHA合成酶基因、和编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因的微生物即可,没有特别限定。作为这样的微生物,不仅可以是原本具有上述PHA合成酶基因、以及编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因的野生株,还可以是对这样的野生株进行人工突变处理而得到的突变株、利用基因工程方法导入了外源的PHA合成酶基因和/或外源的编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因的重组微生物株。
作为本发明中可使用的微生物,具体而言可示例出霉菌、酵母菌、细菌、放线菌、蓝藻、古细菌等,优选为细菌(bacteria)。作为该细菌,例如可列举出属于罗尔斯通氏菌(Ralstonia)属、贪铜菌(Cupriavidus)属、沃特斯氏菌(Wautersia)属、气单胞菌(Aeromonas)属、埃希氏菌(Escherichia)属、产碱菌(Alcaligenes)属、假单胞菌(Pseudomonas)属等的细菌作为优选的例子。从安全性及生产性的观点出发,更优选为属于罗尔斯通氏菌属、贪铜菌属、气单胞菌属、沃特斯氏菌属的细菌,进一步优选为属于贪铜菌属或气单胞菌属的细菌,进一步更优选为属于贪铜菌属的细菌,特别优选为杀虫贪铜菌(Cupriavidus necator)。
在本发明的转化微生物中,对于上述示例的微生物、或者在上述示例的微生物之间,可以修饰上述靶基因组(即,PHA合成酶基因、编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因、以及编码β-酮硫解酶的基因),以便具有上述(1)~(5)的性质。以下对该修饰进行进一步说明。
在本说明书中,具有PHA合成酶基因的微生物能够合成包含3HH单体单元的共聚PHA并不是指在所有的培养条件下能够合成包含3HH单体单元的共聚PHA,只要能够在特定的培养条件下合成包含3HH单体单元的共聚PHA即可。例如,对于后述的比较例1中记载的菌株(KNK005dZ)而言,虽然在以果糖作为单一碳源的培养条件下不合成包含3HH单体单元的共聚PHA,但在包含油脂或脂肪酸作为碳源的培养条件下能够合成包含3HH单体单元的共聚PHA,因此,在本发明中,上述微生物属于“具有能够合成包含3HH单体单元的共聚PHA的PHA合成酶基因的微生物”。
在具有能够合成包含3HH单体单元的共聚PHA的PHA合成酶基因的微生物是利用基因工程方法导入了外源的PHA合成酶基因的重组微生物株的情况下,作为上述外源的PHA合成酶基因,只要是具有吸收3HH而生产包含3HH单体单元的共聚PHA的功能的基因即可,没有特别限定。作为这样的PHA合成酶基因,例如可列举出:编码具有序列号1中记载的氨基酸序列的酶的来自于豚鼠气单胞菌(Aeromonas caviae)的PHA合成酶基因、或者相对于该氨基酸序列具有85%以上、优选具有90%以上、更优选具有95%以上、特别优选具有99%以上的序列同一性且编码具有含3HH单体单元共聚PHA合成活性的多肽的PHA合成酶基因等,但并不限定于此。其中,优选为能够合成作为包含3HH单体单元的共聚PHA的P(3HB-共-3HH)的PHA合成酶基因,其中,更优选为例如编码包含序列号2中记载的氨基酸序列的PHA合成酶的PHA合成酶基因。
另外,在上述微生物是利用基因工程方法导入了外源的编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因的重组微生物株的情况下,作为上述外源的编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因,例如可列举出:编码具有序列号3中记载的氨基酸序列的酶的来自于豚鼠气单胞菌(Aeromonas caviae)的R体特异性烯酰辅酶A水合酶基因、编码具有序列号4及序列号5中记载的氨基酸序列的酶的来自于杀虫贪铜菌的R体特异性烯酰辅酶A水合酶基因、编码具有序列号6中记载的氨基酸序列的酶的来自于解脂耶氏酵母(Yarrowia lipolytica)的多功能酶2型(Multifunctional enzyme type 2:MFE2)基因、或者相对于序列号3~6中记载的各氨基酸序列具有85%以上、优选具有90%以上、更优选具有95%以上、特别优选具有99%以上的序列同一性且编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因等,但不限定于此。
为了增强编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因的表达,例如,可以如PCT国际公开第2015/115619号所记载那样,进行用于增强该基因表达的表达调控序列(启动子序列和/或SD序列)的修饰。
在本发明中,作为成为原始菌株的微生物,最适宜的是向杀虫贪铜菌导入来自于豚鼠气单胞菌的PHA合成酶基因而得到的重组原核微生物株。
接着,对于上述微生物,对抑制编码对碳原子数6的β-酮脂酰辅酶A(即,β-酮己酰辅酶A)具有硫解活性的β-酮硫解酶的基因的表达进行说明。
上述被抑制表达的对象基因只要是编码对碳原子数6的β-酮脂酰辅酶A具有硫解活性的β-酮硫解酶的基因即可,该β-酮硫解酶还可以同时具有对于碳原子数不为6的β-酮脂酰辅酶A的硫解活性。例如,还可以对碳原子数4~6的β-酮脂酰辅酶A具有硫解活性,或者对碳原子数4~18的β-酮脂酰辅酶A具有硫解活性,或者对碳原子数6~20的β-酮脂酰辅酶A具有硫解活性,而且并不限定于此。
通过对包含上述PHA合成酶基因、和编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因的微生物进行该基因的表达抑制而得到的转化微生物能够生产以更高组成比率包含3HH单体单元的共聚PHA。
通常,油脂或脂肪酸(优选为植物来源的油脂或脂肪酸)在微生物内通过β氧化而被代谢,被分解为碳原子数2的脂酰辅酶A(即,乙酰辅酶A)。对于具有编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因的微生物而言,在此期间,作为β氧化的中间代谢产物的碳原子数6的2-烯酰辅酶A的一部分被转化为作为3HH单体单元的前体的碳原子数6的(R)-3-羟基脂酰辅酶A。根据本发明,通过进行上述基因的表达抑制,在以油脂或脂肪酸作为碳源的情况下,β氧化中的碳原子数6的中间代谢产物的分解受到抑制,其结果是,可以推测转化为碳原子数6的(R)-3-羟基脂酰辅酶A的转化量增大,作为最终合成物的共聚PHA中的3HH单体单元的组成比率提高。
另一方面,对于3HH单体单元的组成比率的提高,共聚PHA的产量大幅降低这样的β-酮脂酰辅酶A基因的破坏在工业上是不利的。因此,在考虑到由β-酮脂酰辅酶A基因的破坏所导致的PHA产量降低率和3HH组成比上升率时,优选它们的乘积较大。例如,在PHA产量降低至1/2倍、3HH组成比率上升至1.4倍时,乘积(PHA产量降低率×3HH组成比上升率)为0.7。在本发明中,实施例中所示的培养条件下的PHA产量降低率×3HH组成比上升率的值优选为0.65以上、更优选为0.75以上、进一步优选为0.85以上、更进一步优选为0.95以上、最优选为1以上,但并不限定于此。需要说明的是,上述PHA产量降低率是指,与对β-酮己酰辅酶A具有硫解活性的β-酮硫解酶为完整的转化微生物进行比较、或者与编码该β-酮硫解酶的基因的表达未被抑制的转化微生物进行比较时的共聚PHA产量的比例。
另外,上述3HH组成比上升率是指:与对β-酮己酰辅酶A具有硫解活性的β-酮硫解酶为完整的转化微生物进行比较、或者与编码该β-酮硫解酶的基因的表达未被抑制的转化微生物进行比较时的共聚PHA中的3HH组成比率的比例,是大于1的值,优选为1.2以上,更优选为1.5以上,更进一步优选为1.8以上,只要是大于1的值即可,但并不限定于此。
为了使β-酮硫解酶活性特异性地消失或降低,例如,可以使该酶基因完全缺失、或在该酶基因的序列内部***耐药性基因等完全不同的基因、或使该酶基因的序列的一部分(优选为与酶活性相关的区域)缺失、或利用完全不同的DNA序列进行置换、添加或***,只要能够使该活性消失或降低,可以进行任何可能的表达抑制。在表达抑制中,例如基因破坏操作包括例如使用包含破坏用基因或破坏用DNA的载体的同源重组技术、利用转位子的技术等(参照以下说明)。或者,作为其它破坏方法,可以通过用于破坏靶基因的CRISPR/Cas(例如,Cas9)***、基于TALEN的基因组编集技术(Y.Wangetal.,ACS Synth Biol.2016,5(7):721-732;Bogdanove and Voytas,Science,333:1843-1846,2011;Jinek,et al.,Science,337:816-821,2012;Shalem,et al.,Science,343:84-87,2014;Wang,et al.,Science,343:80-84,2014)等公知的技术来进行。例如,在CRISPR/Cas9***中,向导RNA(gRNA)具有可与应破坏的β-酮硫解酶基因的碱基序列的一部分结合的序列,具有将Cas9输送至靶标的作用。另外,还可以通过该基因周围的碱基序列的缺失、置换、添加、***等突变而使基因的转录/翻译效率、mRNA的稳定性降低等,从而使该酶活性消失或降低。
作为上述被抑制表达的基因,只要是编码对碳原子数6的β-酮脂酰辅酶A具有硫解活性的β-酮硫解酶的基因即可,没有特别限定,例如可列举出:包含来自于杀虫贪铜菌H16株的序列号7所示的碱基序列的bktB基因、或者相对于该碱基序列具有85%以上、优选具有90%以上、更优选具有95%以上、特别优选具有99%以上的序列同一性的bktB基因的同源物。另外,作为其它例子,可列举出:来自于杀虫贪铜菌H16株的具有序列号8所示的碱基序列的基因座H16_A1528的基因(以下有时称为“A1528基因”)、或者相对于该碱基序列具有85%以上、优选具有90%以上、更优选具有95%以上、特别优选具有99%以上的序列同一性的A1528基因的同源物。另一方面,后述的比较例中被抑制表达(例如,破坏)的基因是:具有序列号9中记载的碱基序列的phaA基因,其是编码对碳原子数6的β-酮脂酰辅酶A不具有硫解活性的β-酮硫解酶的基因;或者相对于该碱基序列具有85%以上、优选具有90%以上、更优选具有95%以上、特别优选具有99%以上的序列同一性的phaA基因的同源物;作为其它β-酮硫解酶基因的具有序列号10中记载的碱基序列的基因座H16_A0462的基因(以下有时称为“A0462基因”);或相对于该碱基序列具有85%以上、优选具有90%以上、更优选具有95%以上、特别优选具有99%以上的序列同一性的A0462基因的同源物(参照表1)。
另外,上述非专利文献3中报道了,对于导入了能引入3HH单体的PHA合成酶基因的杀虫贪铜菌株,通过导入R体特异性烯酰辅酶A水合酶基因、或增强该菌株原本保持的R体特异性烯酰辅酶A水合酶基因的表达,从而能够以油脂或脂肪酸(优选为植物来源的油脂或脂肪酸)作为碳源来生产更高3HH组成比的P(3HB-共-3HH)。如上所述,在本发明的转化微生物中,除了抑制上述基因的表达以外,还可以进行编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因的追加导入、或者进行现有的该基因的表达增强。通过编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因的追加导入和/或现有的该基因的表达增强,使上述的碳原子数6的(R)-3-羟基脂酰辅酶A的合成路径增强或效率增高,生产的共聚PHA中的3HH单体单元的组成比率进一步提高。
另外,除了上述基因的表达抑制以外,还可以进行能引入3HH单体的PHA合成酶基因的追加导入、或者进行现有的该基因的表达增强。通过能引入3HH单体的PHA合成酶基因的追加导入和/或现有的该基因的表达增强,使转化量增大的(R)-3-羟基脂酰辅酶A向P(3HB-共-3HH)的引入得到增强或效率增高,生产的共聚PHA中的3HH单体单元的组成比率进一步提高。
对于本发明的转化微生物而言,在导入外源基因的情况下,导入基因可以存在于作为宿主的微生物所具有的染色体上、或者存在于质粒、巨大质粒(megaplasmid)等的DNA上,从导入基因的保持的观点出发,优选存在于微生物所具有的染色体或巨大质粒上,更优选存在于微生物所具有的染色体上。另外,在使作为宿主的微生物原本保持的基因的表达量增加的情况下,可以通过对该基因的上游的碱基序列进行置换、缺失或添加来增加基因的表达量。
将任意的DNA位点特异性地置换或***至微生物所具有的DNA上的方法、或者使微生物所具有的DNA的任意位点缺失的方法是本领域技术人员公知的,可以在制备本发明的转化微生物时使用。作为代表性的方法,可列举出:利用与转位子同源重组的机制的方法(Ohman等,J.Bacteriol.,vol.162:p.1068(1985));以由同源重组的机制引起的位点特异性的引入和由第二阶段的同源重组所致的脱落作为原理的方法(Noti等,MethodsEnzymol.,vol.154,p.197(1987));使来自于枯草芽孢杆菌的sacB基因共存,并通过第二阶段的同源重组将基因脱落的微生物株作为蔗糖添加培养基抗性菌株而容易地分离的方法(Schweizer,Mol.Microbiol.,vol.6,p.1195(1992);Lenz等,J.Bacteriol.,vol.176,p.4385(1994))等,没有特别限定。另外,作为向细胞中导入载体的方法,也没有特别限定,例如可列举出氯化钙法、电穿孔法、聚乙二醇法、原生质球法等。
