含氨基乙烯半胱氨酸核糖体肽的生物合成与化学合成
Biosynthesis and chemical synthesis of ribosomally synthesized and post-translationally modified peptides containing aminovinyl cysteine
- 合成生物学 2024年5卷第5期 页码：981-996
- 作者机构：
1.南京大学化学与生物医药创新研究院，配位化学国家重点实验室，南京大学化学化工学院，江苏省先进有机材料重点实验室，江苏 南京 210093
2.南京药石科技股份有限公司，江苏 南京 210032
- 作者简介：
[ "谢向前（1997—），男，博士研究生。研究方向为天然产物的生物合成等。E-mail：dg21240123@smail.nju.edu.cn" ]
[ "李进（1987—），男，研究员，执行总监。研究方向为非天然氨基酸分子砌块的合成与应用。E-mail：li_jin@PharmaBlock.com" ]
- 基金信息：国家自然科学基金(22325702)
DOI：10.12211/2096-8280.2024-037
中图分类号： Q936收稿：2024-04-17，
修回：2024-07-26，
纸质出版：2024-10-31
- 稿件说明：
移动端阅览
谢向前， 郭雯， 王欢， 李进. 含氨基乙烯半胱氨酸核糖体肽的生物合成与化学合成［J］. 合成生物学， 2024， 5（5）： 981-996
XIE Xiangqian， GUO Wen， WANG Huan， LI Jin. Biosynthesis and chemical synthesis of ribosomally synthesized and post-translationally modified peptides containing aminovinyl cysteine［J］. Synthetic Biology Journal， 2024， 5（5）： 981-996
谢向前， 郭雯， 王欢， 李进. 含氨基乙烯半胱氨酸核糖体肽的生物合成与化学合成［J］. 合成生物学， 2024， 5（5）： 981-996 DOI： 10.12211/2096-8280.2024-037.
XIE Xiangqian， GUO Wen， WANG Huan， LI Jin. Biosynthesis and chemical synthesis of ribosomally synthesized and post-translationally modified peptides containing aminovinyl cysteine［J］. Synthetic Biology Journal， 2024， 5（5）： 981-996 DOI： 10.12211/2096-8280.2024-037.
摘要
核糖体肽是一类拥有化学结构和生物活性多样性的多肽天然产物家族，在药物开发方面具有巨大的发展潜力。氨基乙烯半胱氨酸（AviCys）是部分核糖体肽类天然产物中存在的一种特殊C末端交联结构单元。含有AviCys单元的核糖体肽类天然环肽往往具有优良的抗菌或抗肿瘤活性，且AviCys大环结构对其生物活性至关重要。本文围绕此类天然环肽的生物合成和化学合成进行了总结：①羊毛硫肽、lipolanthines、linaridins和thioamitides四类核糖体肽天然产物中AviCys结构单元的生物合成研究进展，主要包括C末端半胱氨酸的氧化脱羧反应，丝氨酸/苏氨酸或半胱氨酸脱水或脱硫反应，以及AviCys环化反应；②针对含AviCys结构单元环肽的化学合成方法，包括自由基硫醇-炔偶联、氧化脱羧/脱羰、酰胺与缩醛缩合等。本综述同时对相关研究中存在的若干挑战和尚待解决的问题进行了梳理和总结，包括生物合成过程中尚未得到深入解析的环化步骤、化学合成中尚未解决的立体选择性和化学兼容性等。综上，对含AviCys结构单元天然环肽的生物合成途径全面解析及化学合成方法的开发， 有望为此类生物功能环肽及其衍生物的制备与生物工程改造奠定基础，推动该类功能环肽在生命科学和药物科学领域的应用。
Abstract
Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of peptide natural products that often contain noncanonical amino acids and structural motifs with promising potential as drug leads. One unique structural unit found in RiPPs is the C-terminal
S
-[(
Z
)-2-aminoethenyl
]
-D-cysteine (AviCys) or (2
S
3
S
)-
S
-[(
Z
)-2-aminoethenyl
]
-3-methyl-D-cysteine (AviMeCys). Avi(Me)Cys-containing RiPPs usually exhibit potent antimicrobial or anticancer activities
which strictly require the presence of the C-terminal AviCys motifs. Despite the potential of Avi(Me)Cys-containing RiPPs as
drug leads
lack of synthetic methods and biosynthetic systems to access these type of cyclic peptides impede the application of Avi(Me)Cys-containing peptides in medicinal chemistry. In this review
we summarize the current understanding of the biosynthesis of Avi(Me)Cys-containing peptides and the progress made in the development of chemical methods to synthesize Avi(Me)Cys motifs and derivatives. This review contains two following major sections: ① The biosynthetic process of Avi(Me)Cys motifs in the different families of Avi(Me)Cys-containing RiPPs
