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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2022, Vol. 42 Issue (6): 76-85    DOI: 10.13523/j.cb.2201051
综述     
微生物合成奇数链脂肪酸研究进展*
白松,侯正杰,高庚荣,乔斌,程景胜()
天津大学化工学院 教育部合成生物学前沿科学中心 系统生物工程教育部重点实验室 天津 300372
Advances in the Synthesis of Odd-chain Fatty Acids by Microorganisms
BAI Song,HOU Zheng-jie,GAO Geng-rong,QIAO Bin,CHENG Jing-sheng()
Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering Ministry of Education, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300372, China
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摘要：

奇数链脂肪酸(odd-chain fatty acids,OCFA)在自然界分布广泛但含量低,在食品、医药健康和工业等领域有着巨大的应用潜力。目前获取OCFA的方法主要为提取法和化学合成法,但成本高、效率低,而通过微生物发酵有望实现OCFA大规模工业生产。总结OCFA的应用范围和天然合成OCFA的微生物种类,详述微生物合成OCFA的代谢途径,并从基因工程策略和发酵调控策略两方面综述目前提升OCFA产量的研究现状,旨在为利用合成生物学策略改造和提升微生物合成OCFA的能力提供较为系统的理论依据。
关键词： 奇数链脂肪酸;  微生物发酵;  合成生物学;  代谢途径    
Abstract:

Odd-chain fatty acids (OCFAs) are widely distributed in nature, while their level is low. OCFA has huge application potential in the fields of medicine, health, and industry. The current methods of obtaining OCFA are mainly included in the extraction and chemical synthesis, which limits its application due to the higher-cost and the lower-efficiency. Microbial fermentation is one of the most promising strategies for large-scale industrial production. This article briefly discusses the scope of application of OCFA, summarizes the microorganisms that can naturally synthesize OCFA, introduces in detail the related metabolic pathways involved in microbial synthesis of OCFA, and reviews the current strategies of genetic engineering and fermentation regulation for improving OCFA production. Taken together, this summary aims to provide a more systematic and comprehensive theoretical basis for improving OCFA production of microorganism by synthetic biology strategies.
Key words: Odd-chain fatty acid(OCFA)    Microorganism fermentation    Synthetic biology    Metabolic pathways
收稿日期: 2022-01-27 出版日期: 2022-07-07
ZTFLH:  Q939  
基金资助: *国家重点研发计划(2018YFA0902200);国家自然科学基金(21878224)
通讯作者: 程景胜     E-mail: jscheng@tju.edu.cn
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白松
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引用本文:

白松,侯正杰,高庚荣,乔斌,程景胜. 微生物合成奇数链脂肪酸研究进展*[J]. 中国生物工程杂志, 2022, 42(6): 76-85.

BAI Song,HOU Zheng-jie,GAO Geng-rong,QIAO Bin,CHENG Jing-sheng. Advances in the Synthesis of Odd-chain Fatty Acids by Microorganisms. China Biotechnology, 2022, 42(6): 76-85.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2201051    或    https://manu60.magtech.com.cn/biotech/CN/Y2022/V42/I6/76

OCFA的种类 用途 作用机理 参考文献
十三烷二酸(tridecanedioic acid) 用于合成透明聚酰胺 与4,4'-二氨基二环己基甲烷(4,4'-diaminodicyclohexyl methane,PACM)成盐进行反应 [22]
壬二酸(azelaic acid) 治疗黄褐斑、痤疮病、恶性色素病 竞争性酪氨酸酶抑制剂 [23-24]
(9Z)-9-十七碳烯酸[(9Z)-9-heptadecenoic acid] 治疗牛皮癣、过敏、自身免疫疾病 阻止或减少TNF-α等介质的释放,抑制淋巴细胞活化,刺激巨噬细胞,使炎症过程正常化 [15]
庚烷酸(heptanoate) 抗惊厥、治疗癫痫病;长链脂肪酸氧化紊乱 代谢成C5酮、β-酮戊酸盐或β-羟基戊酸盐,通过一元羧酸转运体进入大脑;提供血管间质代谢物,取代缺乏的三羧酸循环中间体;提高有效的能量代谢,显著改善心脏结构和功能 [4,25]
十五烷酸(pentadecanoic acid);十七烷酸(heptadecanoic acid) 与心血管疾病、肥胖症、Ⅱ型糖尿病的发病呈负相关 OCFA能够降低患Ⅱ型糖尿病的风险;血浆磷脂中的C15:0和C17:0浓度与心血管疾病和肥胖指标呈负相关 [25-26]
十五烷酸(pentadecanoic acid) 评估乳脂摄入的标记物 OCFA来源于瘤胃微生物发酵或微生物从头合成,然后转入宿主动物,表现为胆固醇、磷脂、血清和脂肪组织中的C15:0的相对含量与乳脂摄入呈正相关 [27-28]
十五烷酸(pentadecanoic acid) 对人乳腺癌MCF-7/SC细胞具有选择性的细胞毒性作用 抑制IL-6诱导的JAK2/STAT3信号通路,诱导细胞周期阻滞在sub-G1期,并促进MCF-7/SC中半胱天冬酶依赖性细胞凋亡 [29]
十五烷酸(pentadecanoic acid) 减轻炎症、贫血、血脂异常和体内纤维化 可能是通过与关键代谢调节剂结合和修复线粒体功能 [30]
十一烷酸(undecanoic acid);十五烷酸(pentadecanoic acid) 抑制癌细胞增殖 对组蛋白去乙酰化酶具有抑制作用,能够剂量依赖性地促进MCF-7乳腺癌和A549肺癌细胞中α-微管蛋白的乙酰化 [31]
表1  OCFA应用概括
图1  常见奇数链脂肪酸和偶数链脂肪酸的化学结构
图2  Y. lipolytica中脂肪酸内源合成及代谢途径
图3  脂肪酸合成起始路径
图4  微生物合成OCFA代谢途径
生产菌株 OCFA组成 主要策略 含量 参考文献
Escherichia coli C11:0,C13:0 丙酸为碳源,并在大肠杆菌中耦合表达酰基-ACP硫酯酶、丙酰辅酶A合酶和β-酮酰-ACP合酶III 1 205 mg/L,占总脂肪酸的83.2% [9]
Escherichia coli C11:0,C13:0,C15:0 引入硫酯酶基因,过表达来源于S. enterica的丙酰辅酶A合酶,并外源补加丙酸 297 mg/L [41]
Escherichia coli C7-C13的mcl-PHA 引入丙酸同化和代谢途径至反向脂肪酸β-氧化,敲除丙酮酸氧化酶和丙酮酸甲酸裂解酶,异源表达来源于Ralstonia eutropha的prpP和prpE基因 奇数链mcl-PHA约占总产量的20.03% [59]
Yarrowia lipolytica C15:0,C17:0,C17:1,C19:0 构建包含七个基因的模块化代谢途径从头合成奇数链脂肪酸 0.36 g/L [11]
Yarrowia lipolytica C15:0,C17:0,C17:1,C19:0 评估不同来源的丙酸激活酶和丙酰辅酶A转移酶,同时表达β-酮硫醇酶 1.87 g/L [49]
表2  工程策略促进微生物合成OCFA研究进展
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