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The first structure of UDP-glucose dehydrogenase reveals the catalytic residues necessary for the two-fold oxidation

TitleThe first structure of UDP-glucose dehydrogenase reveals the catalytic residues necessary for the two-fold oxidation
Publication TypeJournal Article
Year of Publication2000
AuthorsCampbell, RE, Mosimann, SC, van de Rijn, I, Tanner, ME, Strynadka, NCJ
JournalBiochemistry
Volume39
Pagination7012-7023
Date PublishedJun
Type of ArticleArticle
ISBN Number0006-2960
Keywordsalanine, ALIGNMENT, CRYSTAL-STRUCTURE, ESCHERICHIA-COLI, GROUP-A STREPTOCOCCI, INSIGHTS, MECHANISM, MOLECULAR CHARACTERIZATION, REDUCTASE, SUBSTRATE-BINDING
Abstract

Bacterial UDP-glucose dehydrogenase (UDPGlcDH) is essential for formation of the antiphagocytic capsule that protects many virulent bacteria such as Streptococcus pyrogenes and Streptococcus pneumoniae type 3 from the host’s immune system. We have determined the X-ray structures of both native and Cys260Ser UDPGlcDH from S. pyogenes (74% similarity to S. pneumoniae) in ternary complexes with UDP-xylose/NAD(+) and UDP-glucuronic acid/NAD(H), respectively. The 402 residue homodimeric UDPGlcDH is composed of an N-terminal NAD(+) dinucleotide binding domain and a C-terminal UDP-sugar binding domain connected by a long (48 Angstrom) central alpha-helix. The first 290 residues of UDPGlcDH share structural homology with 6-phosphogluconate dehydrogenase, including conservation of an active site lysine and asparagine that are implicated in the enzyme mechanism. Also proposed to participate in the catalytic mechanism are a threonine and a glutamate that hydrogen bond to a conserved active site water molecule suitably positioned for general acid/base catalysis.

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