Systematic exploration of predicted destabilizing nonsynonymous single nucleotide polymorphisms (nsSNPs) of human aldehyde oxidase: A Bio‐informatics study

Abstract

Aldehyde Oxidase (hAOX1) is a cytosolic enzyme involved in the metabolism of drugs and xenobiotic compounds. The enzyme belongs to the xanthine oxidase (XO) family of Mo containing enzyme and is a homo‐dimer of two 150 kDa monomers. Nonsynonymous Single Nucleotide Polymorphisms (nsSNPs) of hAOX1 have been reported as affecting the ability of the enzyme to metabolize different substrates. Some of these nsSNPs have been biochemically and structurally characterized but the lack of a systematic and comprehensive study regarding all described and validated nsSNPs is urgent, due to the increasing importance of the enzyme in drug development, personalized medicine and therapy, as well as in pharmacogenetic studies. The objective of the present work was to collect all described nsSNPs of hAOX1 and utilize a series of bioinformatics tools to predict their effect on protein structure stability with putative implications on phenotypic functional consequences. Of 526 nsSNPs reported in NCBI‐dbSNP, 119 are identified as deleterious whereas 92 are identified as nondeleterious variants. The stability analysis was performed for 119 deleterious variants and the results suggest that 104 nsSNPs may be responsible for destabilizing the protein structure, whereas five variants may increase the protein stability. Four nsSNPs do not have any impact on protein structure (neutral nsSNPs) of hAOX1. The prediction results of the remaining six nsSNPs are nonconclusive. The in silico results were compared with available experimental data. This methodology can also be used to identify and prioritize the stabilizing and destabilizing variants in other enzymes involved in drug metabolism.

Identification of deleterious single nucleotide polymorphism (SNP)s in the human TBX5 gene & prediction of their structural & functional consequences: An in silico approach

“…Recently bioinformatics approaches have become popular for identifying different human gene SNPs and predicting their structural and functional consequences. In the past few years, damaging SNPs of CCR6 gene [ 81 ], SMPX gene [ 82 ], human aldehyde oxidase gene [ 83 ], PTEN gene [ 84 ], folate pathway genes [ 85 ], human bone morphogenetic protein receptor type 1A gene [ 86 ], SKP2 gene [ 87 ], human adiponectin receptor 2 gene [ 88 ], MMP9 gene [ 89 ], etc. have been identified with the help of different computational biology tools.…”

The rs35217482 (T755I) Single-Nucleotide Polymorphism in Aldehyde Oxidase-1 Attenuates Protein Dimer Formation and Reduces the Rates of Phthalazine Metabolism

“…Another SNP, namely S1271L (rs141786030), found in an Italian population, is located proximate to the E1270 residue, which is essential for oxidation activity, and has been found to be associated with lower k cat and K m values compared with those of the wild-type (WT) enzyme (Foti et al, 2016). In addition to these SNPs, certain non-synonymous SNPs (nsSNPs) are assumed to induce protein structural labilization, based on the findings of an in silico analysis (Coelho et al, 2019). Collectively, the findings of the aforementioned studies indicate that AOX1 can play a potentially important role in inter-individual drug responses, and consequently, it is of particular importance that we gain an understanding of the molecular mechanisms underlying the inter-individual variability of this enzyme's activity.…”

Identification of deleterious single nucleotide polymorphism (SNP)s on the humanTBX5gene & prediction of their structural & functional consequences: Anin silicoapproach

“…SNPs of CCR6 gene[81], SMPX gene[82], human aldehyde oxidase gene[83], PTEN gene[84], folate pathway genes[85], human bone morphogenetic protein receptor type 1A gene[86], SKP2 gene[87], human adiponectin receptor 2 gene[88], MMP9 gene[89], etc. have been identified with the help of different computational biology tools.…”