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New cofactor supports α,β-unsaturated acid decarboxylation via 1,3-dipolar cycloaddition

DOI: 10.1038/nature14560 DOI Help
PMID: 26083754 PMID Help

Authors: Karl A. P. Payne (University of Manchester) , Mark D. White (University of Manchester) , Karl Fisher (University of Manchester) , Basile Khara (University of Manchester) , Samuel S. Bailey (University of Manchester) , David Parker (Innovation/Biodomain, Shell International Exploration and Production) , Nicholas J. W. Rattray (University of Manchester) , Drupad K. Trivedi (University of Manchester) , Royston Goodacre (University of Manchester) , Rebecca Beveridge (University of Manchester) , Perdita Barran (University of Manchester) , Stephen E. J. Rigby (University of Manchester) , Nigel S. Scrutton (University of Manchester) , Sam Hay (University of Manchester) , David Leys (School of Chemistry ; Manchester Interdisciplinary Biocentre, The University of Manchester)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 522 (7557) , PAGES 497 - 501

State: Published (Approved)
Published: June 2015
Diamond Proposal Number(s): 8997

Abstract: The bacterial ubiD and ubiX or the homologous fungal fdc1 and pad1 genes have been implicated in the non-oxidative reversible decarboxylation of aromatic substrates, and play a pivotal role in bacterial ubiquinone (also known as coenzyme Q) biosynthesis1, 2, 3 or microbial biodegradation of aromatic compounds4, 5, 6, respectively. Despite biochemical studies on individual gene products, the composition and cofactor requirement of the enzyme responsible for in vivo decarboxylase activity remained unclear7, 8, 9. Here we show that Fdc1 is solely responsible for the reversible decarboxylase activity, and that it requires a new type of cofactor: a prenylated flavin synthesized by the associated UbiX/Pad110. Atomic resolution crystal structures reveal that two distinct isomers of the oxidized cofactor can be observed, an isoalloxazine N5-iminium adduct and a N5 secondary ketimine species with markedly altered ring structure, both having azomethine ylide character. Substrate binding positions the dipolarophile enoic acid group directly above the azomethine ylide group. The structure of a covalent inhibitor–cofactor adduct suggests that 1,3-dipolar cycloaddition chemistry supports reversible decarboxylation in these enzymes. Although 1,3-dipolar cycloaddition is commonly used in organic chemistry11, 12, we propose that this presents the first example, to our knowledge, of an enzymatic 1,3-dipolar cycloaddition reaction. Our model for Fdc1/UbiD catalysis offers new routes in alkene hydrocarbon production or aryl (de)carboxylation.

Journal Keywords: X-ray crystallography; Enzyme mechanisms

Subject Areas: Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography