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Structural Basis for Cyclopropanation by a Unique Enoyl-Acyl Carrier Protein Reductase.


ABSTRACT: The natural product curacin A, a potent anticancer agent, contains a rare cyclopropane group. The five enzymes for cyclopropane biosynthesis are highly similar to enzymes that generate a vinyl chloride moiety in the jamaicamide natural product. The structural biology of this remarkable catalytic adaptability is probed with high-resolution crystal structures of the curacin cyclopropanase (CurF ER), an in vitro enoyl reductase (JamJ ER), and a canonical curacin enoyl reductase (CurK ER). The JamJ and CurK ERs catalyze NADPH-dependent double bond reductions typical of enoyl reductases (ERs) of the medium-chain dehydrogenase reductase (MDR) superfamily. Cyclopropane formation by CurF ER is specified by a short loop which, when transplanted to JamJ ER, confers cyclopropanase activity on the chimeric enzyme. Detection of an adduct of NADPH with the model substrate crotonyl-CoA provides indirect support for a recent proposal of a C2-ene intermediate on the reaction pathway of MDR enoyl-thioester reductases.

SUBMITTER: Khare D 

PROVIDER: S-EPMC4670573 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Structural Basis for Cyclopropanation by a Unique Enoyl-Acyl Carrier Protein Reductase.

Khare Dheeraj D   Hale Wendi A WA   Tripathi Ashootosh A   Gu Liangcai L   Sherman David H DH   Gerwick William H WH   Håkansson Kristina K   Smith Janet L JL  

Structure (London, England : 1993) 20151029 12


The natural product curacin A, a potent anticancer agent, contains a rare cyclopropane group. The five enzymes for cyclopropane biosynthesis are highly similar to enzymes that generate a vinyl chloride moiety in the jamaicamide natural product. The structural biology of this remarkable catalytic adaptability is probed with high-resolution crystal structures of the curacin cyclopropanase (CurF ER), an in vitro enoyl reductase (JamJ ER), and a canonical curacin enoyl reductase (CurK ER). The JamJ  ...[more]

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