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AuthorAgrahari, Ashish Kumar
AuthorKrishna Priya, M
AuthorPraveen Kumar, Medapalli
AuthorTayubi, Iftikhar Aslam
AuthorSiva, R
AuthorPrabhu Christopher, B
AuthorGeorge Priya Doss, C
AuthorZayed, Hatem
Available date2019-03-06T05:17:22Z
Publication Date2019-02-01
Publication NameComputers in Biology and Medicineen_US
Identifierhttp://dx.doi.org/10.1016/j.compbiomed.2019.02.014
CitationAgrahari AK, Krishna Priya M, Praveen Kumar M, Tayubi IA, Siva R, Prabhu Christopher B, George Priya Doss C, Zayed H. Understanding the structure-function relationship of HPRT1 missense mutations in association with Lesch-Nyhan disease and HPRT1-related gout by in silico mutational analysis. Comput Biol Med. 2019 Feb 23;107:161-171. doi: 10.1016/j.compbiomed.2019.02.014.
ISSN0010-4825
URIhttp://hdl.handle.net/10576/11375
AbstractThe 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.
Languageen
PublisherElsevier
SubjectHPRT1
SubjectLesch–nyhan disease
SubjectMolecular dynamics simulation
SubjectNon-synonymous SNP
TitleUnderstanding the structure-function relationship of HPRT1 missense mutations in association with Lesch-Nyhan disease and HPRT1-related gout by in silico mutational analysis.
TypeArticle
Pagination161-171
Volume Number107
dc.identifier.essn 1879-0534


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