Work

Enediyne Antitumor Antibiotic Maduropeptin Biosynthesis Featuring a C-Methyltransferase That Acts on a CoA-Tethered Aromatic Substrate

Year: 2010

Type: article

Abstract: The enediyne antitumor antibiotic maduropeptin (MDP) is produced by Actinomadura madurae ATCC 39144. The biosynthetic pathway for the 3,6-dimethylsalicylic acid moiety of the MDP chromophore is proposed to be comprised of four enzymes: MdpB, MdpB1, MdpB2, and MdpB3. Based on the previously characterized biosynthesis of the naphthoic acid moiety of neocarzinostatin (NCS), we expected a biosynthetic pathway featuring carboxylic acid activation by the MdpB2 CoA ligase immediately before its coupling to an enediyne core intermediate. Surprisingly, the MDP aromatic acid biosynthetic pathway employs an unusual logic in which MdpB2-catalyzed CoA activation occurs before MdpB1-catalyzed C-methylation, demonstrating that MdpB1 is apparently unique in its ability to C-methylate a CoA-tethered aromatic acid. MdpB2 is a promiscuous CoA ligase capable of activating a variety of salicylic acid analogues, a property that could be potentially exploited to engineer MDP analogues.

Source: Journal of the American Chemical Society

DOI: 10.1021/ja1050814

Authors: Jianya Ling, Geoffrey P. Horsman, Sheng-Xiong Huang, Yinggang Luo, Shuangjun Lin, Ben Shen

Institutions: University of Wisconsin–Madison, Shandong University, State Key Laboratory of Microbial Technology

Language: English

Topic: Microbial Natural Products and Biosynthesis

Subfield: Pharmacology (medical)

Field: Medicine

Domain: Health Sciences

Open Access status: green

Funder: National Cancer Institute

Awards: UWCCC National Cooperative Drug Discovery Group for Can*, Enediyne Biosynthesis and Engineering, G2271657281, G3053038336