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Multiple functionalities of reduced flavin in the non-redox reaction catalyzed by UDP-galactopyranose mutase.

ABSTRACT: Flavin cofactors are widely used by enzymes to catalyze a broad range of chemical reactions. Traditionally, flavins in enzymes are regarded as redox centers, which enable enzymes to catalyze the oxidation or reduction of substrates. However, a new class of flavoenzyme has emerged over the past quarter century in which the flavin functions as a catalytic center in a non-redox reaction. Here we introduce the unifying concept of flavin hot spots to understand and categorize the mechanisms and reactivities of both traditional and noncanonical flavoenzymes. The major hot spots of reactivity include the N5, C4a, and C4O atoms of the isoalloxazine, and the 2' hydroxyl of the ribityl chain. The role of hot spots in traditional flavoenzymes, such as monooxygenases, is briefly reviewed. A more detailed description of flavin hot spots in noncanonical flavoenzymes is provided, with a focus on UDP-galactopyranose mutase, where the N5 functions as a nucleophile that attacks the anomeric carbon atom of the substrate. Recent results from mechanistic enzymology, kinetic crystallography, and computational chemistry provide a complete picture of the chemical mechanism of UDP-galactopyranose mutase.

SUBMITTER: Sobrado P

PROVIDER: S-EPMC5650495 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Multiple functionalities of reduced flavin in the non-redox reaction catalyzed by UDP-galactopyranose mutase.

Sobrado Pablo P Tanner John J JJ

Archives of biochemistry and biophysics 20170624

Flavin cofactors are widely used by enzymes to catalyze a broad range of chemical reactions. Traditionally, flavins in enzymes are regarded as redox centers, which enable enzymes to catalyze the oxidation or reduction of substrates. However, a new class of flavoenzyme has emerged over the past quarter century in which the flavin functions as a catalytic center in a non-redox reaction. Here we introduce the unifying concept of flavin hot spots to understand and categorize the mechanisms and react ...[more]

PMID: 28652025

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Project description:Nematodes represent a diverse phylum of both free living and parasitic species. While the species Caenorhabditis elegans is a valuable model organism, parasitic nematodes or helminths pose a serious threat to human health. Indeed, helminths cause many neglected tropical diseases that afflict humans. Nematode glycoconjugates have been implicated in evasive immunomodulation, a hallmark of nematode infections. One monosaccharide residue present in the glycoconjugates of several human pathogens is galactofuranose (Galf). This five-membered ring isomer of galactose has not been detected in mammals, making Galf metabolic enzymes attractive therapeutic targets. The only known pathway for biosynthetic incorporation of Galf into glycoconjugates depends upon generation of the glycosyl donor UDP-Galf by the flavoenzyme uridine 5'-diphosphate (UDP) galactopyranose mutase (UGM or Glf). A putative UGM encoding gene (glf-1) was recently identified in C. elegans. We sought to assess the catalytic activity of the corresponding gene product (CeUGM). CeUGM catalyzes the isomerization of UDP-Galf and UDP-galactopyranose (UDP-Galp). In the presence of enzyme, substrate, and a hydride source, a galactose-N5-FAD adduct was isolated, suggesting the CeUGM flavin adenine dinucleotide (FAD) cofactor serves as a nucleophile in covalent catalysis. Homology modeling and protein variants indicate that CeUGM possesses an active site similar to that of prokaryotic enzymes, despite the low sequence identity (?15%) between eukaryotic and prokaryotic UGM proteins. Even with the primary sequence differences, heterocyclic UGM inhibitors developed against prokaryotic proteins also inhibit CeUGM activity. We postulate that inhibitors of CeUGM can serve as chemical probes of Galf in nematodes and as anthelmintic leads. The available data suggest that CeUGM facilitates the biosynthetic incorporation of Galf into nematode glycoconjugates through generation of the glycosyl donor UDP-Galf.

Dataset Information

Multiple functionalities of reduced flavin in the non-redox reaction catalyzed by UDP-galactopyranose mutase.

Publications

Multiple functionalities of reduced flavin in the non-redox reaction catalyzed by UDP-galactopyranose mutase.

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