Open and Closed Structures of the UDP-glucose Pyrophosphorylase from Leishmania major

Uridine diphosphate-glucose pyrophosphorylase (UGPase) represents a ubiquitous enzyme, which catalyzes the formation of UDP-glucose, a key metabolite of the carbohydrate pathways of all organisms. In the protozoan parasite Leishmania major, which causes a broad spectrum of diseases and is transmitte...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-04, Vol.282 (17), p.13003-13010
Main Authors: Steiner, Thomas, Lamerz, Anne-Christin, Hess, Petra, Breithaupt, Constanze, Krapp, Stephan, Bourenkov, Gleb, Huber, Robert, Gerardy-Schahn, Rita, Jacob, Uwe
Format: Article
Language:English
Subjects:
Animals
Apoenzymes - chemistry
Apoenzymes - metabolism
Catalysis
Crystallography, X-Ray
Glycoconjugates - biosynthesis
Glycoconjugates - chemistry
Leishmania major
Leishmania major - enzymology
Leishmania major - pathogenicity
Protein Folding
Protein Structure, Secondary
Protein Structure, Tertiary
Protozoan Proteins - chemistry
Protozoan Proteins - metabolism
UTP-Glucose-1-Phosphate Uridylyltransferase - chemistry
UTP-Glucose-1-Phosphate Uridylyltransferase - metabolism
Virulence Factors - chemistry
Virulence Factors - metabolism
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Summary:Uridine diphosphate-glucose pyrophosphorylase (UGPase) represents a ubiquitous enzyme, which catalyzes the formation of UDP-glucose, a key metabolite of the carbohydrate pathways of all organisms. In the protozoan parasite Leishmania major, which causes a broad spectrum of diseases and is transmitted to humans by sand fly vectors, UGPase represents a virulence factor because of its requirement for the synthesis of cell surface glycoconjugates. Here we present the crystal structures of the L. major UGPase in its uncomplexed apo form (open conformation) and in complex with UDP-glucose (closed conformation). The UGPase consists of three distinct domains. The N-terminal domain exhibits species-specific differences in length, which might permit distinct regulation mechanisms. The central catalytic domain resembles a Rossmann-fold and contains key residues that are conserved in many nucleotidyltransferases. The C-terminal domain forms a left-handed parallel β-helix (LβH), which represents a rarely observed structural element. The presented structures together with mutagenesis analyses provide a basis for a detailed analysis of the catalytic mechanism and for the design of species-specific UGPase inhibitors.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M609984200