including lanthipeptides
lipolanthines
linaridins and thioamitides
are introduced with three essential enzymatic steps: first
a cysteine decarboxylase oxidatively decarboxylated the C-terminal cysteine
generating a highly reactive enethiol; subsequently
distinct enzymes catalyze the dehydration of a serine/threonine (Ser/Thr) residue or the dethiolation of a Cys residue in the precursor peptide by incorporating a dehydroalanine (Dha) or dehydrobutyrine (Dhb) residue; finally
a putative cyclase catalyzes the Michael-type addition between the enethiol group and a Dha/Dhb residue to yield the Avi(Me)Cys motif. Detailed enzymatic investigation of these biosynthetic steps are introduced. ② The chemical synthesis of the Avi(Me)Cys building block and their analogues via diverse synthetic methodology
including the radical thiol-yne coupling
the oxidative decarboxylation/decarbonylation
and the condensation of amides with acetals. Overall
further elucidation of the complete biosynthetic pathway for Avi(Me)Cys motifs in related RiPPs
along with advancements in the chemical synthesis of Avi(Me)Cys-containing natural product peptides
will facilitate the effective utilization of these bioactive peptide natural products.
2
关键词
Keywords
references
ARNISON P G , BIBB M J , BIERBAUM G , et al . Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature [J ] . Natural Product Reports , 2013 , 30 ( 1 ): 108 - 160 .
MONTALBÁN-LÓPEZ M , SCOTT T A , RAMESH S , et al . New developments in RiPP discovery, enzymology and engineering [J ] . Natural Product Reports , 2021 , 38 ( 1 ): 130 - 239 .
SCHEIDLER C M , KICK L M , SCHNEIDER S . Ribosomal peptides and small proteins on the rise [J ] . Chembiochem , 2019 , 20 ( 12 ): 1479 - 1486 .
CHENG B T , XUE Y Q , DUAN Y T , et al . Enzymatic formation of an aminovinyl cysteine residue in ribosomal peptide natural products [J ] . ChemPlusChem , 2024 , 89 ( 6 ): e202400047 .
GRANT-MACKIE E S , WILLIAMS E T , HARRIS P W R , et al . Aminovinyl cysteine containing peptides: a unique motif that imparts key biological activity [J ] . JACS Au , 2021 , 1 ( 10 ): 1527 - 1540 .
DISCHINGER J , BASI CHIPALU S , BIERBAUM G . Lantibiotics: promising candidates for future applications in health care [J ] . International Journal of Medical Microbiology , 2014 , 304 ( 1 ): 51 - 62 .
HAYAKAWA Y , SASAKI K , ADACHI H , et al . Thioviridamide, a novel apoptosis inducer in transformed cells from Streptomyces olivoviridis [J ] . Journal of Antibiotics , 2006 , 59 ( 1 ): 1 - 5 .
CASTIGLIONE F , LAZZARINI A , CARRANO L , et al . Determining the structure and mode of action of microbisporicin, a potent lantibiotic active against multiresistant pathogens [J ] . Chemistry & Biology , 2008 , 15 ( 1 ): 22 - 31 .
ALLGAIER H , JUNG G , WERNER R G , et al . Epidermin: sequencing of a heterodetic tetracyclic 21-peptide amide antibiotic [J ] . European Journal of Biochemistry , 1986 , 160 ( 1 ): 9 - 22 .
