Journal article
UDP-Galactopyranose Mutase in Nematodes
Biochemistry (Easton), Vol.52(25), pp.4391-4398
06/25/2013
DOI: 10.1021/bi400264d
PMID: 23697711
Abstract
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 (similar to 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.
Details
- Title: Subtitle
- UDP-Galactopyranose Mutase in Nematodes
- Creators
- Darryl A. Wesener - University of Wisconsin–MadisonJohn F. May - University of Wisconsin–MadisonElizabeth M. Huffman - University of Wisconsin–MadisonLaura L. Kiessling - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- Biochemistry (Easton), Vol.52(25), pp.4391-4398
- DOI
- 10.1021/bi400264d
- PMID
- 23697711
- ISSN
- 0006-2960
- eISSN
- 1520-4995
- Publisher
- Amer Chemical Soc
- Number of pages
- 8
- Grant note
- Shimadzu grant S10RR013790 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) National Science Foundation; National Science Foundation (NSF) Chemistry Department NSF; National Science Foundation (NSF) T32 GM008505; T32 GM007215; S10 RR13790 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Keck grant R56AI063596 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) T32GM008505 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) BIR-9512577 / UW-Madison, NSF
- Language
- English
- Date published
- 06/25/2013
- Academic Unit
- Surgery
- Record Identifier
- 9985139322202771
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