聚酮化合物非天然延伸单元的生物合成与结构改造应用

张俊; 金诗雪; 云倩; 瞿旭东

doi:10.12211/2096-8280.2023-093

您当前的位置：

首页 >

文章列表页 >

聚酮化合物非天然延伸单元的生物合成与结构改造应用

特约评述 | 更新时间：2025-03-19

- 聚酮化合物非天然延伸单元的生物合成与结构改造应用
- Biosynthesis of the unnatural extender units with polyketides and their structural modifications for applications in medicines
- 合成生物学 2024年5卷第3期页码：561-570
- 作者机构：
  
  1.上海交通大学张江高等研究院，上海 201204
  2.复旦大学药学院，上海 201203
- 作者简介：
  
  [ "张俊（1992—），女，博士后。研究方向为聚酮化合物的生物合成与结构改造。E-mail：zhangjun2021@sjtu.edu.cn" ]
  [ "瞿旭东（1980—），男，教授，博士生导师。研究方向为天然产物生物合成与生物催化，通过生物合成与化学合成结合的方式，发展针对各类天然产物骨架的普适、高效的合成与编辑策略，用于拓展结构多样性和提高药物的生产效率，实现对天然产物资源的深度开发及天然药物的高效创制。E-mail：quxd19@sjtu.edu.cn" ]
- 基金信息：
  
  国家自然科学基金青年科学基金(32200033)
- DOI：10.12211/2096-8280.2023-093
  中图分类号： R915
- 收稿：2023-11-30，
  
  修回：2024-01-08，
  
  纸质出版：2024-06-30
- 稿件说明：
移动端阅览
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
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 DOI： 10.12211/2096-8280.2023-093.

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 DOI： 10.12211/2096-8280.2023-093.

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。

Abstract

The natural products polyketides include over 10 000 molecules with a wide range of bioactivities and are among the most prominent classes of approved clinical agents. Usually

active lead compounds require structural modifications to improve their assimilation

distribution

metabolism

and excretion as well as to facilitate the drug development process. However

due to the large number of stereocenters and inert carbon atoms

it is challenging for chemical synthesis to accurately and efficiently derive polyketide scaffolds

making their biological synthesis for structural optimization of the polyketides a hot topic. In nature

the majority of polyketides are assembled from simple the building blocks acetate and propionate catalyzed by polyketide synthases

but a few polyketides with special buil

ding blocks provide inspiration for researchers to introduce unnatural building blocks selectively into the scaffolds of polyketides for their structure modifications. Polyketides can be built with predictable biosynthetic logic

each module of a modular polyketide synthase elongates the product backbone with two carbons by synergetic actions of its three essential domains: ketosynthase

acyltransferase and acyl carrier protein. The acyltransferase domain selects for and loads a carboxyacyl-Coenzyme A extender unit for the phosphopantetheinyl modification of the acyl carrier protein domain

whereas the ketosynthase domain then uses the extender unit to elongate the growing polyketide intermediate

before passing it to the following module. Given the hierarchical domain and module organization of the type Ⅰ modular PKSs that make these molecules

gene sequences and product structures are directly connected such that changes can be introduced site-selectively into the molecule by targeting building blocks and promiscuous acyltransferase domain with the corresponding domain. Besides

the biosynthesis of polyketide scaffolds depends on the assembly of a starter unit and variable extender units

therefore

introducing anticipated structures into the polyketides through incorporating the artificial extender units is considered as a powerful breakthrough for precise and effective modifications of the polyketides. This review summarizes three important enzymatic synthesis methods for unnatural polyketides extender units reported within the past decade. As results

a large number of unnatural extender units have been obtained through mining novel extender unit synthetase and exploring their substrates

or using enzyme engineering methods to modify the substrate spectrum. Also

this review comments on the cases of modifying polyketide structures using unnatural extender units to achieve the desired derivatives either through the natural synthetic pathway of polyketides or by utilizing modified synthetic pathways. Finally

we discuss some challenges existing in this research field and potential solutions for better applications of polyketides

including the compatibility issue of polyketides synthase with unnatural extender units

precursor supply for unnatural extender units

and

etc

. In recent years

interest and enthusiasm for the modifications of polyketides using unnatural extender moieties have increased dramatically

and our review draws a concise and clear map for the research of polyketide structure modifications by artificial extender units

with an expectation of laying a solid foundation for accelerating the development of polyketides drugs.