需要说明的是,关于基因克隆、基因重组技术,可以利用Sambrook,J.et al.,Molecular Cloning,A Laboratory Manual,Cold Spring Harbor Laboratory Press(1989或2001)等中记载的技术。
用于表达上述的各种基因的启动子没有特别限定。可以使用杀虫贪铜菌的phaC1基因的启动子、phaP1基因的启动子、来自于大肠杆菌的lac启动子、lacUV5启动子、trc启动子、tic启动子、tac启动子、或者人工制作的序列号11所示的具有来自于大肠杆菌的修饰碱基序列的lacN17启动子等。
2.共聚PHA的制造方法
利用如下方法可以制造共聚PHA,所述方法包括:通过培养本发明的转化微生物来生产共聚PHA,并对得到的共聚PHA进行回收。
在本发明的共聚PHA的生产中,优选在包含碳源、作为除碳源以外的营养源的氮源、无机盐类、其它有机营养源的培养基中对上述转化微生物进行培养。
作为碳源,只要是本发明的转化微生物能够同化的包含植物油脂或脂肪酸的碳源即可,可以使用任意的碳源,可优选列举出棕榈油、棕榈仁油、玉米油、椰子油、橄榄油、大豆油、菜籽油、麻疯树油(Jatropha oil)等油脂或其分离油类;月桂酸、油酸、硬脂酸、棕榈酸、肉豆蔻酸等脂肪酸或其衍生物等。
作为氮源,例如可列举出氨;氯化铵、硫酸铵、磷酸铵等铵盐;蛋白胨、肉提取物、酵母提取物等。作为无机盐类,例如可列举出磷酸二氢钾、磷酸氢二钠、磷酸镁、硫酸镁、氯化钠等。作为其它有机营养源,例如可列举出甘氨酸、丙氨酸、丝氨酸、苏氨酸、脯氨酸等氨基酸;维生素B1、维生素B12、维生素C等维生素等。
对本发明的转化微生物进行培养时的培养温度、培养时间、培养时pH、培养基等的条件,可以是在培养例如罗尔斯通氏菌属、贪铜菌属、沃特斯氏菌属、气单胞菌属、埃希氏菌属、产碱菌属、假单胞菌属等的宿主微生物时通常使用的条件。
作为本发明中生产的共聚PHA的种类,只要是包含3HH单体单元的共聚PHA就没有特别限定,优选为将选自碳原子数4~16的2-羟基烷酸、3-羟基烷酸(3HH除外)及4-羟基烷酸中的1种以上单体与3HH聚合而得到的共聚PHA,更优选为作为3-羟基丁酸与3-羟基己酸的共聚物的P(3HB-共-3HH)。需要说明的是,生产的共聚PHA的种类可以根据目的通过使用的微生物所具有的或另行导入的PHA合成酶基因的种类、参与其合成的代谢体系的基因的种类、培养条件等而适宜选择。
在本发明中,对培养转化微生物后从菌体回收共聚PHA没有特别限定,例如可以利用如下方法进行。在培养结束后,利用离心分离机等从培养液中分离菌体,通过蒸馏水及甲醇等对该菌体进行清洗,使其干燥。使用氯仿等有机溶剂从该干燥菌体中提取共聚PHA。通过过滤等从包含该共聚PHA的有机溶剂溶液中去除菌体成分,在该滤液中加入甲醇、己烷等不良溶剂,使共聚PHA沉淀。进一步,通过过滤、离心分离去除上清液,使其干燥,回收共聚PHA。
得到的共聚PHA的3HH等单体组成(mol%)的分析例如可以利用(毛细管)气相色谱法、核磁共振法等来进行。
实施例
以下,通过实施例详细地对本发明进行说明,但本发明并不受这些实施例的任何限制。需要说明的是,整体上的基因操作可以如Molecular Cloning(Cold Spring HarborLaboratory Press(1989或2001))中的记载来进行。另外,基因操作中使用的酶、克隆宿主等可以从市场供应商处购入,并按照其说明来使用。需要说明的是,作为酶,只要可用于基因操作就没有特别限定。
以下的制造例、实施例及比较例中使用的KNK005ΔphaZ1,2,6株(以下有时称为“KNK005dZ株”)是在杀虫贪铜菌H16株的染色体上导入来自于豚鼠气单胞菌的PHA合成酶基因(编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因)、并使染色体上的作为PHA分解酶基因的phaZ1,2,6基因缺失而得到的转化微生物。该转化微生物可以按照PCT国际公开第2014/065253号中记载的方法来制备。另外,KNK005 trc-phaJ4b/ΔphaZ1,2,6株(以下有时称为“KNK005dZ/trc-J4b株”)是在KNK005ΔphaZ1,2,6株中增强了染色体上的R体特异性烯酰辅酶A水合酶基因的表达而得到的转化微生物。该转化微生物可以按照PCT国际公开第2015/115619号中记载的方法来制备。具体而言,可以通过对作为该基因的调控序列的启动子序列或核糖体结合位点(Shine-Dalgarno:SD)序列的一部分进行修饰(缺失、置换、添加或***)、或者将这些序列置换为来自于其它细菌的启动子序列或SD序列,从而使上述基因的表达增强。基因表达的增强方法并不限定于此,还可以通过进一步导入同样的基因或编码具有同样活性的酶的基因等来增强。
(制造例1)KNK005dZ/dphaA株的制备
首先,进行了基因破坏用质粒的制备。如下所述进行了制备。
通过使用了合成寡聚DNA的PCR,得到了具有phaA结构基因的上游和下游的碱基序列的DNA片段(序列号12)。用限制性酶SwaI将得到的DNA片段消化。通过DNA连接酶(Ligation High(Toyobo公司制))将该DNA片段与同样经SwaI消化的日本特开2007-259708号公报中记载的载体pNS2X-sacB连接,制备了具有phaA结构基因的上游和下游的碱基序列的基因破坏用质粒载体pNS2X-sacB+phaAUD。
接着,使用基因破坏用质粒载体pNS2X-sacB+phaAUD,如下所述进行基因破坏株KNK005dZ/dphaA株的制备。
利用基因破坏用质粒载体pNS2X-sacB+phaAUD对大肠杆菌S17-1株(ATCC47055)进行转化,将由此得到的转化微生物和KNK005dZ株在Nutrient Agar培养基(Difco公司制)上进行混合培养,进行接合转移(conjugation transfer)。
将得到的培养液接种于包含250mg/L的卡那霉素的Simmons’琼脂培养基(柠檬酸钠2g/L、氯化钠5g/L、七水硫酸镁0.2g/L、磷酸二氢铵1g/L、磷酸氢二钾1g/L、琼脂15g/L、pH6.8),选择在琼脂培养基上生长的菌株,获得了在KNK005dZ株的染色体上引入了质粒的菌株。将该菌株在Nutrient Broth培养基(Difco公司制)中进行两代培养后,稀释并涂布在包含15%的蔗糖的Nutrient Agar培养基上,获得生长出来的菌株作为质粒脱落后的菌株。进一步通过基于PCR及DNA测序的分析分离出了将染色体上的phaA结构基因的起始密码子至终止密码子缺失的1个菌株。将该基因破坏株命名为KNK005dZ/dphaA株。得到的KNK005dZ/dphaA株是如下菌株:杀虫贪铜菌H16株的染色体上的phaZ1基因及phaZ6基因的起始密码子至终止密码子被删除,并且phaZ2基因的第16位密码子至终止密码子被删除,在染色体上导入编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因,并且phaA结构基因的起始密码子至终止密码子被删除的菌株。
(制造例2)KNK005dZ/dbktB株的制备
首先,进行了基因破坏用质粒的制备。如下所述进行了制备。
通过使用了合成寡聚DNA的PCR,得到了具有bktB结构基因的上游和下游的碱基序列的DNA片段(序列号13)。用限制性酶SwaI将得到的DNA片段消化。利用DNA连接酶(Ligation High(Toyobo公司制))将该DNA片段与同样经SwaI消化的日本特开2007-259708号公报中记载的载体pNS2X-sacB连接,制备了具有bktB结构基因的上游和下游的碱基序列的基因破坏用质粒载体pNS2X-sacB+bktBUD。
接着,使用基因破坏用质粒载体pNS2X-sacB+bktBUD,将KNK005dZ株作为亲本菌株,利用与上述同样的方法进行了基因破坏株KNK005dZ/dbktB株的制备。
得到的KNK005dZ/dbktB株为如下菌株:杀虫贪铜菌H16株的染色体上的phaZ1基因及phaZ6基因的起始密码子至终止密码子被删除,并且phaZ2基因的第16位密码子至终止密码子被删除,在染色体上导入编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因,并且bktB结构基因的起始密码子至终止密码子被删除的菌株。
(制造例3)KNK005dZ/dA1528株的制备
首先,进行了基因破坏用质粒的制备。如下所述进行了制备。
通过使用了合成寡聚DNA的PCR,得到了具有A1528结构基因的上游和下游的碱基序列的DNA片段(序列号14)。用限制性酶SwaI将得到的DNA片段消化。利用DNA连接酶(LigationHigh(Toyobo公司制))将该DNA片段与同样经SwaI消化的日本特开2007-259708号公报中记载的载体pNS2X-sacB连接,制备了具有A1528结构基因的上游和下游的碱基序列的基因破坏用质粒载体pNS2X-sacB+A1528UD。
接着,使用基因破坏用质粒载体pNS2X-sacB+A1528UD,将KNK005dZ株作为亲本菌株,利用与上述同样的方法进行了基因破坏株KNK005dZ/dA1528株的制备。
得到的KNK005dZ/dA1528株为如下菌株:杀虫贪铜菌H16株的染色体上的phaZ1基因及phaZ6基因的起始密码子至终止密码子被删除,并且phaZ2基因的第16位密码子至终止密码子被删除,在染色体上导入编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因,并且A1528结构基因的起始密码子至终止密码子被删除的菌株。
(制造例4)KNK005dZ/dbktB/dA1528株的制备
使用制造例3中制备的基因破坏用质粒载体pNS2X-sacB+A1528UD,将制造例2中制备的KNK005dZ/dbktB株作为亲本菌株,利用与上述同样的方法进行了基因破坏株KNK005dZ/dbktB/dA1528株的制备。
得到的KNK005dZ/dbktB/dA1528株为如下菌株:杀虫贪铜菌H16株的染色体上的phaZ1基因及phaZ6基因的起始密码子至终止密码子被删除,并且phaZ2基因的第16位密码子至终止密码子被删除,在染色体上导入编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因,bktB结构基因的起始密码子至终止密码子被删除,并且A1528结构基因的起始密码子至终止密码子被删除的菌株。
(制造例5)KNK005dZ/trc-J4b/dphaA株的制备
使用制造例1中制备的基因破坏用质粒载体pNS2X-sacB+phaAUD,将KNK005dZ/trc-J4b株作为亲本菌株,利用与上述同样的方法进行了基因破坏株KNK005dZ/trc-J4b/dphaA株的制备。
得到的KNK005dZ/trc-J4b/dphaA株为如下菌株:杀虫贪铜菌H16株的染色体上的phaZ1基因及phaZ6基因的起始密码子至终止密码子被删除,并且phaZ2基因的第16位密码子至终止密码子被删除,在染色体上导入编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因,染色体上的R体特异性烯酰辅酶A水合酶基因的表达被增强,并且phaA结构基因的起始密码子至终止密码子被删除的菌株。
(制造例6)KNK005dZ/trc-J4b/dbktB株的制备
使用制造例2中制备的基因破坏用质粒载体pNS2X-sacB+bktBUD,将KNK005dZ/trc-J4b株作为亲本菌株,利用与上述同样的方法进行了基因破坏株KNK005dZ/trc-J4b/dbktB株的制备。
得到的KNK005dZ/trc-J4b/dbktB株为如下菌株:杀虫贪铜菌H16株的染色体上的phaZ1基因及phaZ6基因的起始密码子至终止密码子被删除,并且phaZ2基因的第16位密码子至终止密码子被删除,在染色体上导入编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因,染色体上的R体特异性烯酰辅酶A水合酶基因的表达被增强,并且bktB结构基因的起始密码子至终止密码子被删除的菌株。
(制造例7)KNK005dZ/trc-J4b/dA1528株的制备
使用制造例3中制备的基因破坏用质粒载体pNS2X-sacB+A1528UD,将KNK005dZ/trc-J4b株作为亲本菌株,利用与上述同样的方法进行了基因破坏株KNK005dZ/trc-J4b/dA1528株的制备。
得到的KNK005dZ/trc-J4b/dA1528株为如下菌株:杀虫贪铜菌H16株的染色体上的phaZ1基因及phaZ6基因的起始密码子至终止密码子被删除,并且phaZ2基因的第16位密码子至终止密码子被删除,在染色体上导入编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因,染色体上的R体特异性烯酰辅酶A水合酶基因的表达被增强,并且A1528结构基因的起始密码子至终止密码子被删除的菌株。
(制造例8)KNK005dZ/trc-J4b/dbktB/dA1528株的制备
使用制造例3中制备的基因破坏用质粒载体pNS2X-sacB+A1528UD,将制造例6中制备的KNK005dZ/trc-J4b/dbktB株作为亲本菌株,利用与上述同样的方法进行了基因破坏株KNK005dZ/trc-J4b/dbktB/dA1528株的制备。
得到的KNK005dZ/trc-J4b/dbktB/dA1528株为如下菌株:杀虫贪铜菌H16株的染色体上的phaZ1基因及phaZ6基因的起始密码子至终止密码子被删除,并且phaZ2基因的第16位密码子至终止密码子被删除,在染色体上导入编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因,染色体上的R体特异性烯酰辅酶A水合酶基因的表达被增强,bktB结构基因的起始密码子至终止密码子被删除,并且A1528结构基因的起始密码子至终止密码子被删除的菌株。
