Reaction Mechanism of Human PAICS Elucidated by Quantum Chemical Calculations

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F22%3A00560182" target="_blank" >RIV/61388963:_____/22:00560182 - isvavai.cz</a>

Result on the web

<a href="https://doi.org/10.1021/jacs.2c05072" target="_blank" >https://doi.org/10.1021/jacs.2c05072</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/jacs.2c05072" target="_blank" >10.1021/jacs.2c05072</a>

Result language

angličtina

Original language name

Reaction Mechanism of Human PAICS Elucidated by Quantum Chemical Calculations

Original language description

Human PAICS is a bifunctional enzyme that is involved in the de novo purine biosynthesis, catalyzing the conversion of aminoimidazole ribonucleotide (AIR) into N-succinylcarboxamide-5-aminoimidazole ribonucleo-tide (SAICAR). It comprises two distinct active sites, AIR carboxylase (AIRc) where the AIR is initially converted to carboxyaminoimidazole ribonucleotide (CAIR) by reaction with CO2 and SAICAR synthetase (SAICARs) in which CAIR then reacts with an aspartate to form SAICAR, in an ATP-dependent reaction. Human PAICS is a promising target for the treatment of various types of cancer, and it is therefore of high interest to develop a detailed understanding of its reaction mechanism. In the present work, density functional theory calculations are employed to investigate the PAICS reaction mechanism. Starting from the available crystal structures, two large models of the AIRc and SAICARs active sites are built and different mechanistic proposals for the carboxylation and phosphorylation-condensation mechanisms are examined. For the carboxylation reaction, it is demonstrated that it takes place in a two-step mechanism, involving a C-C bond formation followed by a deprotonation of the formed tetrahedral intermediate (known as isoCAIR) assisted by an active site histidine residue. For the phosphorylation-condensation reaction, it is shown that the phosphorylation of CAIR takes place before the condensation reaction with the aspartate. It is further demonstrated that the three active site magnesium ions are involved in binding the substrates and stabilizing the transition states and intermediates of the reaction. The calculated barriers are in good agreement with available experimental data.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10608 - Biochemistry and molecular biology

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2022

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of the American Chemical Society

ISSN

0002-7863

e-ISSN

1520-5126

Volume of the periodical

144

Issue of the periodical within the volume

31

Country of publishing house

US - UNITED STATES

Number of pages

11

Pages from-to

14258-14268

UT code for WoS article

000836017000001

EID of the result in the Scopus database

2-s2.0-85135768121