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Exploring the factors influencing the ketoenamine-enolimine tautomeric equilibrium of pyridoxal 5′-phosphate in branched-chain aminotransferases

Li, Xue ; Yu, He ; Sun, Jiaqi and Sun, Xiaoli LU (2024) In Molecular Catalysis 569.
Abstract

Pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, is a critical coenzyme for various enzymes. It generates a Schiff base with the substrate and exhibits ketoenamine and enolimine tautomeric forms due to intramolecular proton transfer. This study aims to ascertain the predominant tautomeric form of the PLP Schiff base in MtIlvE and analyze its influencing factors. Molecular dynamics simulations indicate that the ketoenamine tautomer has higher binding free energy than the enolimine tautomer. Density functional theory calculations suggest that, despite their ability to interconvert at a relatively low energy barrier, the ketoenamine tautomer is thermodynamically more stable. Factors affecting the keto-enol tautomeric... (More)

Pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, is a critical coenzyme for various enzymes. It generates a Schiff base with the substrate and exhibits ketoenamine and enolimine tautomeric forms due to intramolecular proton transfer. This study aims to ascertain the predominant tautomeric form of the PLP Schiff base in MtIlvE and analyze its influencing factors. Molecular dynamics simulations indicate that the ketoenamine tautomer has higher binding free energy than the enolimine tautomer. Density functional theory calculations suggest that, despite their ability to interconvert at a relatively low energy barrier, the ketoenamine tautomer is thermodynamically more stable. Factors affecting the keto-enol tautomeric equilibrium were investigated by constructing various QM-cluster models. Our results demonstrate that both the protonation of the pyridine nitrogen and the presence of Tyr209, which stabilizes the O3 anion, shift the tautomeric equilibrium toward the ketoenamine configuration. These findings provide a theoretical basis for investigating enzyme catalytic mechanisms.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Branched-chain aminotransferase, Density functional theory (DFT), Enolimine–ketoenamine tautomerism, Molecular dynamics (MD), pyridoxal 5′-phosphate (PLP)
in
Molecular Catalysis
volume
569
article number
114581
publisher
Elsevier
external identifiers
  • scopus:85205577328
ISSN
2468-8231
DOI
10.1016/j.mcat.2024.114581
language
English
LU publication?
yes
id
2cfce8e8-1220-4b18-bf0e-f277a869700d
date added to LUP
2024-11-26 13:06:14
date last changed
2025-04-04 14:51:54
@article{2cfce8e8-1220-4b18-bf0e-f277a869700d,
  abstract     = {{<p>Pyridoxal 5′-phosphate (PLP), the active form of vitamin B6, is a critical coenzyme for various enzymes. It generates a Schiff base with the substrate and exhibits ketoenamine and enolimine tautomeric forms due to intramolecular proton transfer. This study aims to ascertain the predominant tautomeric form of the PLP Schiff base in MtIlvE and analyze its influencing factors. Molecular dynamics simulations indicate that the ketoenamine tautomer has higher binding free energy than the enolimine tautomer. Density functional theory calculations suggest that, despite their ability to interconvert at a relatively low energy barrier, the ketoenamine tautomer is thermodynamically more stable. Factors affecting the keto-enol tautomeric equilibrium were investigated by constructing various QM-cluster models. Our results demonstrate that both the protonation of the pyridine nitrogen and the presence of Tyr209, which stabilizes the O3 anion, shift the tautomeric equilibrium toward the ketoenamine configuration. These findings provide a theoretical basis for investigating enzyme catalytic mechanisms.</p>}},
  author       = {{Li, Xue and Yu, He and Sun, Jiaqi and Sun, Xiaoli}},
  issn         = {{2468-8231}},
  keywords     = {{Branched-chain aminotransferase; Density functional theory (DFT); Enolimine–ketoenamine tautomerism; Molecular dynamics (MD); pyridoxal 5′-phosphate (PLP)}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Molecular Catalysis}},
  title        = {{Exploring the factors influencing the ketoenamine-enolimine tautomeric equilibrium of pyridoxal 5′-phosphate in branched-chain aminotransferases}},
  url          = {{http://dx.doi.org/10.1016/j.mcat.2024.114581}},
  doi          = {{10.1016/j.mcat.2024.114581}},
  volume       = {{569}},
  year         = {{2024}},
}