(制造例9)KNK005dZ/trc-J4b/lacN17-NSDG株的制备
首先,进行了基因***用质粒的制备。如下所述进行了制备。
通过使用了合成寡聚DNA的PCR,得到了DNA片段(序列号15),其包含phaZ6结构基因的上游和下游的碱基序列、具有序列号11中记载的碱基序列的lacN17启动子、编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因。用限制性酶SwaI将得到的DNA片段消化。利用DNA连接酶(Ligation High(Toyobo公司制))将该DNA片段与同样经SwaI消化的日本特开2007-259708号公报中记载的载体pNS2X-sacB连接,制备了基因***用质粒载体pNS2X-sacB+lacN17-NSDG。
接着,使用基因***用质粒载体pNS2X-sacB+lacN17-NSDG,将KNK005dZ/trc-J4b株作为亲本菌株,利用与上述的基因破坏同样的方法进行染色体DNA的修饰,进行了基因***株KNK005dZ/trc-J4b/lacN17-NSDG株的制备。
得到的KNK005dZ/trc-J4b/lacN17-NSDG株为如下菌株:杀虫贪铜菌H16株的染色体上的phaZ1基因及phaZ6基因的起始密码子至终止密码子被删除,并且phaZ2基因的第16位密码子至终止密码子被删除,在染色体上导入两个拷贝的编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因,并且染色体上的R体特异性烯酰辅酶A水合酶基因的表达被增强的菌株。
(制造例10)KNK005dZ/trc-J4b/lacN17-NSDG/dA0462株的制备
首先,进行了基因破坏用质粒的制备。如下所述进行了制备。
通过使用了合成寡聚DNA的PCR,得到了具有A0462结构基因的上游和下游的碱基序列的DNA片段(序列号16)。用限制性酶SwaI将得到的DNA片段消化。利用DNA连接酶(Ligation High(Toyobo公司制))将该DNA片段与同样经SwaI消化的日本特开2007-259708号公报中记载的载体pNS2X-sacB连接,制备了具有A0462结构基因的上游和下游的碱基序列的基因破坏用质粒载体pNS2X-sacB+A0462UD。
接着,使用基因破坏用质粒载体pNS2X-sacB+A0462UD,将制造例9中制备的KNK005dZ/trc-J4b/lacN17-NSDG株作为亲本菌株,利用与上述同样的方法进行了基因破坏株KNK005dZ/trc-J4b/lacN17-NSDG/dA0462株的制备。
得到的KNK005dZ/trc-J4b/lacN17-NSDG/dA0462株为如下菌株:杀虫贪铜菌H16株的染色体上的phaZ1基因及phaZ6基因的起始密码子至终止密码子被删除,并且phaZ2基因的第16位密码子至终止密码子被删除,在染色体上导入两个拷贝的编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因,染色体上的R体特异性烯酰辅酶A水合酶基因的表达被增强,并且A0462结构基因的起始密码子至终止密码子被删除的菌株。
(制造例11)KNK005dZ/trc-J4b/lacN17-NSDG/dbktB株的制备
使用制造例2中制备的基因破坏用质粒载体pNS2X-sacB+bktBUD,将制造例9中制备的KNK005dZ/trc-J4b/lacN17-NSDG株作为亲本菌株,进行了基因破坏株KNK005dZ/trc-J4b/lacN17-NSDG/dbktB株的制备。
得到的KNK005dZ/trc-J4b/lacN17-NSDG/dbktB株为如下菌株:杀虫贪铜菌H16株的染色体上的phaZ1基因及phaZ6基因的起始密码子至终止密码子被删除,并且phaZ2基因的第16位密码子至终止密码子被删除,在染色体上导入两个拷贝的编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因,染色体上的R体特异性烯酰辅酶A水合酶基因的表达被增强,并且bktB结构基因的起始密码子至终止密码子被删除的菌株。
(制造例12)KNK005dZ/trc-J4b/lacN17-NSDG/dA1528株的制备
使用制造例3中制备的基因破坏用质粒载体pNS2X-sacB+A1528UD,将制造例9中制备的KNK005dZ/trc-J4b/lacN17-NSDG株作为亲本菌株,利用与上述同样的方法进行了基因破坏株KNK005dZ/trc-J4b/lacN17-NSDG/dA1528株的制备。
得到的KNK005dZ/trc-J4b/lacN17-NSDG/dA1528株为如下菌株:杀虫贪铜菌H16株的染色体上的phaZ1基因及phaZ6基因的起始密码子至终止密码子被删除,并且phaZ2基因的第16位密码子至终止密码子被删除,在染色体上导入两个拷贝的编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因,染色体上的R体特异性烯酰辅酶A水合酶基因的表达被增强,并且A1528结构基因的起始密码子至终止密码子被删除的菌株。
(制造例13)KNK005dZ/trc-J4b/lacN17-NSDG/dbktB/dA1528株的制备
使用制造例3中制备的基因破坏用质粒载体pNS2X-sacB+A1528UD,将制造例11中制备的KNK005dZ/trc-J4b/lacN17-NSDG/dbktB株作为亲本菌株,利用与上述同样的方法进行了基因破坏株KNK005dZ/trc-J4b/lacN17-NSDG/dbktB/dA1528株的制备。
得到的KNK005dZ/trc-J4b/lacN17-NSDG/dbktB/dA1528株为如下菌株:杀虫贪铜菌H16株的染色体上的phaZ1基因及phaZ6基因的起始密码子至终止密码子被删除,并且phaZ2基因的第16位密码子至终止密码子被删除,在染色体上导入两个拷贝的编码具有序列号2中记载的氨基酸序列的PHA合成酶的基因,染色体上的R体特异性烯酰辅酶A水合酶基因的表达被增强,bktB结构基因的起始密码子至终止密码子被删除,并且A1528结构基因的起始密码子至终止密码子被删除的菌株。
(比较例1)基于KNK005dZ株的PHA生产
种子培养基的组成为:1w/v%肉浸液(Meat-extract)、1w/v%Bacto-Trypton、0.2w/v%酵母提取物(Yeast-extract)、0.9w/v%Na2HPO4·12H2O、0.15w/v%KH2PO4。
PHA生产中使用的生产培养基的组成为:1.1w/v%Na2HPO4·12H2O、0.19w/v%KH2PO4、0.13w/v%(NH4)2SO4、0.1w/v%MgSO4·7H2O、0.1v/v%微量金属盐溶液(在0.1N盐酸中溶解有1.6w/v%FeCl3·6H2O、1w/v%CaCl2·2H2O、0.02w/v%CoCl2·6H2O、0.016w/v%CuSO4·5H2O、0.012w/v%NiCl2·6H2O而成的溶液)。对于碳源,以1.5w/v%将棕榈仁油添加至培养基中。
将KNK005dZ株的甘油储备液(50μL)接种于种子培养基(5mL)并在培养温度30℃下振荡培养24小时,将得到的培养液作为种子培养物。
在PHA生产培养中,将上述种子培养物1.0v/v%接种于装有50mL生产培养基的坂口烧瓶(Sakaguchi flask),在培养温度30℃下进行振荡培养。培养72小时后,通过离心分离回收菌体,用甲醇进行清洗,进行冷冻干燥,测定了干燥菌体重量。
通过如下方式计算出PHA产量及共聚组成比率。向得到的干燥菌体约20mg添加1ml的硫酸-甲醇混合液(15∶85)和1ml的氯仿并密封,在100℃下加热140分钟,由此得到了PHA分解物的甲酯。在冷却后,向其中加入0.5ml的去离子水并充分混合,然后放置至水层和有机层发生分离。然后,通过毛细管气相色谱对分离得到的有机层中的PHA分解物的单体单元组成进行了分析。气体色谱仪使用岛津制作所GC-17A,毛细管色谱柱使用GL Sciences公司制造的NEUTRA BOND-1(柱长25m、柱内径0.25mm、液态膜厚度0.4μm)。使用He作为载气,柱入口压力为100kPa,注入了1μl样品。温度条件为:在初始温度50~200℃为止以8℃/分的速度升温,进而在200~290℃为止以30℃/分的速度升温。利用上述条件进行分析,结果将得到的PHA的产量及3HH组成比率示于表1。
[表1]
本比较例中生产的PHA是包含3.0mol%的3HH单体单元的P(3HB-共-3HH)。
(比较例2)基于KNK005dZ/dphaA株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对制造例1中制备的KNK005dZ/dphaA株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本比较例中生产的PHA是3HH组成比率为2.9mol%的P(3HB-共-3HH)。即,通过phaA基因的破坏,生产的共聚PHA的3HH组成比没有提高,3HH组成比上升率为1以下。
(实施例1)基于KNK005dZ/dbktB株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对制造例2中制备的KNK005dZ/dbktB株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本实施例中生产的PHA是3HH组成比率为6.5mol%的P(3HB-共-3HH)。即,通过bktB基因的破坏,生产的共聚PHA的3HH组成比提高。上述的乘积(PHA产量降低率×3HH组成比上升率)为1.97。
(实施例2)基于KNK005dZ/dA1528株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对制造例3中制备的KNK005dZ/dA1528株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本实施例中生产的PHA是3HH组成比率为3.3mol%的P(3HB-共-3HH)。即,通过A1528基因的破坏,生产的共聚PHA的3HH组成比提高。上述的乘积(PHA产量降低率×3HH组成比上升率)为1.02。
(实施例3)基于KNK005dZ/dbktB/dA1528株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对制造例4中制备的KNK005dZ/dbktB/dA1528株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本实施例中生产的PHA是3HH组成比率为14.3mol%的P(3HB-共-3HH)。即,通过bktB基因及A1528基因的破坏,生产的共聚PHA的3HH组成比大幅提高。上述的乘积(PHA产量降低率×3HH组成比上升率)为4.13。
(比较例3)基于KNK005dZ/trc-J4b株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对KNK005dZ/trc-J4b株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本比较例中生产的PHA是3HH组成比率为10.1mol%的P(3HB-共-3HH)。
(比较例4)基于KNK005dZ/trc-J4b/dphaA株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对制造例5中制备的KNK005dZ/trc-J4b/dphaA株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本比较例中生产的PHA是3HH组成比率为10.1mol%的P(3HB-共-3HH)。即,通过phaA基因的破坏,生产的共聚PHA的3HH组成比没有提高,3HH组成比上升率为1以下。
(实施例4)基于KNK005dZ/trc-J4b/dbktB株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对制造例6中制备的KNK005dZ/trc-J4b/dbktB株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本实施例中生产的PHA是3HH组成比率为14.3mol%的P(3HB-共-3HH)。即,通过bktB基因的破坏,生产的共聚PHA的3HH组成比提高。上述的乘积(PHA产量降低率×3HH组成比上升率)为1.43。
(实施例5)基于KNK005dZ/trc-J4b/dA1528株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对制造例7中制备的KNK005dZ/trc-J4b/dA1528株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本实施例中生产的PHA是3HH组成比率为10.8mol%的P(3HB-共-3HH)。即,通过A1528基因的破坏,生产的共聚PHA的3HH组成比提高。上述的乘积(PHA产量降低率×3HH组成比上升率)为1.01。
