title: A small disturbance, but a serious disease: the possible mechanism of D52H-mutant of human PRS1 that causes gout.
abstract: Phosphoribosyl pyrophosphate synthetase isoform 1 (PRS1) has an essential role in the de novo and salvage synthesis of human purine and pyrimidine nucleotides. The dysfunction of PRS1 will dramatically influence nucleotides' concentration in patient's body and lead to different kinds of disorders (such as hyperuricemia, gout and deafness). The D52H missense mutation of PRS1 will lead to a conspicuous phosphoribosyl pyrophosphate content elevation in the erythrocyte of patients and finally induce hyperuricemia and serious gout. In this study, the enzyme activity analysis indicated that D52H-mutant possessed similar catalytic activity to the wild-type PRS1, and the 2.27 Å resolution D52H-mutant crystal structure revealed that the stable interaction network surrounding the 52 position of PRS1 would be completely destroyed by the substitution of histidine. These interaction variations would further influence the conformation of ADP-binding pocket of D52H-mutant and reduced the inhibitor sensitivity of PRS1 in patient's body.
authors.affiliation: University of Science and Technology of China, School of Life Sciences, Hefei, Anhui, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Chen
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Li
authors.forename: Jin
authors.initials: J
authors.lastname: Ma
authors.forename: Maikun
authors.initials: M
authors.lastname: Teng
authors.forename: Xu
authors.initials: X
authors.lastname: Li
mesh_terms: D000244:Adenosine Diphosphate / Q000737:chemistry; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004912:Erythrocytes / Q000201:enzymology; D006073:Gout / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012268:Ribose-Phosphate Pyrophosphokinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*
chemical_list: D000244:Adenosine Diphosphate; C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase
keywords: PRS1; crystal structure; gout; mutation; superactivity