Screening and molecular characterization of lethal mutations of human homogentisate 1, 2 dioxigenase

Alkaptonuria (AKU) is an autosomal recessive disorder, which is caused by a site-specific mutation(s) and thus, impaired the function of Homogentisate-1, 2-dioxygenase (HGD), an essential enzyme for the catabolism of phenylalanine and tyrosine. Among frameshift, intronic, splice-site and missense mu...

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Bibliographic Details
Published in:Journal of biomolecular structure & dynamics 2021-03, Vol.39 (5), p.1661-1671
Main Authors: Sen Gupta, Parth Sarthi, Islam, Rifat Nawaz UI, Banerjee, Sahini, Nayek, Arnab, Rana, Malay Kumar, Bandyopadhyay, Amal Kumar
Format: Article
Language:English
Subjects:
AKU
Alkaptonuria
Genes, Lethal
HGD
Homogentisate 1,2-Dioxygenase - genetics
Humans
MD simulations
molecular docking
Molecular Docking Simulation
Mutation
mutations
PCA
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Summary:Alkaptonuria (AKU) is an autosomal recessive disorder, which is caused by a site-specific mutation(s) and thus, impaired the function of Homogentisate-1, 2-dioxygenase (HGD), an essential enzyme for the catabolism of phenylalanine and tyrosine. Among frameshift, intronic, splice-site and missense mutations, the latter has been the most common form of genetic variations for the disease. How do the acquired mutations in HGD correlate with the disease? Systematic staged-screening of some sixty-five mutations, which are known to have a relation with the disease, by GVGD, SIFT, SNAP, PANTHER, SDM, PHD-SNP, Meta-SNP, Pmut and Mutpred methods, showed that mutations, W60G, A122D and V300G are potentially related with the severity of AKU. Detailed analyses on molecular docking and molecular dynamics simulation (MDS) of these mutants against the wild-type HGD reveal the loss of structural and molecular dynamic properties of the enzyme. Further, the observed conformational flexibility in mutants at targeted peptide segments seems to have a relation with the impairment of the function of HGD. Taken together, the study involves a designed computational methodology to analyse the disease-associated nsSNPs for AKU, the knowledge of which seems to have potential applications in drug therapies for the disease in particular and other similar systems in general. Communicated by Ramaswamy H. Sarma
ISSN:0739-1102
1538-0254
DOI:10.1080/07391102.2020.1736158