Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0022716 (
Menkes
)
1,057
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The bifunctional enzyme UDP-GlcNAc 2-epimerase/ ManNAc kinase (GNE/
MNK
), encoded by the GNE gene, catalyzes the first two committed, rate-limiting steps in the biosynthesis of N-acetylneuraminic acid (sialic acid). GNE/
MNK
is feedback inhibited by binding of the downstream product,
CMP
-sialic acid in its allosteric site. GNE mutations can result in two human disorders, hereditary inclusion body myopathy (HIBM) or sialuria. So far, no active site geometry predictions or conformational transitions involved with function are available for mammalian GNE/
MNK
. The N-terminal GNE domain is homologous to various prokaryotic 2-epimerases, some of which have solved crystallographic structures. The C-terminal
MNK
domain belongs to the sugar kinases superfamily; its crystallographic structure is solved at 2.84 A and three-dimensional structures have also been reported for several other kinases. In this work, we employed available structural data of GNE/
MNK
homologs to model the active sites of human GNE/
MNK
and identify critical amino acid residues responsible for interactions with substrates. In addition, we modeled effects of GNE/
MNK
missense mutations associated with HIBM or sialuria on helix arrangement, substrate binding, and enzyme action. We found that all reported mutations are associated with the active sites or secondary structure interfaces of GNE/
MNK
. The Persian-Jewish HIBM founder mutation p.M712T is located at the interface alpha4alpha10 and likely affects GlcNAc, Mg2+, and ATP binding. This work contributes to further understanding of GNE/
MNK
function and ligand binding, which may assist future studies for therapeutic options that target misfolded GNE/
MNK
in HIBM and/or sialuria.
...
PMID:Molecular modeling of the bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase and predictions of structural effects of mutations associated with HIBM and sialuria. 1991 66
