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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 10 e0120304 (2015)
Related entries: 3s5j, 4lzn, 4lzo, 4m0p, 4m0u

Cited: 11 times
EuropePMC logo PMID: 25781187

Abstract

Human 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.

Reviews - 4lyg mentioned but not cited (1)

  1. Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance. Hove-Jensen B, Andersen KR, Kilstrup M, Martinussen J, Switzer RL, Willemoës M. Microbiol Mol Biol Rev 81 e00040-16 (2017)

Articles - 4lyg mentioned but not cited (1)

  1. 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 10 e0120304 (2015)


Reviews citing this publication (2)

  1. Contribution of Model Organisms to Investigating the Far-Reaching Consequences of PRPP Metabolism on Human Health and Well-Being. Ugbogu EA, Schweizer LM, Schweizer M. Cells 11 1909 (2022)
  2. PRPS-Associated Disorders and the Drosophila Model of Arts Syndrome. Delos Santos K, Kwon E, Moon NS. Int J Mol Sci 21 E4824 (2020)

Articles citing this publication (7)

  1. Conversion of PRPS Hexamer to Monomer by AMPK-Mediated Phosphorylation Inhibits Nucleotide Synthesis in Response to Energy Stress. Qian X, Li X, Tan L, Lee JH, Xia Y, Cai Q, Zheng Y, Wang H, Lorenzi PL, Lu Z. Cancer Discov 8 94-107 (2018)
  2. Functional characterization of a novel loss-of-function mutation of PRPS1 related to early-onset progressive nonsyndromic hearing loss in Koreans (DFNX1): Potential implications on future therapeutic intervention. Kim SY, Kim AR, Kim NK, Lee C, Han JH, Kim MY, Jeon EH, Park WY, Mittal R, Yan D, Liu XZ, Choi BY. J Gene Med 18 353-358 (2016)
  3. Filamentation modulates allosteric regulation of PRPS. Hu HH, Lu GM, Chang CC, Li Y, Zhong J, Guo CJ, Zhou X, Yin B, Zhang T, Liu JL. Elife 11 e79552 (2022)
  4. Human PRPS1 filaments stabilize allosteric sites to regulate activity. Hvorecny KL, Hargett K, Quispe JD, Kollman JM. Nat Struct Mol Biol 30 391-402 (2023)
  5. Molecular mechanism of c-Myc and PRPS1/2 against thiopurine resistance in Burkitt's lymphoma. Li T, Song L, Zhang Y, Han Y, Zhan Z, Xv Z, Li Y, Tang Y, Yang Y, Wang S, Li S, Zheng L, Li Y, Gao Y. J Cell Mol Med 24 6704-6715 (2020)
  6. NRF2-directed PRPS1 upregulation to promote the progression and metastasis of melanoma. Xiong G, Feng Y, Yi X, Zhang X, Li X, Yang L, Yi Z, Sai B, Yang Z, Zhang Q, Kuang Y, Zhu Y. Front Immunol 13 989263 (2022)
  7. Direct stimulation of de novo nucleotide synthesis by O-GlcNAcylation. Chen L, Zhou Q, Zhang P, Tan W, Li Y, Xu Z, Ma J, Kupfer GM, Pei Y, Song Q, Pei H. Nat Chem Biol 20 19-29 (2024)


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