3s5j | pdb_00003s5j
2.0A Crystal structure of human phosphoribosyl pyrophosphate synthetase 1
Structural highlights
DiseasePRPS1_HUMAN Defects in PRPS1 are the cause of phosphoribosylpyrophosphate synthetase superactivity (PRPS1 superactivity) [MIM:300661; also known as PRPS-related gout. It is a familial disorder characterized by excessive purine production, gout and uric acid urolithiasis. Defects in PRPS1 are the cause of Charcot-Marie-Tooth disease X-linked recessive type 5 (CMTX5) [MIM:311070; also known as optic atrophy-polyneuropathy-deafness or Rosenberg-Chutorian syndrome. CMTX5 is a form of Charcot-Marie-Tooth disease, the most common inherited disorder of the peripheral nervous system. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies characterized by severely reduced motor nerve conduction velocities (NCVs) (less than 38m/s) and segmental demyelination and remyelination, and primary peripheral axonal neuropathies characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy.[1] Defects in PRPS1 are the cause of ARTS syndrome (ARTS) [MIM:301835; also known as fatal ataxia X-linked with deafness and loss of vision. ARTS is a disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy. Susceptibility to infections, especially of the upper respiratory tract, can result in early death.[2] Defects in PRPS1 are the cause of deafness X-linked type 1 (DFNX1) [MIM:304500; also known as congenital sensorineural deafness X-linked 2 (DFN2). It is a form of deafness characterized by progressive, severe-to-profound sensorineural hearing loss in males. Females manifest mild to moderate hearing loss.[3] FunctionPRPS1_HUMAN Catalyzes the synthesis of phosphoribosylpyrophosphate (PRPP) that is essential for nucleotide synthesis. Publication Abstract from PubMedHuman PRS1, which is indispensable for the biosynthesis of nucleotides, deoxynucleotides and their derivatives, is associated directly with multiple human diseases because of single base mutation. However, a molecular understanding of the effect of these mutations is hampered by the lack of understanding of its catalytic mechanism. Here, we reconstruct the 3D EM structure of the PRS1 apo state. Together with the native stain EM structures of AMPNPP, AMPNPP and R5P, ADP and the apo states with distinct conformations, we suggest the hexamer is the enzymatically active form. Based on crystal structures, sequence analysis, mutagenesis, enzyme kinetics assays, and MD simulations, we reveal the conserved substrates binding motifs and make further analysis of all pathogenic mutants. Crystal and EM Structures of Human Phosphoribosyl Pyrophosphate Synthase I (PRS1) Provide Novel Insights into the Disease-Associated Mutations.,Chen P, Liu Z, Wang X, Peng J, Sun Q, Li J, Wang M, Niu L, Zhang Z, Cai G, Teng M, Li X PLoS One. 2015 Mar 17;10(3):e0120304. doi: 10.1371/journal.pone.0120304., eCollection 2015. PMID:25781187[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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