Base analogs are powerful endogenous antimetabolites and dangerous mutagens forming under oxidative stress, inflammation and aberrant nucleotide synthesis. Human inosine triphosphate pyrophosphohydrolase (ITPA) catalyzes the hydrolysis of triphosphates of non-canonic purine bases (ITP, dITP, XTP, dXTP) and thus regulates the nucleotide pool and protects cells from DNA damage. The polymorphic allele c.94C>A, which encodes the enzyme with P32T substitution, causes enzymatic activity loss in erythrocytes and ITP accumulation. An association is observed between the mutant allele P32T-ITPA and adverse sensitivity to purine base analog drugs that are used in the treatment of acute lymphoblastic leukemia and inflammatory intestinal diseases and for preventing organ rejection after transplantation. The inactivation mechanism of the polymorph P32T-ITPA enzyme is unknown. A simulation of the enzyme's mutant form showed weakening of the interconnection between the two subunits [1]. Indeed, the experimental data indicate that the mutant enzyme is less stable but active in vivo [2]. The assumption made in the literature that the hydrophobic residue is pushed outside, which is a signal for proteasome degradation, has not been confirmed in silico [1]. To understand the mechanism of inactivation in vivo, it is necessary to examine the molecular mechanisms of gene expression in more detail. It has been found that alternative splicing and formation of three forms is possible; the latter's proportion being tissue specific. Numerous strips are observed in protein electrophoresis [4]. In the present work, using special programs that identify the potential chemical modification sites, we have determined the potential sites of phosphorylation, ubiquitination, and SUMOliation. It is assumed that chemical modifications participate in the regulation of the enzyme's location and activity. Hypothetic mechanisms are suggested. The results allow us to carry out a further experimental check of the existence of modified forms and to simulate the impact of chemical modifications on enzyme activity.
single nucleotide polymorphism, ITPA gene, mutant inosine triphosphatase P32T-ITPA, computer simulation, potential sites of regulatory chemical modifications
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