CHATTERJEE S , CHATTERJEE S , LAD S J , et al . Mersacidin, a new antibiotic from Bacillus . Fermentation, isolation, purification and chemical characterization [J ] . Journal of Antibiotics , 1992 , 45 ( 6 ): 832 - 838 .
XU M , ZHANG F , CHENG Z , et al . Functional genome mining reveals a classⅤlanthipeptide containing a D-amino acid introduced by an F 420 H 2 -dependent reductase [J ] . Angewandte Chemie International Edition , 2020 , 59 ( 41 ): 18029 - 18035 .
WIEBACH V , MAINZ A , SIEGERT M A J , et al . The anti-staphylococcal lipolanthines are ribosomally synthesized lipopeptides [J ] . Nature Chemical Biology , 2018 , 14 ( 7 ): 652 - 654 .
KOZAKAI R , ONO T , HOSHINO S , et al . Acyltransferase that catalyses the condensation of polyketide and peptide moieties of goadvionin hybrid lipopeptides [J ] . Nature Chemistry , 2020 , 12 ( 9 ): 869 - 877 .
REN H Q , HUANG C S , PAN Y W , et al . Non-modular fatty acid synthases yield distinct N-terminal acylation in ribosomal peptides [J/OL ] . Nature Chemistry , 2024 . ( 2024-03-25 )[ 2024-04-01 ] . https://doi.org/10.1038/s41557-024-01491-3 https://doi.org/10.1038/s41557-024-01491-3 .
KOMIYAMA K , OTOGURO K , SEGAWA T , et al . A new antibiotic, cypemycin. Taxonomy, fermentation, isolation and biological characteristics [J ] . Journal of Antibiotics , 1993 , 46 ( 11 ): 1666 - 1671 .
SHANG Z , WINTER J M , KAUFFMAN C A , et al . Salinipeptins: integrated genomic and chemical approaches reveal unusual D-amino acid-containing ribosomally synthesized and post-translationally modified peptides (RiPPs) from a great salt lake Streptomyces sp [J ] . ACS Chemical Biology , 2019 , 14 ( 3 ): 415 - 425 .
DAHLEM C , SIOW W X , LOPATNIUK M , et al . Thioholgamide A, a new anti-proliferative anti-tumor agent, modulates macrophage polarization and metabolism [J ] . Cancers , 2020 , 12 ( 5 ): 1288 .
ONGEY E L , NEUBAUER P . Lanthipeptides: chemical synthesis versus in vivo biosynthesis as tools for pharmaceutical production [J ] . Microbial Cell Factories , 2016 , 15 : 97 .
ONGEY E L , YASSI H , PFLUGMACHER S , et al . Pharmacological and pharmacokinetic properties of lanthipeptides undergoing clinical studies [J ] . Biotechnology Letters , 2017 , 39 ( 4 ): 473 - 482 .
BANERJEE B , LITVINOV D N , KANG J , et al . Stereoselective additions of thiyl radicals to terminal ynamides [J ] . Organic Letters , 2010 , 12 ( 11 ): 2650 - 2652 .
GARCÍA-REYNAGA P , CARRILLO A K , VANNIEUWENHZE M S . Decarbonylative approach to the synthesis of enamides from amino acids: stereoselective synthesis of the ( Z )- aminovinyl-D-cysteine unit of mersacidin [J ] . Organic Letters , 2012 , 14 ( 4 ): 1030 - 1033 .
CARRILLO A K , VANNIEUWENHZE M S . Synthesis of the AviMeCys-containing D-ring of mersacidin [J ] . Organic Letters , 2012 , 14 ( 4 ): 1034 - 1037 .
LUTZ J A , SUBASINGHEGE DON V , KUMAR R , et al . Influence of sulfur on acid-mediated enamide formation [J ] . Organic Letters , 2017 , 19 ( 19 ): 5146 - 5149 .
LUTZ J A , TAYLOR C M . Synthesis of the aminovinylcysteine-containing C-terminal macrocycle of the linaridins [J ] . Organic Letters , 2020 , 22 ( 5 ): 1874 - 1877 .
