Free-Energy Profile Analysis of the Catalytic Reaction of Glycinamide Ribonucleotide Synthetase.

Norifumi Yamamoto,Genichi Sampei,Gota Kawai

doi:10.3390/life12020281

Norifumi Yamamoto, Genichi Sampei + Show 1 more

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https://doi.org/10.3390/life12020281

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Abstract

The second step in the de novo biosynthetic pathway of purine is catalyzed by PurD, which consumes an ATP molecule to produce glycinamide ribonucleotide (GAR) from glycine and phosphoribosylamine (PRA). PurD initially reacts with ATP to produce an intermediate, glycyl-phosphate, which then reacts with PRA to produce GAR. The structure of the glycyl-phosphate intermediate bound to PurD has not been determined. Therefore, the detailed reaction mechanism at the molecular level is unclear. Here, we developed a computational protocol to analyze the free-energy profile for the glycine phosphorylation process catalyzed by PurD, which examines the free-energy change along a minimum energy path based on a perturbation method combined with the quantum mechanics and molecular mechanics hybrid model. Further analysis revealed that during the formation of glycyl-phosphate, the partial atomic charge distribution within the substrate molecules was not localized according to the formal charges, but was delocalized overall, which contributed significantly to the interaction with the charged amino acid residues in the ATP-grasp domain of PurD.

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IntroductionPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations
Received: 30 December 2021Accepted: 12 February 2022Published: 14 February 2022Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Licensee MDPI, Basel, Switzerland.De novo purine nucleotide biosynthesis pathway is evolutionarily conserved in all organisms, including plants [1,2], microorganisms [3], and mammals [4]
We investigated the reaction mechanism of the second step in the de novo biosynthetic pathway of purine nucleotides catalyzed by PurD enzyme based on the free-energy profile analysis

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. De novo purine nucleotide biosynthesis pathway is evolutionarily conserved in all organisms, including plants [1,2], microorganisms [3], and mammals [4]. Purine nucleotide synthesis starts with the formation of 5-phosphoribosyl-1-pyrophosphate from simple molecules such as carbonates, amino acids, and tetrahydrofolate, which yields inosine monophosphate (IMP) as an intermediate precursor. After IMP is produced, the pathway splits into two branches to produce adenosine monophosphate (AMP) and guanosine monophosphate (GMP). AMP and GMP are eventually phosphorylated to form adenosine triphosphate (ATP) and guanosine triphosphate

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