(实施例6)基于KNK005dZ/trc-J4b/dbktB/dA1528株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对制造例8中制备的KNK005dZ/trc-J4b/dbktB/dA1528株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本实施例中生产的PHA是3HH组成比率为23.0mol%的P(3HB-共-3HH)。即,通过bktB基因及A1528基因的破坏,生产的共聚PHA的3HH组成比大幅提高。上述的乘积(PHA产量降低率×3HH组成比上升率)为2.01。
(比较例5)基于KNK005dZ/trc-J4b/lacN17-NSDG株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对制造例9中制备的KNK005dZ/trc-J4b/lacN17-NSDG株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本比较例中生产的PHA是3HH组成比率为12.9mol%的P(3HB-共-3HH)。
(比较例6)基于KNK005dZ/trc-J4b/lacN17-NSDG/dA0462株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对制造例10中制备的KNK005dZ/trc-J4b/lacN17-NSDG/dA0462株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本比较例中生产的PHA是3HH组成比率为12.4mol%的P(3HB-共-3HH)。即,通过A0462基因的破坏,生产的共聚PHA的3HH组成比没有提高,3HH组成比上升率为1以下。
(实施例7)基于KNK005dZ/trc-J4b/lacN17-NSDG/dbktB株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对制造例11中制备的KNK005dZ/trc-J4b/lacN17-NSDG/dbktB株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本实施例中生产的PHA是3HH组成比率为17.1mol%的P(3HB-共-3HH)。即,通过bktB基因的破坏,生产的共聚PHA的3HH组成比提高。上述的乘积(PHA产量降低率×3HH组成比上升率)为1.28。
(实施例8)基于KNK005dZ/trc-J4b/lacN17-NSDG/dA1528株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对制造例12中制备的KNK005dZ/trc-J4b/lacN17-NSDG/dA1528株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本实施例中生产的PHA是3HH组成比率为13.6mol%的P(3HB-共-3HH)。即,通过A1528基因的破坏,生产的共聚PHA的3HH组成比提高。上述的乘积(PHA产量降低率×3HH组成比上升率)为0.96。
(实施例9)基于KNK005dZ/trc-J4b/lacN17-NSDG/dbktB/dA1528株的PHA生产
种子培养基及PHA生产培养基的组成、碳源与比较例1记载的相同。
利用与比较例1同样的方法对制造例13中制备的KNK005dZ/trc-J4b/lacN17-NSDG/dbktB/dA1528株进行培养,通过与比较例1同样的方法计算出PHA产量及3HH组成比率。将得到的PHA产量及3HH组成比率示于表1。
本实施例中生产的PHA是3HH组成比率为29.5mol%的P(3HB-共-3HH)。即,通过bktB基因及A1528基因的破坏,生产的共聚PHA的3HH组成比大幅提高。上述的乘积(PHA产量降低率×3HH组成比上升率)为0.95。
工业实用性
根据本发明,可以在不使PHA产量大幅降低的情况下合成包含例如14mol%以上或20mol%以上的高组成比率的3HH的共聚PHA,这样的PHA能够用于需要高柔软性的聚合物的用途。
序列表自由文本
序列号11:来自于大肠杆菌的经人工修饰的启动子
本说明书中引用的全部刊物、专利及专利申请通过引用整体并入本说明书中。
序列表
<110> 株式会社钟化(KANEKA CORPORATION)
<120> 生产包含高组成比率的3HH单体单元的共聚PHA的转化微生物、以及基于该转化微生物的PHA的制造方法
<130> B170585
<150> JP 2018-005998
<151> 2018-01-17
<160> 16
<170> PatentIn version 3.5
<210> 1
<211> 594
<212> PRT
<213> 豚鼠气单胞菌(Aeromonas caviae)
<400> 1
Met Ser Gln Pro Ser Tyr Gly Pro Leu Phe Glu Ala Leu Ala His Tyr
1 5 10 15
Asn Asp Lys Leu Leu Ala Met Ala Lys Ala Gln Thr Glu Arg Thr Ala
20 25 30
Gln Ala Leu Leu Gln Thr Asn Leu Asp Asp Leu Gly Gln Val Leu Glu
35 40 45
Gln Gly Ser Gln Gln Pro Trp Gln Leu Ile Gln Ala Gln Met Asn Trp
50 55 60
Trp Gln Asp Gln Leu Lys Leu Met Gln His Thr Leu Leu Lys Ser Ala
65 70 75 80
Gly Gln Pro Ser Glu Pro Val Ile Thr Pro Glu Arg Ser Asp Arg Arg
85 90 95
Phe Lys Ala Glu Ala Trp Ser Glu Gln Pro Ile Tyr Asp Tyr Leu Lys
100 105 110
Gln Ser Tyr Leu Leu Thr Ala Arg His Leu Leu Ala Ser Val Asp Ala
115 120 125
Leu Glu Gly Val Pro Gln Lys Ser Arg Glu Arg Leu Arg Phe Phe Thr
130 135 140
Arg Gln Tyr Val Asn Ala Met Ala Pro Ser Asn Phe Leu Ala Thr Asn
145 150 155 160
Pro Glu Leu Leu Lys Leu Thr Leu Glu Ser Asp Gly Gln Asn Leu Val
165 170 175
Arg Gly Leu Ala Leu Leu Ala Glu Asp Leu Glu Arg Ser Ala Asp Gln
180 185 190
Leu Asn Ile Arg Leu Thr Asp Glu Ser Ala Phe Glu Leu Gly Arg Asp
195 200 205
Leu Ala Leu Thr Pro Gly Arg Val Val Gln Arg Thr Glu Leu Tyr Glu
210 215 220
Leu Ile Gln Tyr Ser Pro Thr Thr Glu Thr Val Gly Lys Thr Pro Val
225 230 235 240
Leu Ile Val Pro Pro Phe Ile Asn Lys Tyr Tyr Ile Met Asp Met Arg
245 250 255
Pro Gln Asn Ser Leu Val Ala Trp Leu Val Ala Gln Gly Gln Thr Val
260 265 270
Phe Met Ile Ser Trp Arg Asn Pro Gly Val Ala Gln Ala Gln Ile Asp
275 280 285
Leu Asp Asp Tyr Val Val Asp Gly Val Ile Ala Ala Leu Asp Gly Val
290 295 300
Glu Ala Ala Thr Gly Glu Arg Glu Val His Gly Ile Gly Tyr Cys Ile
305 310 315 320
Gly Gly Thr Ala Leu Ser Leu Ala Met Gly Trp Leu Ala Ala Arg Arg
325 330 335
Gln Lys Gln Arg Val Arg Thr Ala Thr Leu Phe Thr Thr Leu Leu Asp
340 345 350
Phe Ser Gln Pro Gly Glu Leu Gly Ile Phe Ile His Glu Pro Ile Ile
355 360 365
Ala Ala Leu Glu Ala Gln Asn Glu Ala Lys Gly Ile Met Asp Gly Arg
370 375 380
Gln Leu Ala Val Ser Phe Ser Leu Leu Arg Glu Asn Ser Leu Tyr Trp
385 390 395 400
Asn Tyr Tyr Ile Asp Ser Tyr Leu Lys Gly Gln Ser Pro Val Ala Phe
405 410 415
Asp Leu Leu His Trp Asn Ser Asp Ser Thr Asn Val Ala Gly Lys Thr
420 425 430
His Asn Ser Leu Leu Arg Arg Leu Tyr Leu Glu Asn Gln Leu Val Lys
435 440 445
Gly Glu Leu Lys Ile Arg Asn Thr Arg Ile Asp Leu Gly Lys Val Lys
450 455 460
Thr Pro Val Leu Leu Val Ser Ala Val Asp Asp His Ile Ala Leu Trp
465 470 475 480
Gln Gly Thr Trp Gln Gly Met Lys Leu Phe Gly Gly Glu Gln Arg Phe
485 490 495
Leu Leu Ala Glu Ser Gly His Ile Ala Gly Ile Ile Asn Pro Pro Ala
500 505 510
Ala Asn Lys Tyr Gly Phe Trp His Asn Gly Ala Glu Ala Glu Ser Pro
515 520 525
Glu Ser Trp Leu Ala Gly Ala Thr His Gln Gly Gly Ser Trp Trp Pro
530 535 540
Glu Met Met Gly Phe Ile Gln Asn Arg Asp Glu Gly Ser Glu Pro Val
545 550 555 560
Pro Ala Arg Val Pro Glu Glu Gly Leu Ala Pro Ala Pro Gly His Tyr
565 570 575
Val Lys Val Arg Leu Asn Pro Val Phe Ala Cys Pro Thr Glu Glu Asp
580 585 590
Ala Ala
<210> 2
<211> 594
<212> PRT
<213> 豚鼠气单胞菌(Aeromonas caviae)
<400> 2
Met Ser Gln Pro Ser Tyr Gly Pro Leu Phe Glu Ala Leu Ala His Tyr
1 5 10 15
Asn Asp Lys Leu Leu Ala Met Ala Lys Ala Gln Thr Glu Arg Thr Ala
20 25 30
Gln Ala Leu Leu Gln Thr Asn Leu Asp Asp Leu Gly Gln Val Leu Glu
35 40 45
Gln Gly Ser Gln Gln Pro Trp Gln Leu Ile Gln Ala Gln Met Asn Trp
50 55 60
Trp Gln Asp Gln Leu Lys Leu Met Gln His Thr Leu Leu Lys Ser Ala
65 70 75 80
Gly Gln Pro Ser Glu Pro Val Ile Thr Pro Glu Arg Ser Asp Arg Arg
85 90 95
Phe Lys Ala Glu Ala Trp Ser Glu Gln Pro Ile Tyr Asp Tyr Leu Lys
100 105 110
Gln Ser Tyr Leu Leu Thr Ala Arg His Leu Leu Ala Ser Val Asp Ala
115 120 125
Leu Glu Gly Val Pro Gln Lys Ser Arg Glu Arg Leu Arg Phe Phe Thr
130 135 140
Arg Gln Tyr Val Ser Ala Met Ala Pro Ser Asn Phe Leu Ala Thr Asn
145 150 155 160
Pro Glu Leu Leu Lys Leu Thr Leu Glu Ser Gly Gly Gln Asn Leu Val
165 170 175
Arg Gly Leu Ala Leu Leu Ala Glu Asp Leu Glu Arg Ser Ala Asp Gln
180 185 190
Leu Asn Ile Arg Leu Thr Asp Glu Ser Ala Phe Glu Leu Gly Arg Asp
195 200 205
Leu Ala Leu Thr Pro Gly Arg Val Val Gln Arg Thr Glu Leu Tyr Glu
