合成生物学 ›› 2024, Vol. 5 ›› Issue (3): 561-570.DOI: 10.12211/2096-8280.2023-093
张俊1, 金诗雪2, 云倩2, 瞿旭东1
收稿日期:
2023-11-30
修回日期:
2024-01-08
出版日期:
2024-06-30
发布日期:
2024-07-12
通讯作者:
瞿旭东
作者简介:
基金资助:
ZHANG Jun1, JIN Shixue2, YUN Qian2, QU Xudong1
Received:
2023-11-30
Revised:
2024-01-08
Online:
2024-06-30
Published:
2024-07-12
Contact:
QU Xudong
摘要:
聚酮天然产物包括10 000多种具有广泛生物活性的分子,是获批临床药物中最著名的类别之一。已知活性先导化合物通常需要经过结构修饰改良其吸收、分布、代谢和排泄等特性,从而促进成药开发,但针对聚酮化合物的结构修饰极具挑战,需要应对聚酮骨架中大量的立体中心以及多个惰性碳原子,导致化学合成手段难以对聚酮骨架进行精准和高效的衍生化,因此,通过合成生物学方法实现其结构优化就成为了研究者们关注的热点。自然界中,绝大多数聚酮化合物主要由简单的乙酸盐和丙酸盐结构单元通过聚酮合酶组装而成,而少数存在的具有特殊结构单元的聚酮案例给了研究者以灵感——通过设置和引入非天然结构单元从而有选择性地高效改造聚酮结构。聚酮骨架的生物合成有赖于一个起始单元与多个延伸单元的组装,因此,通过人工设计延伸单元向聚酮引入预期结构被认为是精准高效改造聚酮的有力突破点。本文在此总结了近十年来报道的聚酮非天然延伸单元的三种重要的酶促合成方法,通过挖掘新颖的延伸单元合成酶并探索其底物宽泛性,或利用酶工程手段改造延伸单元合成酶的底物催化范围,获得了大量自然界不存在的延伸单元。此外,本文还归纳了利用非天然延伸单元对聚酮结构进行改造的案例,借助聚酮的天然合成途径或利用改造的合成途径达到预期目的。最后,作者讨论了该研究领域内存在的一些制约因素以及可优化的研究方向,包括聚酮合酶对非天然延伸单元的兼容性问题、非天然延伸单元的前体供给等。近年来,利用非天然延伸单元改造聚酮结构的研究兴趣和热度日益高涨,本文绘制了一份基于延伸单元改造聚酮结构研究的简明清晰的图谱,期望为加速聚酮类药物的高效开发打下坚实基础。
中图分类号:
张俊, 金诗雪, 云倩, 瞿旭东. 聚酮化合物非天然延伸单元的生物合成与结构改造应用[J]. 合成生物学, 2024, 5(3): 561-570.
ZHANG Jun, JIN Shixue, YUN Qian, QU Xudong. Biosynthesis of the unnatural extender units with polyketides and their structural modifications for applications in medicines[J]. Synthetic Biology Journal, 2024, 5(3): 561-570.
图1 代表性聚酮类药物(a)和经典的聚酮天然产物红霉素A的生物合成途径(b)AT—酰基转移酶;ACP—酰基载体蛋白;DEBS—6-脱氧红霉内酯合酶;DH—脱水酶;ER—烯基还原酶;KR—酮还原酶;KS—酮缩合酶;TE—硫酯酶
Fig. 1 Selected polyketide drugs (a) and the classical polyketide synthase assembly line for the biosynthesis of erythromycin A (b)AT—acyltransferase; ACP—acyl carrier protein; DEBS—6-deoxyerythronolide B synthase; DH—dehydratase; ER—enoylreductase; KR—ketoreductase; KS—ketosynthase; TE—thioesterase
图2 天然延伸单元结构分类(a)和丙二酰辅酶A类延伸单元生物合成途径(b)MCS—丙二酰辅酶A合酶;CCRC—巴豆酰辅酶A还原/羧化酶;ACC—酰基辅酶A羧化酶;MCE—甲基丙二酰辅酶A异构酶;CoA—辅酶A;ACP—酰基载体蛋白
Fig. 2 Two classes of natural extender units (a) and the biosynthesis of malonyl-CoA extender units (b)MCS—malonyl-CoA synthetase; CCRC—crotonyl-CoA reductase/carboxylase; ACC—acyl-CoA carboxylase; MCE—methyl malonyl-CoA epimerase; CoA—coenzyme A; ACP—acyl carrier protein
图3 通过酶底物谱探索或酶工程改造途径合成的非天然延伸单元MCS—丙二酰辅酶A合酶;CCRC—巴豆酰辅酶A还原/羧化酶;ACC—酰基辅酶A羧化酶;CoA—辅酶A;SNAC—N-乙酰半胱胺;Pant—泛硫乙胺
Fig. 3 Biosynthesis of unnatural extender units through engineering substrate spectrum or the enzymesMCS—malonyl-CoA synthetase; CCRC—crotonyl-CoA reductase/carboxylase; ACC—acyl-CoA carboxylase; CoA—Coenzyme A; SNAC—N-acetylcysteamine; Pant—pantetheine
图4 利用天然底物混杂性的AT改造聚酮侧链案例(蓝色为非天然延伸单元引入的非天然侧链)
Fig. 4 Modifications of polyketide sidechains through the biosynthesis of unnatural extender units with a natural promiscuous AT(Blue represents unnatural sidechains introduced by unnatural extender units)
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