Stereochemistry and Mechanism of Undecylprodigiosin Oxidative Carbocyclization to Streptorubin B by the Rieske Oxygenase RedG

The prodiginines are a group of specialized metabolites that share a 4-methoxypyrrolyldipyrromethene core structure. Streptorubin B is a structurally remarkable member of the prodiginine group produced by Streptomyces coelicolor A3(2) and other actinobacteria. It is biosynthesized from undecylprodig...

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Published in:Journal of the American Chemical Society 2015-06, Vol.137 (24), p.7889-7897
Main Authors: Withall, David M, Haynes, Stuart W, Challis, Gregory L
Format: Article
Language:English
Subjects:
Cyclization
Oxidation-Reduction
Oxygenases - metabolism
Prodigiosin - analogs & derivatives
Prodigiosin - chemistry
Prodigiosin - metabolism
Pyrroles - chemistry
Pyrroles - metabolism
Stereoisomerism
Streptomyces - chemistry
Streptomyces - enzymology
Streptomyces - metabolism
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Summary:The prodiginines are a group of specialized metabolites that share a 4-methoxypyrrolyldipyrromethene core structure. Streptorubin B is a structurally remarkable member of the prodiginine group produced by Streptomyces coelicolor A3(2) and other actinobacteria. It is biosynthesized from undecylprodigiosin by an oxidative carbocyclization catalyzed by the Rieske oxygenase-like enzyme RedG. Undecylprodigiosin derives from the RedH-catalyzed condensation of 2-undecylpyrrole and 4-methoxy-2, 2′-bipyrrole-5-carboxaldehyde (MBC). To probe the mechanism of the RedG-catalyzed reaction, we synthesized 2-(5-pentoxypentyl)-pyrrole, an analogue of 2-undecylpyrrole with an oxygen atom next to the site of C–C bond formation, and fed it, along with synthetic MBC, to Streptomyces albus expressing redH and redG. This resulted in the production of the 6′-oxa analogue of undecylprodigiosin. In addition, a small amount of a derivative of this analogue lacking the n-pentyl group was produced, consistent with a RedG catalytic mechanism involving hydrogen abstraction from the alkyl chain of undecylprodigiosin prior to pyrrole functionalization. To investigate the stereochemistry of the RedG-catalyzed oxidative carbocyclization, [7′-2H]­(7′R)-2-undecylpyrrole and [7′-2H]­(7′S)-2-undecylpyrrole were synthesized and fed separately, along with MBC, to S. albus expressing redH and redG. Analysis of the extent of deuterium incorporation into the streptorubin B produced in these experiments showed that the pro-R hydrogen atom is abstracted from C-7′ of undecylprodigiosin and that the reaction proceeds with inversion of configuration at C-7′. This contrasts sharply with oxidative heterocyclization reactions catalyzed by other nonheme iron-dependent oxygenase-like enzymes, such as isopenicillin N synthase and clavaminate synthase, which proceed with retention of configuration at the carbon center undergoing functionalization.
ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.5b03994