Enediyne antitumor antibiotic maduropeptin biosynthesis featuring a C-methyltransferase that acts on a CoA-tethered aromatic substrate.
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.
Ling
Jianya
J
Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
Horsman
Geoffrey P
GP
Huang
Sheng-Xiong
SX
Luo
Yinggang
Y
Lin
Shuangjun
S
Shen
Ben
B
D039903:Actinobacteria / Q000201:enzymology / Q000378:metabolism; D055162:Biocatalysis; D003066:Coenzyme A Ligases / Q000378:metabolism*; D053281:Enediynes / Q000737:chemistry / Q000378:metabolism*; D008780:Methyltransferases / Q000378:metabolism*; D015394:Molecular Structure; D013237:Stereoisomerism; D013379:Substrate Specificity
D053281:Enediynes; C509891:maduropeptin enediyne; D008780:Methyltransferases; D003066:Coenzyme A Ligases