4ZHT

Crystal structure of UDP-GlcNAc 2-epimerase

Summary for 4ZHT

• Entry DOI: 10.2210/pdb4zht/pdb
• Descriptor: Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, URIDINE-5'-DIPHOSPHATE, CYTIDINE-5'-MONOPHOSPHATE-5-N-ACETYLNEURAMINIC ACID, ... (5 entities in total)
• Functional Keywords: inhibitor, complex, epimerase, isomerase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : Q9Y223
• Total number of polymer chains: 4
• Total formula weight: 192596.48

Authors

Chen, S.C.,Yang, C.S.,Ko, T.P.,Chen, Y. (deposition date: 2015-04-27, release date: 2016-06-01, Last modification date: 2024-11-13)

Primary citation

Chen, S.C.,Huang, C.H.,Lai, S.J.,Yang, C.S.,Hsiao, T.H.,Lin, C.H.,Fu, P.K.,Ko, T.P.,Chen, Y.
Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis.
Sci Rep, 6:23274-23274, 2016

PubMed Abstract: The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) plays a key role in sialic acid production. It is different from the non-hydrolyzing enzymes for bacterial cell wall biosynthesis, and it is feed-back inhibited by the downstream product CMP-Neu5Ac. Here the complex crystal structure of the N-terminal epimerase part of human GNE shows a tetramer in which UDP binds to the active site and CMP-Neu5Ac binds to the dimer-dimer interface. The enzyme is locked in a tightly closed conformation. By comparing the UDP-binding modes of the non-hydrolyzing and hydrolyzing UDP-GlcNAc epimerases, we propose a possible explanation for the mechanistic difference. While the epimerization reactions of both enzymes are similar, Arg113 and Ser302 of GNE are likely involved in product hydrolysis. On the other hand, the CMP-Neu5Ac binding mode clearly elucidates why mutations in Arg263 and Arg266 can cause sialuria. Moreover, full-length modelling suggests a channel for ManNAc trafficking within the bifunctional enzyme.

PubMed: 26980148
DOI: 10.1038/srep23274

Experimental method

X-RAY DIFFRACTION (2.69 Å)