Conformational Changes Induced by P32T Substitution in Human Phosphatase ITPA

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

Journal Name: Current Chemical Biology

Volume 12 , Issue 2 , 2018

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Graphical Abstract:


Background: Enzyme ITPA participates in purine metabolism and its deficiency plays a role in several human diseases. There is growing evidence that ITPA polymorphism is also an important pharmacogenic phenotype, leading to a change in sensitivity to several drugs. ITPA deficiency exists in humans and is observed as elevated levels of ITP.

Objective: Allele P32T-ITPA has more pronounced effects but the mechanism of enzyme inactivation is not known. Based on crystallographic data, it was assumed that the mutant loop containing P32T substitution led to uncovering of a hydrophobic residue (Phe31) that served as a marker for enzyme degradation.

Method: As the crystal structure of the enzyme may differ from the native structure in a solution, we tested this hypothesis using computer modeling. We simulated the structures of the wild-type homodimer and mutant homo- and heterodimers of the ITPA protein and analyzed these models at small time steps for detecting short-term effects of the conformations of the ITPA enzyme.

Results: Comparison of mutant structures with the wild-type structure revealed that the differences were more pronounced for the mutant homodimer than for the heterodimer. There were two regions of strong distinctions – loops between α1-β2 and β5-β6. Two neighboring hydrophobic amino acids (Phe31 and Pro32) were changed by hydrophilic amino acids (Thr32 and Cys33) in the first loop (res. 28-33) due to mutation Phe31-Рro32Тhr-Cys33. The model structure differs from the crystal structure of P32T-ITPA. The position of Phe31 in modeled mutant chains was inward-directed as compared to outward-directed in the crystal and did not serve as a signal for degradation as was predicted.

Conclusion: Further investigations are needed for understanding the mechanism of enzyme inactivation by P32T substitution in ITPA.

Keywords: Molecular dynamics simulations, inosine triphosphate pyrophosphatase, mutant P32T homoand heterodimeric enzymes, P32T substitution, hydrophobic amino acids, ITPA polymorphism.

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Article Details

Year: 2018
Published on: 07 August, 2018
Page: [158 - 168]
Pages: 11
DOI: 10.2174/2212796812666180101141809
Price: $25

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