Mechanism and inhibition of human UDP-GlcNAc 2-epimerase, the key enzyme in sialic acid biosynthesis

• DOI: 10.1038/srep23274
• Publication Date: 2016-03-16T10:11:29Z
• Authors: Sheng-Chia Chen; Chi-Hung Huang; Shu-Jung Lai; Chia Shin Yang; Tzu-Hung Hsiao; Ching-Heng Lin; Pin-Kuei Fu; Tzu-Ping Ko; Yeh Chen
• Keywords: Phosphofructokinase 2; Tetramer

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 feed-back inhibited by downstream product CMP-Neu5Ac. Here complex crystal structure of N-terminal epimerase part human GNE shows tetramer which UDP binds to active site CMP-Neu5Ac dimer-dimer interface. locked tightly closed conformation. By comparing UDP-binding modes hydrolyzing epimerases, we propose possible explanation mechanistic difference. While epimerization reactions both are similar, Arg113 Ser302 likely involved hydrolysis. On other hand, binding mode clearly elucidates why mutations Arg263 Arg266 can cause sialuria. Moreover, full-length modelling suggests channel ManNAc trafficking within enzyme.