210 215 220
Leu Ile Gln Tyr Ser Pro Thr Thr Glu Thr Val Gly Lys Thr Pro Val
225 230 235 240
Leu Ile Val Pro Pro Phe Ile Asn Lys Tyr Tyr Ile Met Asp Met Arg
245 250 255
Pro Gln Asn Ser Leu Val Ala Trp Leu Val Ala Gln Gly Gln Thr Val
260 265 270
Phe Met Ile Ser Trp Arg Asn Pro Gly Val Ala Gln Ala Gln Ile Asp
275 280 285
Leu Asp Asp Tyr Val Val Asp Gly Val Ile Ala Ala Leu Asp Gly Val
290 295 300
Glu Ala Ala Thr Gly Glu Arg Glu Val His Gly Ile Gly Tyr Cys Ile
305 310 315 320
Gly Gly Thr Ala Leu Ser Leu Ala Met Gly Trp Leu Ala Ala Arg Arg
325 330 335
Gln Lys Gln Arg Val Arg Thr Ala Thr Leu Phe Thr Thr Leu Leu Asp
340 345 350
Phe Ser Gln Pro Gly Glu Leu Gly Ile Phe Ile His Glu Pro Ile Ile
355 360 365
Ala Ala Leu Glu Ala Gln Asn Glu Ala Lys Gly Ile Met Asp Gly Arg
370 375 380
Gln Leu Ala Val Ser Phe Ser Leu Leu Arg Glu Asn Ser Leu Tyr Trp
385 390 395 400
Asn Tyr Tyr Ile Asp Ser Tyr Leu Lys Gly Gln Ser Pro Val Ala Phe
405 410 415
Asp Leu Leu His Trp Asn Ser Asp Ser Thr Asn Val Ala Gly Lys Thr
420 425 430
His Asn Ser Leu Leu Arg Arg Leu Tyr Leu Glu Asn Gln Leu Val Lys
435 440 445
Gly Glu Leu Lys Ile Arg Asn Thr Arg Ile Asp Leu Gly Lys Val Lys
450 455 460
Thr Pro Val Leu Leu Val Ser Ala Val Asp Asp His Ile Ala Leu Trp
465 470 475 480
Gln Gly Thr Trp Gln Gly Met Lys Leu Phe Gly Gly Glu Gln Arg Phe
485 490 495
Leu Leu Ala Glu Ser Gly His Ile Ala Gly Ile Ile Asn Pro Pro Ala
500 505 510
Ala Asn Lys Tyr Gly Phe Trp His Asn Gly Ala Glu Ala Glu Ser Pro
515 520 525
Glu Ser Trp Leu Ala Gly Ala Thr His Gln Gly Gly Ser Trp Trp Pro
530 535 540
Glu Met Met Gly Phe Ile Gln Asn Arg Asp Glu Gly Ser Glu Pro Val
545 550 555 560
Pro Ala Arg Val Pro Glu Glu Gly Leu Ala Pro Ala Pro Gly His Tyr
565 570 575
Val Lys Val Arg Leu Asn Pro Val Phe Ala Cys Pro Thr Glu Glu Asp
580 585 590
Ala Ala
<210> 3
<211> 134
<212> PRT
<213> 豚鼠气单胞菌(Aeromonas caviae)
<400> 3
Met Ser Ala Gln Ser Leu Glu Val Gly Gln Lys Ala Arg Leu Ser Lys
1 5 10 15
Arg Phe Gly Ala Ala Glu Val Ala Ala Phe Ala Ala Leu Ser Glu Asp
20 25 30
Phe Asn Pro Leu His Leu Asp Pro Ala Phe Ala Ala Thr Thr Ala Phe
35 40 45
Glu Arg Pro Ile Val His Gly Met Leu Leu Ala Ser Leu Phe Ser Gly
50 55 60
Leu Leu Gly Gln Gln Leu Pro Gly Lys Gly Ser Ile Tyr Leu Gly Gln
65 70 75 80
Ser Leu Ser Phe Lys Leu Pro Val Phe Val Gly Asp Glu Val Thr Ala
85 90 95
Glu Val Glu Val Thr Ala Leu Arg Glu Asp Lys Pro Ile Ala Thr Leu
100 105 110
Thr Thr Arg Ile Phe Thr Gln Gly Gly Ala Leu Ala Val Thr Gly Glu
115 120 125
Ala Val Val Lys Leu Pro
130
<210> 4
<211> 158
<212> PRT
<213> 杀虫贪铜菌(Cupriavidus necator)
<400> 4
Met Arg Thr Ile Ala Ser Leu Glu Glu Leu Glu Gly Leu Gln Gly Gln
1 5 10 15
Glu Val Ala Val Ser Asp Trp Ile Glu Val Thr Gln Gln Gln Val Asn
20 25 30
Gln Phe Ala Asp Ala Thr Gly Asp His Gln Trp Ile His Ile Asp Val
35 40 45
Glu Arg Ala Lys Lys Glu Ser Pro Tyr Gly Gly Pro Ile Ala His Gly
50 55 60
Phe Leu Thr Leu Ser Leu Leu Pro Lys Phe Met His Asn Ala Leu His
65 70 75 80
Met Pro Ser Lys Ile Gly Val Asn Tyr Gly Leu Asn Arg Val Arg Phe
85 90 95
Thr Ala Pro Val Pro Val Gly Ser Lys Leu Arg Ala Arg Ile Lys Leu
100 105 110
Leu Lys Val Glu Arg Leu Asp Pro Leu Pro Lys Ser Pro Glu Leu Val
115 120 125
Gly Ala Gln Ser Thr Trp Glu Val Thr Val Glu Arg Glu Gly Ser Asp
130 135 140
Arg Pro Val Cys Val Ala Glu Ser Ile Thr Arg Arg Tyr Gly
145 150 155
<210> 5
<211> 151
<212> PRT
<213> 杀虫贪铜菌(Cupriavidus necator)
<400> 5
Met Lys Thr Tyr Glu Asn Ile Ala Asp Leu Gln Pro Leu Val Gly Glu
1 5 10 15
Val Ile Gly Thr Ser Glu Trp Leu Ala Leu Asp Gln Ala Arg Ile Asn
20 25 30
Thr Phe Ala Asp Ala Thr Gly Asp His Gln Trp Ile His Val Asp Val
35 40 45
Glu Arg Ala Lys Asn Gly Pro Phe Gly Ala Pro Ile Ala His Gly Phe
50 55 60
Leu Thr Leu Ser Leu Leu Pro Ala Phe Thr His Ser Ala Tyr Arg Ile
65 70 75 80
Arg Asn Ser Ser Thr Gly Val Asn Tyr Gly Leu Asp Lys Val Arg Phe
85 90 95
Pro Ala Pro Val Pro Val Asp Ser Leu Leu Arg Ala Gln Phe Lys Leu
100 105 110
Met Ser Tyr Glu Ala Leu Glu Asn Gly Gly Ala Gln Phe Lys Val Glu
115 120 125
Met Met Val Glu Arg Gln Gly Gly Ser Lys Pro Val Cys Ile Ala Glu
130 135 140
Ser Ile Leu Arg Arg Phe Pro
145 150
<210> 6
<211> 901
<212> PRT
<213> 解脂耶氏酵母(Yarrowia lipolytica)
<400> 6
Met Ser Gly Glu Leu Arg Tyr Asp Gly Lys Val Val Ile Val Thr Gly
1 5 10 15
Ala Gly Gly Gly Leu Gly Lys Ala Tyr Ala Leu Phe Tyr Gly Ser Arg
20 25 30
Gly Ala Ser Val Val Val Asn Asp Leu Gly Gly Asp Phe Lys Gly Asp
35 40 45
Gly Ala Gln Ala Gly Ser Gly Lys Arg Val Ala Asp Val Val Val Asp
50 55 60
Glu Ile Val Ser Lys Gly Gly Lys Ala Val Ala Asn Tyr Asp Ser Val
65 70 75 80
Glu Asn Gly Asp Lys Ile Val Glu Thr Ala Val Lys Ala Phe Gly Ser
85 90 95
Val His Ile Val Ile Asn Asn Ala Gly Ile Leu Arg Asp Ile Ser Phe
100 105 110
Lys Lys Met Thr Asp Lys Asp Trp Asp Leu Val Tyr Lys Val His Val
115 120 125
Phe Gly Ala Tyr Lys Val Thr Arg Ala Ala Trp Pro Tyr Phe Arg Lys
130 135 140
Gln Lys Tyr Gly Arg Val Ile Ser Thr Ser Ser Ala Ala Gly Leu Tyr
145 150 155 160
Gly Asn Phe Gly Gln Thr Asn Tyr Ser Ala Ala Lys Leu Ala Leu Val
165 170 175
Gly Phe Gly Glu Thr Leu Ala Lys Glu Gly Ala Lys Tyr Asn Ile Thr
180 185 190
Ser Asn Val Ile Ala Pro Leu Ala Ala Ser Arg Met Thr Glu Thr Val
195 200 205
Met Pro Glu Asp Ile Leu Lys Leu Leu Lys Pro Glu Tyr Val Val Pro
210 215 220
Leu Val Gly Tyr Leu Thr His Asp Ser Val Thr Glu Ser Tyr Gly Ile
225 230 235 240
Tyr Glu Val Gly Ala Gly Tyr Met Ala Lys Ile Arg Trp Glu Arg Gly
245 250 255
Asn Gly Ala Val Phe Lys Gly Asp Asp Thr Phe Thr Pro Ser Ala Ile
260 265 270
Leu Lys Arg Trp Asp Glu Val Thr Ser Phe Glu Ser Pro Thr Tyr Pro
275 280 285
Asn Gly Pro Ala Asp Phe Phe Lys Tyr Ala Glu Glu Ser Val Lys Arg
290 295 300
Pro Glu Asn Pro Gln Gly Pro Thr Val Ser Phe Lys Asp Gln Val Val
305 310 315 320
Ile Val Thr Gly Ala Gly Ala Gly Ile Gly Arg Ala Tyr Ser His Leu
325 330 335
Leu Ala Lys Leu Gly Ala Lys Val Val Val Asn Asp Phe Gly Asn Pro
340 345 350
Gln Lys Val Val Asp Glu Ile Lys Ala Leu Gly Gly Ile Ala Val Ala
355 360 365
Asp Lys Asn Asn Val Ile His Gly Glu Lys Val Val Gln Thr Ala Ile