关键词

Keywords

references

ROBERTSEN H L , MUSIOL-KROLL E M . Actinomycete-derived polyketides as a source of antibiotics and lead structures for the development of new antimicrobial drugs [J ] . Antibiotics , 2019 , 8 ( 4 ): 157 .

DAVISON E K , BRIMBLE M A . Natural product derived privileged scaffolds in drug discovery [J ] . Current Opinion in Chemical Biology , 2019 , 52 : 1 - 8 .

NEWMAN D J , CRAGG G M . Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019 [J ] . Journal of Natural Products , 2020 , 83 ( 3 ): 770 - 803 .

LI G , LOU H X . Strategies to diversify natural products for drug discovery [J ] . Medicinal Research Reviews , 2018 , 38 ( 4 ): 1255 - 1294 .

KENNEDY J . Mutasynthesis, chemobiosynthesis, and back to semi-synthesis: combining synthetic chemistry and biosynthetic engineering for diversifying natural products [J ] . Natural Product Reports , 2008 , 25 ( 1 ): 25 - 34 .

LIN Z , QU X D . Emerging diversity in polyketide synthase [J ] . Tetrahedron Letters , 2022 , 110 : 154183 .

YAN X L , ZHANG J , TAN H Q , et al . A pair of atypical KAS Ⅲ homologues with initiation and elongation functions program the polyketide biosynthesis in Asukamycin [J ] . Angewandte Chemie International Edition , 2022 , 61 ( 19 ): e202200879 .

KEATINGE-CLAY A T . The structures of type Ⅰ polyketide synthases [J ] . Natural Product Reports , 2012 , 29 ( 10 ): 1050 - 1073 .

ROBBINS T , LIU Y C , CANE D E , et al . Structure and mechanism of assembly line polyketide synthases [J ] . Current Opinion in Structural Biology , 2016 , 41 : 10 - 18 .

HERTWECK C . The biosynthetic logic of polyketide diversity [J ] . Angewandte Chemie International Edition , 2009 , 48 ( 26 ): 4688 - 4716 .

FISCHBACH M A , WALSH C T . Assembly-line enzymology for polyketide and nonribosomal peptide antibiotics: logic, machinery, and mechanisms [J ] . Chemical Reviews , 2006 , 106 ( 8 ): 3468 - 3496 .

WALKER P D , WEIR A N M , WILLIS C L , et al . Polyketide β-branching: diversity, mechanism and selectivity [J ] . Natural Product Reports , 2021 , 38 ( 4 ): 723 - 756 .

CHAN Y A , PODEVELS A M , KEVANY B M , et al . Biosynthesis of polyketide synthase extender units [J ] . Natural Product Reports , 2009 , 26 ( 1 ): 90 - 114 .

LITTLE R F , HERTWECK C . Chain release mechanisms in polyketide and non-ribosomal peptide biosynthesis [J ] . Natural Product Reports , 2022 , 39 ( 1 ): 163 - 205 .

MOORE B S , HERTWECK C . Biosynthesis and attachment of novel bacterial polyketide synthase starter units [J ] . Natural Product Reports , 2002 , 19 ( 1 ): 70 - 99 .

WILSON M C , MOORE B S . Beyond ethylmalonyl-CoA: the functional role of crotonyl-CoA carboxylase/reductase homologs in expanding polyketide diversity [J ] . Natural Product Reports , 2012 , 29 ( 1 ): 72 - 86 .

RAY L , MOORE B S . Recent advances in the biosynthesis of unusual polyketide synthase substrates [J ] . Natural Product Reports , 2016 , 33 ( 2 ): 150 - 161 .

BISSELL A U , RAUTSCHEK J , HOEFGEN S , et al . Biosynthesis of the sphingolipid inhibitors sphingofungins in filamentous fungi requires aminomalonate as a metabolic precursor [J ] . ACS Chemical Biology , 2022 , 17 ( 2 ): 386 - 394 .

ZHAO C H , COUGHLIN J M , JU J H , et al . Oxazolomycin biosynthesis in Streptomyces albus JA3453 featuring an “acyltransferase-less” type Ⅰ polyketide synthase that incorporates two distinct extender units [J ] . Journal of Biological Chemistry , 2010 , 285 ( 26 ): 20097 - 20108 .

CHEN D D , ZHANG Q , ZHANG Q L , et al . Improvement of FK506 production in Streptomyces tsukubaensis by genetic enhancement of the supply of unusual pol yketide extender units via utilization of two distinct site-specific recombination systems [J ] . Applied and Environmental Microbiology , 2012 , 78 ( 15 ): 5093 - 5103 .

