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2013 , Vol. 33 >Issue 06: 1254 - 1262

DOI: https://doi.org/10.6023/cjoc201212004

综述与进展

大环内酯类免疫抑制剂他克莫司的生物合成机制研究进展

  • 陈单丹 ,
  • 岑沛霖 ,
  • 刘文 ,
  • 徐志南
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  • a 浙江大学化工系生物工程研究所 杭州 310027;
    b 中国科学院上海有机化学研究所 生命有机国家重点实验室 上海 200032

收稿日期: 2012-12-05

  修回日期: 2013-01-06

  网络出版日期: 2013-01-11

基金资助

国家自然科学基金(Nos.20832009, 21176214, 91213303);国家重点基础研究发展计划(973计划, Nos.2010CB833200, 2012CB721100).

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Progress in Studying the Biosynthetic Mechanism of the Macrolide Immunosuppressant Tacrolimus

  • Chen Dandan ,
  • Cen Peilin ,
  • Liu Wen ,
  • Xu Zhinan
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  • a Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027;
    b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032

Received date: 2012-12-05

  Revised date: 2013-01-06

  Online published: 2013-01-11

Supported by

Project supported by the National Natural Science Foundation of China (Nos.20832009, 21176214, 91213303), the National Basic Research Program of China (973 Program, Nos.2010CB833200, 2012CB721100).

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摘要

他克莫司(FK506)是一种来源于土壤链霉菌的大环内酯类免疫抑制剂, 由典型的聚酮合酶(PKS)-非核糖体肽合成酶(NRPS)杂合系统负责催化其生物合成.他克莫司的化学结构特殊, 包括骨架环的哌啶单元、4-羟基-3-甲氧基环己基官能团, 以及甲氧基和烯丙基侧链.近年来, 关于他克莫司的生物合成机制, 特别是其特殊前体的形成途径的研究发展迅速.对他克莫司生物合成的酶学基础进行了系统性地综述, 重点总结了其前体形成机制的研究新进展.

关键词： 他克莫司; FK506; 生物合成; 聚酮合酶; 非核糖体肽合成酶; 前体; 途径特异性

本文引用格式

陈单丹 , 岑沛霖 , 刘文 , 徐志南 . 大环内酯类免疫抑制剂他克莫司的生物合成机制研究进展[J]. 有机化学, 2013 , 33(06) : 1254 -1262 . DOI: 10.6023/cjoc201212004

Abstract

Tacrolimus (FK506), derived from various soil Streptomyces species, is a potent macrolide immunosuppressant that is assembled by a typical polyketide synthase (PKS)-nonribosomal peptide synthetase (NRPS) hybrid system.Its chemical structure is unique, with a piperidine unit consisting in the polyketide skeleton, a 4-methoxy, 5-hydroxy-cyclohexyl functional group, as well as methoxyl and allyl side chains.Recently, studies on the biosynthetic mechanism of tacrolimus, particularly for the pathways encoding the unusual precursors, achieved great successes.In this review, we summarize the enzymatic basis in correspondence to the biosynthesis of tacrolimus, and emphasize on the recent progress in understanding the biosynthetic pathways of the unusual precursors 4,5-dihydroxycyclohex-1-enecarboxylic acid (DHCHC), methoxymalonyl-acyl carrier protein (ACP), allylmalonyl-coenzyme A (CoA) and L-pipecolic acid.

Key words： tacrolimus; FK506; biosynthesis; polyketide synthase (PKS); nonribosomal peptide synthetase (NRPS); precursor; pathway-specific

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