370 375 380
Asp Ala Phe Gly Ala Val His Ala Val Val Asn Asn Ala Gly Ile Leu
385 390 395 400
Arg Asp Lys Ser Phe Ala Asn Met Asp Asp Glu Met Trp Gln Leu Ile
405 410 415
Phe Asp Val His Leu Asn Gly Thr Tyr Ser Val Thr Lys Ala Ala Trp
420 425 430
Pro His Phe Leu Lys Gln Lys Tyr Gly Arg Val Ile Asn Thr Thr Ser
435 440 445
Thr Ser Gly Ile Tyr Gly Asn Phe Gly Gln Ala Asn Tyr Ser Ala Ala
450 455 460
Lys Ala Gly Ile Leu Gly Phe Ser Arg Ala Leu Ala Arg Glu Gly Glu
465 470 475 480
Lys Tyr Asn Ile Leu Val Asn Thr Ile Ala Pro Asn Ala Gly Thr Ala
485 490 495
Met Thr Ala Ser Val Phe Thr Glu Glu Met Leu Glu Leu Phe Lys Pro
500 505 510
Asp Phe Ile Ala Pro Ile Thr Val Leu Leu Ala Ser Asp Gln Ala Pro
515 520 525
Val Thr Gly Asp Leu Phe Glu Thr Gly Ser Ala Trp Ile Gly Gln Thr
530 535 540
Arg Trp Gln Arg Ala Gly Gly Lys Ala Phe Asn Thr Lys Lys Gly Val
545 550 555 560
Thr Pro Glu Met Val Arg Asp Ser Trp Ala Lys Ile Val Asp Phe Asp
565 570 575
Asp Gly Asn Ser Thr His Pro Thr Thr Pro Ser Glu Ser Thr Thr Gln
580 585 590
Ile Leu Glu Asn Ile Phe Asn Val Pro Asp Glu Glu Val Glu Glu Thr
595 600 605
Ala Leu Val Ala Gly Pro Gly Gly Pro Gly Ile Leu Asn Lys Glu Gly
610 615 620
Glu Pro Phe Asp Tyr Thr Tyr Thr Tyr Arg Asp Leu Ile Leu Tyr Asn
625 630 635 640
Leu Gly Leu Gly Ala Lys Ala Asn Glu Leu Lys Tyr Val Phe Glu Gly
645 650 655
Asp Asp Asp Phe Gln Thr Val Pro Thr Phe Gly Val Ile Pro Tyr Met
660 665 670
Gly Gly Leu Ile Thr Thr Asn Tyr Gly Asp Phe Val Pro Asn Phe Asn
675 680 685
Pro Met Met Leu Leu His Gly Glu Gln Tyr Leu Glu Ile Arg Gln Trp
690 695 700
Pro Ile Pro Thr Asn Ala Thr Leu Glu Asn Lys Ala Lys Val Ile Asp
705 710 715 720
Val Val Asp Lys Gly Lys Ala Ala Leu Leu Val Thr Ala Thr Thr Thr
725 730 735
Thr Asn Lys Glu Thr Gly Glu Glu Val Phe Tyr Asn Glu Ser Ser Leu
740 745 750
Phe Ile Arg Gly Ser Gly Gly Phe Gly Gly Lys Ser Thr Gly Thr Asp
755 760 765
Arg Gly Ala Ala Thr Ala Ala Asn Lys Pro Pro Ala Arg Ala Pro Asp
770 775 780
Phe Val Lys Glu Ile Lys Ile Gln Glu Asp Gln Ala Ala Ile Tyr Arg
785 790 795 800
Leu Ser Gly Asp Tyr Asn Pro Leu His Ile Asp Pro Ala Phe Ala Ala
805 810 815
Val Gly Asn Phe Asp Arg Pro Ile Leu His Gly Leu Cys Ser Phe Gly
820 825 830
Val Ser Gly Lys Ala Leu Tyr Asp Gln Phe Gly Pro Phe Lys Asn Ala
835 840 845
Lys Val Arg Phe Ala Gly His Val Phe Pro Gly Glu Thr Leu Lys Val
850 855 860
Glu Gly Trp Lys Glu Gly Asn Lys Val Ile Phe Gln Thr Lys Val Val
865 870 875 880
Glu Arg Gly Thr Thr Ala Ile Ser Asn Ala Ala Ile Glu Leu Phe Pro
885 890 895
Lys Asp Ala Lys Leu
900
<210> 7
<211> 1185
<212> DNA
<213> 杀虫贪铜菌(Cupriavidus necator)
<400> 7
atgacgcgtg aagtggtagt ggtaagcggt gtccgtaccg cgatcgggac ctttggcggc 60
agcctgaagg atgtggcacc ggcggagctg ggcgcactgg tggtgcgcga ggcgctggcg 120
cgcgcgcagg tgtcgggcga cgatgtcggc cacgtggtat tcggcaacgt gatccagacc 180
gagccgcgcg acatgtatct gggccgcgtc gcggccgtca acggcggggt gacgatcaac 240
gcccccgcgc tgaccgtgaa ccgcctgtgc ggctcgggcc tgcaggccat tgtcagcgcc 300
gcgcagacca tcctgctggg cgataccgac gtcgccatcg gcggcggcgc ggaaagcatg 360
agccgcgcac cgtacctggc gccggcagcg cgctggggcg cacgcatggg cgacgccggc 420
ctggtcgaca tgatgctggg tgcgctgcac gatcccttcc atcgcatcca catgggcgtg 480
accgccgaga atgtcgccaa ggaatacgac atctcgcgcg cgcagcagga cgaggccgcg 540
ctggaatcgc accgccgcgc ttcggcagcg atcaaggccg gctacttcaa ggaccagatc 600
gtcccggtgg tgagcaaggg ccgcaagggc gacgtgacct tcgacaccga cgagcacgtg 660
cgccatgacg ccaccatcga cgacatgacc aagctcaggc cggtcttcgt caaggaaaac 720
ggcacggtca cggccggcaa tgcctcgggc ctgaacgacg ccgccgccgc ggtggtgatg 780
atggagcgcg ccgaagccga gcgccgcggc ctgaagccgc tggcccgcct ggtgtcgtac 840
ggccatgccg gcgtggaccc gaaggccatg ggcatcggcc cggtgccggc gacgaagatc 900
gcgctggagc gcgccggcct gcaggtgtcg gacctggacg tgatcgaagc caacgaagcc 960
tttgccgcac aggcgtgcgc cgtgaccaag gcgctcggtc tggacccggc caaggttaac 1020
ccgaacggct cgggcatctc gctgggccac ccgatcggcg ccaccggtgc cctgatcacg 1080
gtgaaggcgc tgcatgagct gaaccgcgtg cagggccgct acgcgctggt gacgatgtgc 1140
atcggcggcg ggcagggcat tgccgccatc ttcgagcgta tctga 1185
<210> 8
<211> 1179
<212> DNA
<213> 杀虫贪铜菌(Cupriavidus necator)
<400> 8
atgaacgaag cagtcatcgt atccaccgcg cggaccccgc tggccaagag ctggaagggc 60
gccttcaaca tgacccacgg cgccacgctc ggcggtcatg ccgtccagca cgccattgcc 120
cgcgccaaga tcgaggccgc cgaagtggaa gacgtgctga tgggctgcgc caacccggaa 180
ggtgccaccg gcgccaacat cgcacgccag atcgcactgc gcgccggctg cccggtgacc 240
gtgcccggcg ccaccgtcaa ccgcttctgc tcgtccggcc tgcagaccat cgccatggcc 300
gcgcagcgcg tgatcgctga tgagggcgac atcttcgtcg ccggcggcgt ggaaagcatc 360
tcgtgcgtgc agcaggagat gaaccgccat atggtccagg aaagctggct gctgaagaac 420
aagccggaaa tctactggaa catgctgcag accgccgaga acgtggccaa gcgctacaac 480
atctcgaagg agcgccagga cgagtacggc gtgcgcagcc agcaacgcgc cgccgccggg 540
caggaagccg gcaagttcaa ggacgagatc gtgccgatga cggtgctggc gggcgtggcc 600
gacaagtcga ccggccagct ggtgaccaag gaagtcaccg tctccgccga cgagggcatc 660
cgcgccgata ccacgctgga aggcgtctcc aagatccgca gcgcggtgcc gggtggcgtg 720
atcaccgccg gcaatgcctc gcagttctcg gacggcgctt cggcagcggt ggtgatgaat 780
gcgcgcgtcg ccgaggcccg cggcctgcag ccgctgggcg tgttccgcgg ctttgccgtg 840
gctggctgcg agccggacga gatgggtatc ggcccggtct ttgctgtgcc caagctgctg 900
aagaaggccg gcctgaaggt cgacgacatc ggcctgtggg agctgaacga agccttcgcc 960
gtgcaggtgc tgtactgcgc cgacacgctc ggcatcccga tggaccggct gaacgtcaac 1020
ggcggcgcca tcgccgtggg ccacccctac ggtgtgtcgg gcgcgcgcct ggtcggccat 1080
gcgctgatcg aaggcaagcg ccgcggcgtc aagtacgtgg tggtgaccat gtgcatcggc 1140
ggcggccagg gcgcggccgg cctgttcgaa gtgctctga 1179
<210> 9
<211> 1182
<212> DNA
<213> 杀虫贪铜菌(Cupriavidus necator)
<400> 9
atgactgacg ttgtcatcgt atccgccgcc cgcaccgcgg tcggcaagtt tggcggctcg 60
ctggccaaga tcccggcacc ggaactgggt gccgtggtca tcaaggccgc gctggagcgc 120
gccggcgtca agccggagca ggtgagcgaa gtcatcatgg gccaggtgct gaccgccggt 180
tcgggccaga accccgcacg ccaggccgcg atcaaggccg gcctgccggc gatggtgccg 240
gccatgacca tcaacaaggt gtgcggctcg ggcctgaagg ccgtgatgct ggccgccaac 300
gcgatcatgg cgggcgacgc cgagatcgtg gtggccggcg gccaggaaaa catgagcgcc 360
gccccgcacg tgctgccggg ctcgcgcgat ggtttccgca tgggcgatgc caagctggtc 420