KATO Y , BAI L Q , XUE Q , et al . Functional expression of genes involved in the biosynthesis of the novel polyketide chain extension unit, methoxymalonyl-acyl carrier protein, and engineered biosynthesis of 2-desmethyl-2-methoxy-6-deoxyerythronolide B [J ] . Journal of the American Chemical Society , 2002 , 124 ( 19 ): 5268 - 5269 .

CARPENTER S M , WILLIAMS G J . Extender unit promiscuity and orthogonal protein interactions of an aminomalonyl-ACP utilizing trans -acyltransferase from zwittermicin biosynthesis [J ] . ACS Chemical Biology , 2018 , 13 ( 12 ): 3361 - 3373 .

DODGE G J , MALONEY F P , SMITH J L . Protein-protein interactions in “ cis -AT” polyketide synthases [J ] . Natural Product Reports , 2018 , 35 ( 10 ): 1082 - 1096 .

KOSOL S , JENNER M , LEWANDOWSKI J R , et al . Protein-protein interactions in trans -AT polyketide synthases [J ] . Natural Product Reports , 2018 , 35 ( 10 ): 1097 - 1109 .

ZHANG F , JI H N , ALI I , et al . Structural and biochemical insight into the recruitment of acyl carrier protein-linked extender units in ansamitocin biosynthesis [J ] . Chembiochem , 2020 , 21 ( 9 ): 1309 - 1314 .

ZHENG M M , ZHANG J , ZHANG W , et al . An atypical acyl-CoA synthetase enables efficient biosynthesis of extender units for engineering a polyketide carbon scaffold [J ] . Angewandte Chemie International Edition , 2022 , 61 ( 43 ): e202208734 .

AN J H , KIM Y S . A gene cluster encoding malonyl-CoA decarboxylase (MatA), malonyl-CoA synthetase (MatB) and a putative dicarboxylate carrier protein (MatC) in Rhizobium trifolii : cloning, sequencing, and expression of the enzymes in Escherichia coli [J ] . European Journal of Biochemistry , 1998 , 257 ( 2 ): 395 - 402 .

POHL N L , HANS M , LEE H Y , et al . Remarkably broad substrate tolerance of malonyl-CoA synthetase, an enzyme capable of intracellular synthesis of polyketide precursors [J ] . Journal of the American Chemical Society , 2001 , 123 ( 24 ): 5822 - 5823 .

HUGHES A J , KEATINGE-CLAY A . Enzymatic extender unit generation for in vitro polyketide synthase reactions: structural and functional showcasing of Streptomyces coelicolor MatB [J ] . Chemistry & Biology , 2011 , 18 ( 2 ): 165 - 176 .

ERB T J , BERG I A , BRECHT V , et al . Synthesis of C5-dicarboxylic acids from C2-units involving crotonyl-CoA carboxylase/reductase: the ethylmalonyl-CoA pathway [J ] . Proceedings of the National Academy of Sciences of the United States of America , 2007 , 104 ( 25 ): 10631 - 10636 .

YAN Y , CHEN J , ZHANG L H , et al . Multiplexing of combinatorial chemistry in antimycin biosynthesis: expansion of molecular diversity and utility [J ] . Angewandte Chemie International Edition , 2013 , 52 ( 47 ): 12308 - 12312 .

VÖGELI B , GEYER K , GERLINGER P D , et al . Combining promiscuous acyl-CoA oxidase and enoyl-CoA carboxylase/reductases for atypical polyketide extender unit biosynthesis [J ] . Cell Chemical Biology , 2018 , 25 ( 7 ): 833 - 839.e4 .

RAY L , VALENTIC T R , MIYAZAWA T , et al . A crotonyl-CoA reductase-carboxylase independent pathway for assembly of unusual alkylmalonyl-CoA polyketide synthase extender units [J ] . Nature Communications , 2016 , 7 : 13609 .

ZHANG J , ZHENG M M , YAN J Y , et al . A permissive medium chain acyl-CoA carboxylase enables the efficient biosynthesis of extender units for engineering polyketide carbon scaffolds [J ] . ACS Catalysis , 2021 , 11 ( 19 ): 12179 - 12185 .

TRAN T H , HSIAO Y S , JO J , et al . Structure and function of a single-chain, multi-domain long-chain acyl-CoA carboxylase [J ] . Nature , 2015 , 518 ( 7537 ): 120 - 124 .