KUMASHIRO M , OHSAWA K , DOI T . Photocatalyzed oxidative decarboxylation forming aminovinylcysteine containing peptides [J ] . Catalysts , 2022 , 12 ( 12 ): 1615 .
ROGERS L A , WHITTIER E O . Limiting factors in the lactic fermentation [J ] . Journal of Bacteriology , 1928 , 16 ( 4 ): 211 - 229 .
REPKA L M , CHEKAN J R , NAIR S K , et al . Mechanistic understanding of lanthipeptide biosynthetic enzymes [J ] . Chemical Reviews , 2017 , 117 ( 8 ): 5457 - 5520 .
GENG M X , SMITH L . Improving the attrition rate of Lanthipeptide discovery for commercial applications [J ] . Expert Opinion on Drug Discovery , 2018 , 13 ( 2 ): 155 - 167 .
BAKHTIARY A , COCHRANE S A , MERCIER P , et al . Insights into the mechanism of action of the two-peptide lantibiotic lacticin 3147 [J ] . Journal of the American Chemical Society , 2017 , 139 ( 49 ): 17803 - 17810 .
BREUKINK E , DE KRUIJFF B . Lipid Ⅱ as a target for antibiotics [J ] . Nature Reviews Drug Discovery , 2006 , 5 ( 4 ): 321 - 323 .
BRÖTZ H , JOSTEN M , WIEDEMANN I , et al . Role of lipid-bound peptidoglycan precursors in the formation of pores by nisin, epidermin and other lantibiotics [J ] . Molecular Microbiology , 1998 , 30 ( 2 ): 317 - 327 .
HSU S T D , BREUKINK E , TISCHENKO E , et al . The nisin-lipid Ⅱ complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics [J ] . Nature Structural & Molecular Biology , 2004 , 11 ( 10 ): 963 - 967 .
DICKMAN R , MITCHELL S A , FIGUEIREDO A M , et al . Molecular recognition of lipid Ⅱ by lantibiotics: synthesis and conformational studies of analogues of nisin and mutacin rings A and B [J ] . Journal of Organic Chemistry , 2019 , 84 ( 18 ): 11493 - 11512 .
POKHREL R , BHATTARAI N , BARAL P , et al . Molecular mechanisms of pore formation and membrane disruption by the antimicrobial lantibiotic peptide Mutacin 1140 [J ] . Physical Chemistry Chemical Physics , 2019 , 21 ( 23 ): 12530 - 12539 .
HSU S T D , BREUKINK E , BIERBAUM G , et al . NMR study of mersacidin and lipid Ⅱ interaction in dodecylphosphocholine micelles. Conformational changes are a key to antimicrobial activity [J ] . Journal of Biological Chemistry , 2003 , 278 ( 15 ): 13110 - 13117 .
KRUSZEWSKA D , SAHL H G , BIERBAUM G , et al . Mersacidin eradicates methicillin-resistant Staphylococcus aureus (MRSA) in a mouse rhinitis model [J ] . Journal of Antimicrobial Chemotherapy , 2004 , 54 ( 3 ): 648 - 653 .
BLAESSE M , KUPKE T , HUBER R , et al . Crystal structure of the peptidyl-cysteine decarboxylase EpiD complexed with a pentapeptide substrate [J ] . EMBO Journal , 2000 , 19 ( 23 ): 6299 - 6310 .
BLAESSE M , KUPKE T , HUBER R , et al . Structure of MrsD, an FAD-binding protein of the HFCD family [J ] . Acta Crystallographica Section D , Biological Crystallography, 2003 , 59 ( Pt 8 ): 1414 - 1421 .
MO T L , YUAN H , WANG F T , et al . Convergent evolution of the Cys decarboxylases involved in aminovinyl-cysteine (AviCys) biosynthesis [J ] . FEBS Letters , 2019 , 593 ( 6 ): 573 - 580 .
SIT C S , YOGANATHAN S , VEDERAS J C . Biosynthesis of aminovinyl-cysteine-containing peptides and its application in the production of potential drug candidates [J ] . Accounts of Chemical Research , 2011 , 44 ( 4 ): 261 - 268 .
