Compartmentalized biosynthesis of mycophenolic acid
文献类型:期刊论文
作者 | Zhang, Wei1; Du, Lei; Qu, Zepeng2; Zhang, Xingwang1; Li, Fengwei; Li, Zhong2; Qi, Feifei; Wang, Xiao; Jiang, Yuanyuan2; Men, Ping2 |
刊名 | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA |
出版日期 | 2019 |
卷号 | 116期号:27页码:13305-13310 |
ISSN号 | 0027-8424 |
关键词 | PEROXISOMAL-BETA-OXIDATION POLYKETIDE SYNTHASE MOLECULAR-BASIS GENE CYTOCHROME-P450 MITOCHONDRIAL INVOLVEMENT HYDROLASE |
DOI | 10.1073/pnas.1821932116 |
英文摘要 | Mycophenolic acid (MPA) from filamentous fungi is the first natural product antibiotic to be isolated and crystallized, and a first-line immunosuppressive drug for organ transplantations and autoimmune diseases. However, some key biosynthetic mechanisms of such an old and important molecule have remained unclear. Here, we elucidate the MPA biosynthetic pathway that features both compartmentalized enzymatic steps and unique cooperation between biosynthetic and beta-oxidation catabolism machineries based on targeted gene inactivation, feeding experiments in heterologous expression hosts, enzyme functional characterization and kinetic analysis, and microscopic observation of protein subcellular localization. Besides identification of the oxygenase MpaB' as the long-sought key enzyme responsible for the oxidative cleavage of the farnesyl side chain, we reveal the intriguing pattern of compartmentalization for the MPA biosynthetic enzymes, including the cytosolic polyketide synthase MpaC' and O-methyltransferase MpaG', the Golgi apparatus-associated prenyltransferase MpaA', the endoplasmic reticulum-bound oxygenase MpaB' and P450-hydrolase fusion enzyme MpaDE', and the peroxisomal acyl-coenzyme A (CoA) hydrolase MpaH'. The whole pathway is elegantly comediated by these compartmentalized enzymes, together with the peroxisomal beta-oxidation machinery. Beyond characterizing the remaining outstanding steps of the MPA biosynthetic steps, our study highlights the importance of considering subcellular contexts and the broader cellular metabolism in natural product biosynthesis. |
学科主题 | Science & Technology - Other Topics |
语种 | 英语 |
WOS记录号 | WOS:000473427900030 |
源URL | [http://ir.xtbg.org.cn/handle/353005/11335] |
专题 | 中国科学院西双版纳热带植物园 西双版纳热带植物园_2012年后新成立研究组 |
作者单位 | 1.Chinese Acad Sci, Shandong Prov Key Lab Synthet Biol, Chinese Acad Sci CAS Key Lab Biofuels, Qingdao Inst Bioenergy & Bioproc Technol, Qingdao 266101, Shandong, Peoples R China 2.Shandong Univ, State Key Lab Microbial Technol, Qingdao 266237, Shandong, Peoples R China 3.Univ Chinese Acad Sci, Sch Life Sci, Beijing 100049, Peoples R China 4.Jianghan Univ, Sch Chem & Environm Engn, Key Lab Optoelect Chem Mat & Devices, Minist Educ, Wuhan 430056, Hubei, Peoples R China 5.Chinese Acad Sci, Xishuangbanna Trop Bot Garden, CAS Key Lab Trop Plant Resources & Sustainable Us, Menglun 666303, Yunnan, Peoples R China 6.Qingdao Natl Lab Marine Sci & Technol, Lab Marine Biol & Biotechnol, Qingdao 266237, Shandong, Peoples R China |
推荐引用方式 GB/T 7714 | Zhang, Wei,Du, Lei,Qu, Zepeng,et al. Compartmentalized biosynthesis of mycophenolic acid[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2019,116(27):13305-13310. |
APA | Zhang, Wei.,Du, Lei.,Qu, Zepeng.,Zhang, Xingwang.,Li, Fengwei.,...&Li, Shengying.(2019).Compartmentalized biosynthesis of mycophenolic acid.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,116(27),13305-13310. |
MLA | Zhang, Wei,et al."Compartmentalized biosynthesis of mycophenolic acid".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 116.27(2019):13305-13310. |
入库方式: OAI收割
来源:西双版纳热带植物园
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