FARINAS E T , BULTER T , ARNOLD F H . Directed enzyme evolution [J ] . Current Opinion in Biotechnology , 2001 , 12 ( 6 ): 545 - 551 .

NODA-GARCIA L , TAWFIK D S . Enzyme evolution in natural products biosynthesis: target- or diversity-oriented? [J ] . Current Opinion in Chemical Biology , 2020 , 59 : 147 - 154 .

KORYAKINA I , WILLIAMS G J . Mutant malonyl-CoA synthetases with altered specificity for polyketide synthase extender unit generation [J ] . Chembiochem , 2011 , 12 ( 15 ): 2289 - 2293 .

KORYAKINA I , MCARTHUR J , RANDALL S , et al . Poly specific trans -acyltransferase machinery revealed via engineered acyl-CoA synthetases [J ] . ACS Chemical Biology , 2013 , 8 ( 1 ): 200 - 208 .

ZHANG L H , MORI T , ZHENG Q F , et al . Rational control of polyketide extender units by structure-based engineering of a crotonyl-CoA carboxylase/reductase in antimycin biosynthesis [J ] . Angewandte Chemie International Edition , 2015 , 54 ( 45 ): 13462 - 13465 .

QUADE N , HUO L J , RACHID S , et al . Unusual carbon fixation gives rise to diverse polyketide extender units [J ] . Nature Chemical Biology , 2012 , 8 ( 1 ): 117 - 124 .

TIAN W Y , CHEN X R , ZHANG J , et al . Biosynthesis of tetronates by a nonribosomal peptide synthetase-polyketide synthase system [J ] . Organic Letters , 2023 , 25 ( 10 ): 1628 - 1632 .

AWAKAWA T , FUJIOKA T , ZHANG L H , et al . Reprogramming of the antimycin NRPS-PKS assembly lines inspired by gene evolution [J ] . Nature Communications , 2018 , 9 ( 1 ): 3534 .

WALKER M C , THURONYI B W , CHARKOUDIAN L K , et al . Expanding the fluorine chemistry of living systems using engineered polyketide synthase pathways [J ] . Science , 2013 , 341 ( 6150 ): 1089 - 1094 .

SIRIRUNGRUANG S , AD O , PRIVALSKY T M , et al . Engineering site-selective incorporation of fluorine into polyketides [J ] . Nature Chemical Biology , 2022 , 18 ( 8 ): 886 - 893 .

RITTNER A , JOPPE M , SCHMIDT J J , et al . Chemoenzymatic synthesis of fluorinated polyketides [J ] . Nature Chemistry , 2022 , 14 ( 9 ): 1000 - 1006 .

LI Y , ZHANG W , ZHANG H , et al . Structural basis of a broadly selective acyltransferase from the polyketide synthase of splenocin [J ] . Angewandte Chemie International Edition , 2018 , 57 ( 20 ): 5823 - 5827 .

KALKREUTER E , CROWETIPTON J M , LOWELL A N , et al . Engineering the substrate specificity of a modular polyketide synthase for installation of consecutive non-natural extender units [J ] . Journal of the American Chemical Society , 2019 , 141 ( 5 ): 1961 - 1969 .

ENGLUND E , SCHMIDT M , NAVA A A , et al . Expanding extender substrate selection for unnatural polyketide biosynthesis by acyltransferase domain exchange within a modular polyketide synthase [J ] . Journal of the American Chemical Society , 2023 , 145 ( 16 ): 8822 - 8832 .

MUSIOL-KROLL E M , WOHLLEBEN W . Acyltransferases as tools for polyketide synthase engineering [J ] . Antibiotics , 2018 , 7 ( 3 ): 62 .

CHANG C C , HUANG R , YAN Y , et al . Uncovering the formation and selection of benzylmalonyl-CoA from the biosynthesis of splenocin and enterocin reveals a versatile way to introduce amino acids into polyketide carbon scaffolds [J ] . Journal of the American Chemical Society , 2015 , 137 ( 12 ): 4183 - 4190 .

ZHU X J , LIU J , ZHANG W J . De novo biosynthesis of terminal alkyne-labeled natural products [J ] . Nature Chemical Biology , 2015 , 11 ( 2 ): 115 - 120 .

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

卤化酶在生物催化中的应用：机制解析、定向进化和绿色制造的进展

黄酮类化合物生物合成及其在化妆品中应用的研究

含氨基乙烯半胱氨酸核糖体肽的生物合成与化学合成

近十年天然产物药物的生物合成研究进展