UDP-glucose dehydrogenase: structure and function of a potential drug target.
Biosynthesis of the glycosaminoglycan precursor UDP-α-D-glucuronic acid occurs through a 2-fold oxidation of UDP-α-D-glucose that is catalysed by UGDH (UDP-α-D-glucose 6-dehydrogenase). Structure-function relationships for UGDH and proposals for the enzymatic reaction mechanism are reviewed in the present paper, and structure-based sequence comparison is used for subclassification of UGDH family members. The eukaryotic group of enzymes (UGDH-II) utilize an extended C-terminal domain for the formation of complex homohexameric assemblies. The comparably simpler oligomerization behaviour of the prokaryotic group of enzymes (UGDH-I), in which dimeric forms prevail, is traced back to the lack of relevant intersubunit contacts and trimmings within the C-terminal region. The active site of UGDH contains a highly conserved cysteine residue, which plays a key role in covalent catalysis. Elevated glycosaminoglycan formation is implicated in a variety of human diseases, including the progression of tumours. The inhibition of synthesis of UDP-α-D-glucuronic acid using UGDH antagonists might therefore be a useful strategy for therapy.
Egger
Sigrid
S
Institute of Biotechnology and Biochemical Engineering, Graz University of Technology, Petersgasse 12, A-8010 Graz, Austria.
Chaikuad
Apirat
A
Kavanagh
Kathryn L
KL
Oppermann
Udo
U
Nidetzky
Bernd
B
D000818:Animals; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D014533:Uridine Diphosphate Glucose Dehydrogenase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D004791:Enzyme Inhibitors; D014535:Uridine Diphosphate Glucuronic Acid; D006820:Hyaluronic Acid; D014533:Uridine Diphosphate Glucose Dehydrogenase