Ermuhammad B. Dushanov* and Natalia A. Koltovaya Pages 45 - 53 ( 9 )
Background. Cells have specific enzymes (nucleoside triphosphate pyrophosphohydrolase) that hydrolyze non-canonic nucleoside triphosphates into nucleoside monophosphophates and pyrophosphate, thus removing them from metabolic processes. This class of enzymes includes inosine triphosphate pyrophosphatase (ITPA) which has specificity to ITP, dITP, XTP, dXTP.
Objective. The mutation (94C→A) rather often occurs in humans and can affect sensitivity of patients to medicines . This mutation leads to a Pro32Thr substitution in the human ITPA protein. The mechanism for the inactivating effect of the mutation is unknown yet.
Method. Molecular modeling of the polymorphic form of inosine triphosphate pyrophosphohydrolase Р32Т-hITPA showing the greatest decrease in the enzyme activity  is performed. The analysis is given for four dimer variants: wild-type (P32/P32) and mutant (T32/T32) homodimers and two mutant heterodimers (Р32/Т32 and Т32/Р32).
Results. The analysis does not show the motion of the loop between α2 and β2 where mutation localized. Thus, the hypothesis  of the flipped-out hydrophobic residue and subsequent of protein degradation has not confirmed. Dimer displacements were much higher than subunit displacements. Analysis of hydrogen bonds between subunits shows that there are the more stable hydrogen bonds in the wild-type homodimer and fewer in the mutant homodimer, while heterodimers have intermediate stability.
Conclusion. The results confirm the assumption of possible weakening of bonds between the mutant subunits .
Dimer, inosine triphosphate pyrophosphatase, MD modeling, mutant homo- and heterodimeric Р32Т enzyme variants, polymorphic forms, subunits.
Laboratory of Radiation Biology, Joint Institute for Nuclear Research, Dubna, Laboratory of Radiation Biology, Joint Institute for Nuclear Research, Dubna