LU J X , LI J , WU Y , et al . Characterization of the FMN-dependent cysteine decarboxylase from thioviridamide biosynthesis [J ] . Organic Letters , 2019 , 21 ( 12 ): 4676 - 4679 .
KUPKE T , KEMPTER C , JUNG G , et al . Oxidative decarboxylation of peptides catalyzed by flavoprotein EpiD. Determination of substrate specificity using peptide libraries and neutral loss mass spectrometry [J ] . Journal of Biological Chemistry , 1995 , 270 ( 19 ): 11282 - 11289 .
XIA Y Z , YI Y C , SHI Y , et al . Enzymatic generation of thioaldehyde motifs by flavin-dependent cysteine decarboxylases for peptide bioconjugation and macrocyclization [J ] . Organic Letters , 2023 , 25 ( 32 ): 6035 - 6039 .
WANG S , WU K W , TANG Y J , et al . Dehydroamino acid residues in bioactive natural products [J ] . Natural Product Reports , 2024 , 41 ( 2 ): 273 - 297 .
BOTHWELL I R , COGAN D P , KIM T , et al . Characterization of glutamyl-tRNA-dependent dehydratases using nonreactive substrate mimics [J ] . Proceedings of the National Academy of Sciences of the United States of America , 2019 , 116 ( 35 ): 17245 - 17250 .
CHATTERJEE C , MILLER L M , LEUNG Y L , et al . Lacticin 481 synthetase phosphorylates its substrate during lantibiotic production [J ] . Journal of the American Chemical Society , 2005 , 127 ( 44 ): 15332 - 15333 .
DONG S H , TANG W X , LUKK T , et al . The enterococcal cytolysin synthetase has an unanticipated lipid kinase fold [J ] . eLife , 2015 , 4 : e07607 .
HUANG S Q , WANG Y , CAI C X , et al . Discovery of a unique structural motif in lanthipeptide synthetases for substrate binding and interdomain interactions [J ] . Angewandte Chemie International Edition , 2022 , 61 ( 45 ): e202211382 .
HERNANDEZ GARCIA A , NAIR S K . Structure and function of a class Ⅲ metal-independent lanthipeptide synthetase [J ] . ACS Central Science , 2023 , 9 ( 10 ): 1944 - 1956 .
SIGURDSSON A , MARTINS B M , DÜTTMANN S A , et al . Discovery of the lanthipeptide curvocidin and structural insights into its trifunctional synthetase CuvL [J ] . Angewandte Chemie International Edition , 2023 , 62 ( 23 ): e202302490 .
LIANG H Q , LOPEZ I J , SÁNCHEZ-HIDALGO M , et al . Mechanistic studies on dehydration in class Ⅴ lanthipeptides [J ] . ACS Chemical Biology , 2022 , 17 ( 9 ): 2519 - 2527 .
XUE Y Q , LI M , HU L , et al . Mechanistic investigations into the catalytic mode of a dehydratase complex involved in the biosynthesis of lantibiotic cacaoidin [J ] . Chinese Journal of Chemistry , 2023 , 41 ( 24 ): 3579 - 3586 .
LI B , YU J P , BRUNZELLE J S , et al . Structure and mechanism of the lantibiotic cyclase involved in nisin biosynthesis [J ] . Science , 2006 , 311 ( 5766 ): 1464 - 1467 .
MUKHERJEE S , VAN DER DONK W A . Mechanistic studies on the substrate-tolerant lanthipeptide synthetase ProcM [J ] . Journal of the American Chemical Society , 2014 , 136 ( 29 ): 10450 - 10459 .
THIBODEAUX C J , HA T , VAN DER DONK W A . A price to pay for relaxed substrate specificity: a comparative kinetic analysis of the class Ⅱ lanthipeptide synthetases ProcM and HalM2 [J ] . Journal of the American Chemical Society , 2014 , 136 ( 50 ): 17513 - 17529 .
