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.
Highlights
SNPs are modifications occurring in a specific region of the genome, on a single nucleotide
The Nonsynonymous Single Nucleotide Polymorphisms (nsSNPs) can be further divided into mis‐ sense, if the nucleotide modification gives rise to a different amino acid residue, and nonsense, when the point mutation results in a premature stop codon that leads to a truncated form of the protein
The human enzyme is mainly expressed in the liver as a homo‐dimer, and each 150 kDa monomer consists of three different domains: the small N‐terminal domain I (20 kDa) with two spectroscopically distinct [2Fe‐2S] clusters; the central FAD domain II (40 kDa); and the C‐terminal catalytic do‐ main III (90 kDa) which encloses the molybdopterin cofactor (Moco) (Figure 1)
Summary
SNPs are modifications occurring in a specific region of the genome, on a single nucleotide. There has been great interest in SNPs dis‐ covery since these are responsible for the majority of the genetic variations among the human population, and are expected to facili‐ tate large‐scale genetic association studies.[1] SNPs in coding regions are either synonymous, if they do not affect the protein sequence, or nonsynonymous (nsSNP) if they change the amino acid sequence of the codified protein. Mutation of human Moco sulfurase gene is responsible for classical type II xanthinuria, due to the failure of the mechanism respon‐ sible for inserting the essential sulfur atom into the active center of hAOX1 and XO.[16] The presence of nsSNPs in hAOX1 leading to loss of the Moco insertion may be related with the pres‐ ence of type II xanthinuria disease conditions and should be further investigated. This study constitutes the first extensive analysis for the presence of nsSNPs in hAOX1 and can be used to guide future pharmacogenetic, struc‐ tural and functional studies regarding interindividual variability of the human enzyme
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