8dbf | pdb_00008dbf
Human PRPS1 with ADP; Filament Interface
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 PubMedThe universally conserved enzyme phosphoribosyl pyrophosphate synthetase (PRPS) assembles filaments in evolutionarily diverse organisms. PRPS is a key regulator of nucleotide metabolism, and mutations in the human enzyme PRPS1 lead to a spectrum of diseases. Here we determine structures of human PRPS1 filaments in active and inhibited states, with fixed assembly contacts accommodating both conformations. The conserved assembly interface stabilizes the binding site for the essential activator phosphate, increasing activity in the filament. Some disease mutations alter assembly, supporting the link between filament stability and activity. Structures of active PRPS1 filaments turning over substrate also reveal coupling of catalysis in one active site with product release in an adjacent site. PRPS1 filaments therefore provide an additional layer of allosteric control, conserved throughout evolution, with likely impact on metabolic homeostasis. Stabilization of allosteric binding sites by polymerization adds to the growing diversity of assembly-based enzyme regulatory mechanisms. Human PRPS1 filaments stabilize allosteric sites to regulate activity.,Hvorecny KL, Hargett K, Quispe JD, Kollman JM Nat Struct Mol Biol. 2023 Mar;30(3):391-402. doi: 10.1038/s41594-023-00921-z. , Epub 2023 Feb 6. PMID:36747094[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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