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. 2010 Sep 15;132(36):12534-6.
doi: 10.1021/ja1050814.

Enediyne antitumor antibiotic maduropeptin biosynthesis featuring a C-methyltransferase that acts on a CoA-tethered aromatic substrate

Affiliations

Enediyne antitumor antibiotic maduropeptin biosynthesis featuring a C-methyltransferase that acts on a CoA-tethered aromatic substrate

Jianya Ling et al. J Am Chem Soc. .

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.

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Figures

Figure 1
Figure 1
Selected enediynes and biosynthesis of the aromatic acid moieties: (A) the enediyne chromophores of C-1027 (1), NCS (2), and MDP (3) with the aromatic acid moieties highlighted in red; (B) biosynthesis of the naphthoic acid moiety of 2; and (C) early and (D) revised biosynthesis of the salicylyl moiety of 3.
Figure 2
Figure 2
HPLC analysis of MdpB2- and MdpB1-catalyzed sequential conversion of 6 (○) to 5 (◆): (A) MdpB2-catalyzed conversion of 6 (○) to 7 (●) (I) and control without enzyme (II) and (B) authentic standards of 7 (●) and 4 (▼) (I) and time course of MdpB1-catalyzed conversion of 7 (●) to 5 (◆) and its degradation product 4 (▼) upon 1.5 h (II) and 4.5 h (III) incubation.

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