Effect of Substitution Pro32Thr on the Interaction between Dimer Subunits of Human Phosphatase ITPA

Author(s): Ermuhammad B. Dushanov*, Natalia A. Koltovaya.

Journal Name: Current Enzyme Inhibition

Volume 15 , Issue 1 , 2019

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Abstract:

Background: Cells have specific enzymes (nucleoside triphosphate pyrophosphohydrolase) that hydrolyze non-canonic nucleoside triphosphates into nucleoside monophosphophates and pyrophosphate, thus removing them from the metabolic processes. This class of enzymes includes inosine triphosphate pyrophosphatase (ITPA) which has specificity to ITP, dITP, XTP and dXTP.

Objective: The mutation (94C→A) rather often occurs in humans and can affect the 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.

Methods: 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 have not been confirmed. Dimer displacements were much higher than subunit displacements. The 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.

Keywords: Dimer, inosine triphosphate pyrophosphatase, MD modeling, mutant homo- and heterodimeric Р32Т enzyme variants, polymorphic forms, subunits.

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Article Details

VOLUME: 15
ISSUE: 1
Year: 2019
Page: [46 - 54]
Pages: 9
DOI: 10.2174/1573408015666190327174841

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