The Catalytic Mechanism of Pdx2 Glutaminase Driven by a Cys-His-Glu Triad: A Computational Study was written by Pina, Andre F.;Sousa, Sergio F.;Cerqueira, Nuno M. F. S. A.. And the article was included in ChemBioChem in 2022.Safety of (4-Formyl-5-hydroxy-6-methylpyridin-3-yl)methyl dihydrogen phosphate The following contents are mentioned in the article:
The catalytic mechanism of Pdx2 was studied with at. detail employing the computational ONIOM hybrid QM/MM methodol. Pdx2 employs a Cys-His-Glu catalytic triad to deaminate glutamine to glutamate and ammonia – the source of the nitrogen of pyridoxal 5′-phosphate (PLP). This enzyme is, therefore, a rate-limiting step in the PLP biosynthetic pathway of Malaria and Tuberculosis pathogens that rely on this mechanism to obtain PLP. For this reason, Pdx2 is considered a novel and promising drug target to treat these diseases. The results obtained show that the catalytic mechanism of Pdx2 occurs in six steps that can be divided into four stages: (i) activation of Cys87, (ii) deamination of glutamine with the formation of the glutamyl-thioester intermediate, (iii) hydrolysis of the formed intermediate, and (iv) enzymic turnover. The kinetic data available in the literature (19.1-19.5 kcal mol-1) agree very well with the calculated free energy barrier of the hydrolytic step (18.2 kcal.mol-11), which is the rate-limiting step of the catalytic process when substrate is readily available in the active site. This catalytic mechanism differs from other known amidases in three main points: i) it requires the activation of the nucleophile Cys87 to a thiolate; ii) the hydrolysis occurs in a single step and therefore does not require the formation of a second tetrahedral reaction intermediate, as it is proposed, and iii) Glu198 does not have a direct role in the catalytic process. Together, these results can be used for the synthesis of new transition state analog inhibitors capable of inhibiting Pdx2 and impair diseases like Malaria and Tuberculosis. This study involved multiple reactions and reactants, such as (4-Formyl-5-hydroxy-6-methylpyridin-3-yl)methyl dihydrogen phosphate (cas: 54-47-7Safety of (4-Formyl-5-hydroxy-6-methylpyridin-3-yl)methyl dihydrogen phosphate).
(4-Formyl-5-hydroxy-6-methylpyridin-3-yl)methyl dihydrogen phosphate (cas: 54-47-7) belongs to pyridine derivatives. In contrast to benzene, Pyridine’s electron density is not evenly distributed over the ring, reflecting the negative inductive effect of the nitrogen atom. Pyridine derivatives are also useful as small-molecule α-helix mimetics that inhibit protein-protein interactions, as well as functionally selective GABA ligands.Safety of (4-Formyl-5-hydroxy-6-methylpyridin-3-yl)methyl dihydrogen phosphate