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Understanding the structure-function relationship of HPRT1 missense mutations in association with Lesch–Nyhan disease and HPRT1-related gout by in silico mutational analysis
Agrahari A.K, Krishna Priya M, Tayubi I.A, , Prabhu Christopher B, , , Zayed H.
Published in Elsevier BV
PMID: 30831305
Volume: 107
Pages: 161 - 171
The nucleotide salvage pathway is used to recycle degraded nucleotides (purines and pyrimidines); one of the enzymes that helps to recycle purines is hypoxanthine guanine phosphoribosyl transferase 1 (HGPRT1). Therefore, defects in this enzyme lead to the accumulation of DNA and nucleotide lesions and hence replication errors and genetic disorders. Missense mutations in hypoxanthine phosphoribosyl transferase 1 (HPRT1) are associated with deficiencies such as Lesch–Nyhan disease and chronic gout, which have manifestations such as arthritis, neurodegeneration, and cognitive disorders. In the present study, we collected 88 non-synonymous single nucleotide polymorphisms (nsSNPs) from the UniProt, dbSNP, ExAC, and ClinVar databases. We used a series of sequence-based and structure-based in silico tools to prioritize and characterize the most pathogenic and stabilizing or destabilizing nsSNPs. Moreover, to obtain the structural impact of the pathogenic mutations, we mapped the mutations to the crystal structure of the HPRT protein. We further subjected these mutant proteins to a 50 ns molecular dynamics simulation (MDS). The MDS trajectory showed that all mutant proteins altered the structural conformation and dynamic behavior of the HPRT protein and corroborated its association with LND and gout. This study provides essential information regarding the use of HPRT protein mutants as potential targets for therapeutic development. © 2019 Elsevier Ltd
About the journal
JournalData powered by TypesetComputers in Biology and Medicine
PublisherData powered by TypesetElsevier BV
Open AccessNo
Authors (3)