gacaccatga tcgtcgacgg cctgtgggac gtgtacaacc agtaccacat gggcatcacc 480
gccgagaacg tggccaagga atacggcatc acacgcgagg cgcaggatga gttcgccgtc 540
ggctcgcaga acaaggccga agccgcgcag aaggccggca agtttgacga agagatcgtc 600
ccggtgctga tcccgcagcg caagggcgac ccggtggcct tcaagaccga cgagttcgtg 660
cgccagggcg ccacgctgga cagcatgtcc ggcctcaagc ccgccttcga caaggccggc 720
acggtgaccg cggccaacgc ctcgggcctg aacgacggcg ccgccgcggt ggtggtgatg 780
tcggcggcca aggccaagga actgggcctg accccgctgg ccacgatcaa gagctatgcc 840
aacgccggtg tcgatcccaa ggtgatgggc atgggcccgg tgccggcctc caagcgcgcc 900
ctgtcgcgcg ccgagtggac cccgcaagac ctggacctga tggagatcaa cgaggccttt 960
gccgcgcagg cgctggcggt gcaccagcag atgggctggg acacctccaa ggtcaatgtg 1020
aacggcggcg ccatcgccat cggccacccg atcggcgcgt cgggctgccg tatcctggtg 1080
acgctgctgc acgagatgaa gcgccgtgac gcgaagaagg gcctggcctc gctgtgcatc 1140
ggcggcggca tgggcgtggc gctggcagtc gagcgcaaat aa 1182
<210> 10
<211> 1197
<212> DNA
<213> 杀虫贪铜菌(Cupriavidus necator)
<400> 10
atgaaacaac tgcaagacgc atatatcgtt gcggccaccc gctcgccgat cggcaaggcc 60
ccgaagggcg cgttcaagaa cacgcgcccg gacgacctgc tggcaaccat cctgaaggct 120
gccgtggcgc aggtgccgga cctggacccg aagctgatcg aagacgccat cgtcggctgc 180
gcgattcctg aggcgcagca gggcctgaac gtggcgcgca tcggtgcgct gctgtcgggc 240
ctgcccaata ccgtgggcgg catcaccgtc aaccgcttct gcgcctcggg cgtgagcgcg 300
gtggcgatgg ctgccgaccg catccgcgtg ggcgagtccg acgtgatgat cgccgccggc 360
gtggaatcga tgagcatggt gccgatgatg ggcaactcgc cgtcgatgtc gccggagatc 420
ttcacccgcg acgagaacgt gggcatcgcc tacggcatgg gcctgaccgc cgagaaggtg 480
gcgcagcaat ggcaggtcag ccgcgaggac caggatgcgt tctcgctggc ctcgcaccag 540
aaggccatcg cggcgcagca ggccggcgag ttcaaggacg agatcacgcc gatcgagatc 600
gtcgagcgct tcccggacct cgccagcggc caggtgaacg tgaagtcgcg cacgatctcg 660
ctggacgaag gcccgcgccc ggagacctcg ctggaaggcc tgggcaagct gcgcccggtg 720
tttgccaaca agggcagcgt caccgccggc aacagctcgc agacctccga cggcgccggc 780
gcgctgatcc tggtctcgga aaagatcctc aagcagttca acctggtgcc gctggcgcgc 840
ttcgtctcgt tcgcggtgcg cggcgtgccg cccgagatca tgggcatcgg ccccaaggaa 900
gcgattccgg cggcgctgaa ggctgcgggc ctgacccagg accagcttga ctggatcgaa 960
ctgaacgagg cctttgccgc gcagtcgctg gcggtgatgc gcgacctgca gctggatccg 1020
gccaaggtca accgcatggg cggcgcgatt gcgctgggcc acccgctcgg tgccaccggt 1080
gcgatccgtt cggccacggt ggtgcacgcg ctgcgccgtc acaacctgaa gtacggcatg 1140
gtgaccatgt gcgttggcac gggcatgggc gccgcaggta tcttcgagcg cgtctga 1197
<210> 11
<211> 70
<212> DNA
<213> 人工的
<220>
<223> 来自于大肠杆菌的人工突变启动子
<400> 11
caggctttac acttatgctt ccggctcgta tgttgtgtgg aattgtgagc ggataacaat 60
ttcacacagg 70
<210> 12
<211> 842
<212> DNA
<213> 杀虫贪铜菌(Cupriavidus necator)
<400> 12
gcgcgcattt aaatcacctg gcagggcatg aagctgtttg gcggggagca gcgcttcctc 60
ctggcggagt ccggccacat cgccggcatc atcaacccgc cggccgccaa caagtacggc 120
ttctggcaca acggggccga ggccgagagc ccggagagct ggctggcagg ggcgacgcac 180
cagggcggct cctggtggcc cgagatgatg ggctttatcc agaaccgtga cgaagggtca 240
gagcccgtcc ccgcgcgggt cccggaggaa gggctggccc ccgcccccgg ccactatgtc 300
aaggtgcggc tcaaccccgt gtttgcctgc ccaacagagg aggacgccgc atgacgcttg 360
catgagtgcc ggcgtgcgtc atgcacggcg ccggcaggcc tgcaggttcc ctcccgtttc 420
cattgaaagg actacacaat gactcagcgc attgcgtatg tgaccggcgg catgggtggt 480
atcggaaccg ccatttgcca gcggctggcc aaggatggct ttcgtgtggt ggccggttgc 540
ggccccaact cgccgcgccg cgaaaagtgg ctggagcagc agaaggccct gggcttcgat 600
ttcattgcct cggaaggcaa tgtggctgac tgggactcga ccaagaccgc attcgacaag 660
gtcaagtccg aggtcggcga ggttgatgtg ctgatcaaca acgccggtat cacccgcgac 720
gtggtgttcc gcaagatgac ccgcgccgac tgggatgcgg tgatcgacac caacctgacc 780
tcgctgttca acgtcaccaa gcaggtgatc gacggcatgg ccgaccgtat ttaaatgcgc 840
gc 842
<210> 13
<211> 1009
<212> DNA
<213> 杀虫贪铜菌(Cupriavidus necator)
<400> 13
gcgcgcattt aaatggagtt ccagaccctg ctcgacttta tcgccgaagc cgaactggac 60
cgcgtcggct gcttcgccta ctcgccggtg gagggcgcca ccgccaatga cctgccgggc 120
gcgctgcccg acgaggtgcg cgaggaacgc cgcgcccgct tcatggaagt ggccgaagag 180
gtctcggcgc gccgcctgca gcgcaaggtc ggccagaccc tgcgcgtgct ggtggacgag 240
gtcaaccagg atggcggcat cggccgttcg tccgcggatg cgccggaaat cgacggcctc 300
gtctatatcg cgccgccgga acgccacgcc cagcgctatc gcgccggcga gttcgtcgac 360
gtgaagatca ccggcgccga tggccacgac ctgtggggcg cggtctgaaa cgggttgatt 420
aggtaaaagt acgctcgttc gatttcgtcc gcgtcccgct atactgtgcg gtgcaacata 480
acctcatgga gacaaagtcg gttagccttg cgccttgctt cgctgacgaa gaacctctgc 540
gcgctcggcc tggccgccgt gctcgcgctg gcgggcacgg cgcaggcagc gccggcgacc 600
gagctgtcga ccggcccggt taacaccggg ccagccggcg gcgaaggcct gggcatcaac 660
caggccattc gcgacggcga agcccggcgc ggcggcacct cgctttccac tggcgcgcca 720
aaacccctgg cgccgcggcc ggaatatgcg tcgctgccgg tctacgtcgg caaggtcggc 780
gaccagccgg tgcggctgcg cctgggcccc aagcctgacg agcgcgacag cgtgcgtggc 840
gaatacgccg gccgtggcgc cggtgtgcgc ctgctggcag gcgagtggga ggacggcgcc 900
ttcctgatgg aggagtccga cgacggcacc cgcgtatcgg gcaactggga aggcagcatc 960
gacgccagcg gcgccgtgcg cggcacctgg accgaattta aatgcgcgc 1009
<210> 14
<211> 829
<212> DNA
<213> 杀虫贪铜菌(Cupriavidus necator)
<400> 14
gcgcgcattt aaattgcatg cgggcttgca cgtgccgcat gcgcggctgg tgatccgcaa 60
gggccaccat gccgacgtgg acagctactc cgccttcctg gaggcggacc gcaccacgcg 120
caccgggctg gccggctacc tgcgcgagca tggcgtcagg cgcgtgttct gcgcgggtct 180
ggcgacggac tactgcgtgg cctggagcgc gctcgatgca cgcgccgcgg gcttcgcggc 240
cgcggtgatc gaggatgcct gccgcgccat cgacctggaa gggtcgctgg ccaaagcatg 300
gcaggacctc ggcgccgccg gcgttgcgcg cgtcacgtcc gctgaactgc tcaagggcca 360
gggctgaacc gaaccaccga actgaacgac acaagagaat ccgaggagca agacatgtcg 420
gctgcgggca ccgcgcgggc cacgcccgcc gacatgctcg cctggggccg ggaggtgctg 480
gccagccagc ccttctcggt cctggtcggc accgaactgg cggcgttgtc gccgggcaag 540
gctgagttgc gcctgccgat ccgtcaggac ctgcggcagc agcacggctt cctgcacggc 600
ggcgtggtca gctacctggc cgacaatgcg ctgacctacg cgggcggcgc ggccatggcg 660
gtgccggtcg tgacatccga gtacaagatc aactacgtgc gcccggcgat cggcgagctg 720
ctggtcgccc gcgccgaatg cgtcagcgcc ggccgccagc aggcggtggt gcgctgcgac 780
gtgtacgtcg tcagggatgg cgaggagagg ctctgattta aatgcgcgc 829
<210> 15
<211> 3038
<212> DNA
<213> 豚鼠气单胞菌(Aeromonas caviae)