YANG X , VAN DER DONK W A . Michael-type cyclizations in lantibiotic biosynthesis are reversible [J ] . ACS Chemical Biology , 2015 , 10 ( 5 ): 1234 - 1238 .
YU Y , MUKHERJEE S , VAN DER DONK W A . Product formation by the promiscuous lanthipeptide synthetase ProcM is under kinetic control [J ] . Journal of the American Chemical Society , 2015 , 137 ( 15 ): 5140 - 5148 .
LU J X , LI Y Q , BAI Z B , et al . Enzymatic macrocyclization of ribosomally synthesized and posttranslational modified peptides via C—S and C—C bond formation [J ] . Natural Product Reports , 2021 , 38 ( 5 ): 981 - 992 .
WIEBACH V , MAINZ A , SCHNEGOTZKI R , et al . An amphipathic alpha-helix guides maturation of the ribosomally-synthesized lipolanthines [J ] . Angewandte Chemie International Edition , 2020 , 59 ( 38 ): 16777 - 16785 .
CHU L X , CHENG J D , ZHOU C Z , et al . Hijacking a linaridin biosynthetic intermediate for lanthipeptide production [J ] . ACS Chemical Biology , 2022 , 17 ( 11 ): 3198 - 3206 .
XUE Y Q , WANG X F , LIU W . Reconstitution of the linaridin pathway provides access to the family-determining activity of two membrane-associated proteins in the formation of structurally underestimated cypemycin [J ] . Journal of the American Chemical Society , 2023 , 145 ( 12 ): 7040 - 7047 .
CLAESEN J , BIBB M . Genome mining and genetic analysis of cypemycin biosynthesis reveal an unusual class of posttranslationally modified peptides [J ] . Proceedings of the National Academy of Sciences of the United States of America , 2010 , 107 ( 37 ): 16297 - 16302 .
CLAESEN J , BIBB M J . Biosynthesis and regulation of grisemycin, a new member of the linaridin family of ribosomally synthesized peptides produced by Streptomyces griseus IFO 13350 [J ] . Journal of Bacteriology , 2011 , 193 ( 10 ): 2510 - 2516 .
WANG F T , WEI W Q , ZHAO J F , et al . Genome mining and biosynthesis study of a type B linaridin reveals a highly versatile α- N -methyltransferase [J ] . CCS Chemistry , 2020 , 3 ( 3 ): 1049 - 1057 .
GEORGIOU M A , DOMMARAJU S R , GUO X R , et al . Bioinformatic and reactivity-based discovery of linaridins [J ] . ACS Chemical Biology , 2020 , 15 ( 11 ): 2976 - 2985 .
LU J X , WU Y , LI Y Q , et al . The utilization of lanthipeptide synthetases is a general strategy for the biosynthesis of 2-aminovinyl-cysteine motifs in thioamitides [J ] . Angewandte Chemie International Edition , 2021 , 60 ( 4 ): 1951 - 1958 .
DENOËL T , LEMAIRE C , LUXEN A . Progress in lanthionine and protected lanthionine synthesis [J ] . Chemistry , 2018 , 24 ( 58 ): 15421 - 15441 .
JIMÉNEZ J C , BAYÓ N , CHAVARRÍA B , et al . Synthesis of peptides containing α,β-didehydroamino acids. Scope and limitations [J ] . Letters in Peptide Science , 2002 , 9 ( 2 ): 135 - 141 .
0
浏览量
2
下载量
0
CSCD
- 网络PDF下载
- WORD下载
- Meta-XML下载
- BibTeX下载
- Endnote下载
- RefMan 下载
- NoteExpress下载
- NoteFirst下载
关联资源
相关文章
相关作者
相关机构
- 地址：北京市东城区青年湖南街13号 邮编：100000
- 联系电话：010-64519339
- 技术支持由北京北大方正电子有限公司提供 京ICP备09064830号-19
京公网安备11010802024621 - 本系统建议在Chrome、 IE9+ 以上版本浏览器阅读本站内容，360浏览器请切换至极速模式
- Cookies帮助我们提供服务并提供个性化体验。使用本网站，即表示您同意我们使用Cookies