1i3k
MOLECULAR BASIS FOR SEVERE EPIMERASE-DEFICIENCY GALACTOSEMIA: X-RAY STRUCTURE OF THE HUMAN V94M-SUBSTITUTED UDP-GALACTOSE 4-EPIMERASE
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OverviewOverview
Galactosemia is an inherited disorder characterized by an inability to, metabolize galactose. Although classical galactosemia results from, impairment of the second enzyme of the Leloir pathway, namely, galactose-1-phosphate uridylyltransferase, alternate forms of the disorder, can occur due to either galactokinase or UDP-galactose 4-epimerase, deficiencies. One of the more severe cases of epimerase deficiency, galactosemia arises from an amino acid substitution at position 94. It has, been previously demonstrated that the V94M protein is impaired relative to, the wild-type enzyme predominantly at the level of V(max) rather than, K(m). To address the molecular consequences the mutation imparts on the, three-dimensional architecture of the enzyme, we have solved the, structures of the V94M-substituted human epimerase complexed with NADH and, UDP-glucose, UDP-galactose, UDP-GlcNAc, or UDP-GalNAc. In the wild-type, enzyme, the hydrophobic side chain of Val(94) packs near the aromatic, group of the catalytic Tyr(157) and serves as a molecular "fence" to limit, the rotation of the glycosyl portions of the UDP-sugar substrates within, the active site. The net effect of the V94M substitution is an opening up, of the Ala(93) to Glu(96) surface loop, which allows free rotation of the, sugars into nonproductive binding modes.
DiseaseDisease
Known disease associated with this structure: Galactose epimerase deficiency OMIM:[606953]
About this StructureAbout this Structure
1I3K is a Single protein structure of sequence from Homo sapiens with , , , and as ligands. Active as UDP-glucose 4-epimerase, with EC number 5.1.3.2 Full crystallographic information is available from OCA.
ReferenceReference
Molecular basis for severe epimerase deficiency galactosemia. X-ray structure of the human V94m-substituted UDP-galactose 4-epimerase., Thoden JB, Wohlers TM, Fridovich-Keil JL, Holden HM, J Biol Chem. 2001 Jun 8;276(23):20617-23. Epub 2001 Mar 7. PMID:11279193
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