<400> 15
gcgcgcattt aaatccggac cttcgtgcgg ctcaagcccc agcacgtcgc cgggcagcga 60
aaaacccgtt acctgccgcc agcccagcgg cgattcatag acctgcttgg cgctgccatg 120
gcgcagcggg tagaccgtca gcgcagggcg gccctggcga aacacatgct cgccggtgcg 180
cacctctacc agctccggct gcagcgccat cggcgcgtgc ggcagggggg cttgtggccc 240
ggcattgtgg caaacgtggc gaaagaggca gagcaggcag gctggggcgc cgctgtccgg 300
catggtgtca ttgtcctccg gtgacgatgg ccaagtataa aacgccggca acgcaagcca 360
tctcgctgcg atctgcattc tttcgtatgg ctggtttaaa aatttcgcat tacgggggcg 420
aggctcgttg cgtttgtgcc ataagcgcgg gagcacgccg gcgggcgtaa tgcggattgt 480
gatatgctgc aacgcaacaa taaaggcata ggaggagatc gcgtcacacg atcaggagtc 540
ctccaattgg cgcaacgcaa ttaatgtgag ttagctcact cattaggcac cccaggcttt 600
acacttatgc ttccggctcg tatgttgtgt ggaattgtga gcggataaca atttcacaca 660
ggaaacaatt gcacgtgcag agagacaatc aaatcatgag ccaaccatct tatggcccgc 720
tgttcgaggc cctggcccac tacaatgaca agctgctggc catggccaag gcccagacag 780
agcgcaccgc ccaggcgctg ctgcagacca atctggacga tctgggccag gtgctggagc 840
agggcagcca gcaaccctgg cagctgatcc aggcccagat gaactggtgg caggatcagc 900
tcaagctgat gcagcacacc ctgctcaaaa gcgcaggcca gccgagcgag ccggtgatca 960
ccccggagcg cagcgatcgc cgcttcaagg ccgaggcctg gagcgaacaa cccatctatg 1020
actacctcaa gcagtcctac ctgctcaccg ccaggcacct gctggcctcg gtggatgccc 1080
tggagggcgt cccccagaag agccgggagc ggctgcgttt cttcacccgc cagtacgtca 1140
gcgccatggc ccccagcaac ttcctggcca ccaaccccga gctgctcaag ctgaccctgg 1200
agtccggcgg ccagaacctg gtgcgcggac tggccctctt ggccgaggat ctggagcgca 1260
gcgccgatca gctcaacatc cgcctgaccg acgaatccgc cttcgagctc gggcgggatc 1320
tggccctgac cccgggccgg gtggtgcagc gcaccgagct ctatgagctc attcagtaca 1380
gcccgactac cgagacggtg ggcaagacac ctgtgctgat agtgccgccc ttcatcaaca 1440
agtactacat catggacatg cggccccaga actccctggt cgcctggctg gtcgcccagg 1500
gccagacggt attcatgatc tcctggcgca acccgggcgt ggcccaggcc caaatcgatc 1560
tcgacgacta cgtggtggat ggcgtcatcg ccgccctgga cggcgtggag gcggccaccg 1620
gcgagcggga ggtgcacggc atcggctact gcatcggcgg caccgccctg tcgctcgcca 1680
tgggctggct ggcggcgcgg cgccagaagc agcgggtgcg caccgccacc ctgttcacta 1740
ccctgctgga cttctcccag cccggggagc ttggcatctt catccacgag cccatcatag 1800
cggcgctcga ggcgcaaaat gaggccaagg gcatcatgga cgggcgccag ctggcggtct 1860
ccttcagcct gctgcgggag aacagcctct actggaacta ctacatcgac agctacctca 1920
agggtcagag cccggtggcc ttcgatctgc tgcactggaa cagcgacagc accaatgtgg 1980
cgggcaagac ccacaacagc ctgctgcgcc gtctctacct ggagaaccag ctggtgaagg 2040
gggagctcaa gatccgcaac acccgcatcg atctcggcaa ggtgaagacc cctgtgctgc 2100
tggtgtcggc ggtggacgat cacatcgccc tctggcaggg cacctggcag ggcatgaagc 2160
tgtttggcgg ggagcagcgc ttcctcctgg cggagtccgg ccacatcgcc ggcatcatca 2220
acccgccggc cgccaacaag tacggcttct ggcacaacgg ggccgaggcc gagagcccgg 2280
agagctggct ggcaggggcg acgcaccagg gcggctcctg gtggcccgag atgatgggct 2340
ttatccagaa ccgtgacgaa gggtcagagc ccgtccccgc gcgggtcccg gaggaagggc 2400
tggcccccgc ccccggccac tatgtcaagg tgcggctcaa ccccgtgttt gcctgcccaa 2460
cagaggagga cgccgcatga gcctgacctg ccggcctggt tcaaccagtc ggcagccgac 2520
tagtagtcgg gcagcaccaa tgcgcatcaa gcgcgcacaa gtaaagggag ggcgcctgcc 2580
ctcccttttt ccttgcagca gccgcgtcag ccgcgcgagc ggtccttgac gaacagcgca 2640
gtcaccatgc ccagcacgca cagcgcgacc acatagtggg ccggtgccag cggatcctgc 2700
ttcagcatca gcgtgacgac catcggcgtc agcccgccga agatcgcata cgacacgttg 2760
tacgagaatg acaggcccga gaagcgcacc tgcgccggga acgcattgac cagcacgaac 2820
ggcaccgcgc cgatggtgcc gaccaggaag ccggtcagcg catagagcgg cagcagcagg 2880
tcggggcggg tgaagatcgt cgtgtagaac atataggcgc agatggccag cagcaggccg 2940
ccgacgaaca gcgtgcggcg cgcaccgatg cggtcggcta atgcgccgga gacgacacag 3000
ccgatcgtca ggcacagcgt ggcgatttaa atgcgcgc 3038
<210> 16
<211> 828
<212> DNA
<213> 杀虫贪铜菌(Cupriavidus necator)
<400> 16
gcgcgcattt aaatgccgtc cgacaagatc gtcttcaacg tgcacgagct gctgtacgtg 60
gcgcagaacg aagtgcgcgc gctggccagc gccggctacc gcgcgccgct gccgacgctg 120
gtcccggtgg ccggccgctc gggcattgcc accatcaagg catcgctggt caatatgcgc 180
gacggcggct ttatctcgac gcacgacttc ctgatcgcca gccgcatcgc cgaggcggtg 240
tgcggcggcg acgtcgaggc cggctcgctg gtgagcgagg actggctgct ggcgctggag 300
cgcaaggcct ttgtcgacct gctcggcacc ggcaagacgc aggagcgcat catgggcatg 360
ctgcagaccg gcaagccggt gcgtaactaa cagggcaagc gaggaaccga catcacgcgc 420
ctgcgggacg gtccctcggg actgtcccgc ccttctgcat caggtgaaga aagcagtaac 480
cgggggctgc cgcccgcgac gcgggtcacc aggtagggag gagacaataa tatgcaggag 540
acagccatcc tggccgatgc cgcgtgcgat ctgccgcgcg acgtcatggc ccagctgaag 600
gtccacacga ttccgttccg catccgcgcg ggcgaacact ttgtcgccga tacgcgcgat 660
gaagacgcgc tgcccacgct ctaccagcaa tacctgatcg gccgccagga ccactacgcc 720
gaatcgatcc cgctgctcga gcgcgagctg gaagaacacc tgctgcgcaa cgtggtggcc 780
cactgcgacc gcgccatcct cttcaccatt gccaatttaa atgcgcgc 828
Claims (8)
1.一种转化微生物,其包含:编码氨基酸序列如SEQ ID NO:2所示的PHA合成酶基因、和编码氨基酸序列如SEQ ID NO:5所示且具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因,
所述PHA合成酶基因能够合成包含3-羟基己酸(3HH)单体单元的共聚聚羟基烷酸酯(共聚PHA),
所述转化微生物抑制编码对作为碳原子数6的β-酮脂酰辅酶A的β-酮己酰辅酶A具有硫解活性的至少1种β-酮硫解酶的基因的表达,使该酶活性消失或降低,
phaA基因没有被破坏,
所述转化微生物为来源于杀虫贪铜菌H16株的转化微生物,
编码所述β-酮硫解酶的基因包含源***虫贪铜菌H16株的bktB基因。
2.根据权利要求1所述的转化微生物,其中,所述源***虫贪铜菌H16株的bktB基因包含SEQ ID NO:7所示的碱基序列。
3.根据权利要求1所述的转化微生物,其中,编码所述β-酮硫解酶的基因还包含:
源***虫贪铜菌H16株的A1528基因。
4.根据权利要求1所述的转化微生物,其中,所述源***虫贪铜菌H16株的A1528基因含有SEQ ID NO:8所示的碱基序列。
5.根据权利要求1所述的转化微生物,其进一步使编码具有R体特异性烯酰辅酶A水合酶活性的蛋白质的基因的表达增强。
6.根据权利要求1~3中任一项所述的转化微生物,其进一步使能够合成包含3HH单体单元的共聚PHA的PHA合成酶基因的表达增强。
7.一种包含3HH单体单元的共聚PHA的制造方法,该方法包括:
使用含有油脂或脂肪酸的碳源来培养权利要求1~6中任一项所述的转化微生物的工序、以及对包含3HH单体单元的共聚PHA进行回收的工序。
8.根据权利要求7所述的方法,其中,所述共聚PHA为聚(3-羟基丁酸酯-共-3-羟基己酸酯),即P(3HB-共-3HH)。
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CN114616320A (zh) * | 2019-09-09 | 2022-06-10 | 株式会社钟化 | 转化微生物、以及使用了该微生物的聚羟基烷酸酯的制造方法 |
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JP7270556B2 (ja) | 2023-05-10 |
US11453896B2 (en) | 2022-09-27 |
US20200340020A1 (en) | 2020-10-29 |
EP3741840A4 (en) | 2021-12-08 |
JPWO2019142845A1 (ja) | 2021-01-07 |
WO2019142845A1 (ja) | 2019-07-25 |
CN111615555A (zh) | 2020-09-01 |
EP3741840A1 (en) | 2020-11-25 |
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