Quantum mechanical study of the intermediates formed following the reaction of the histidine decarboxylase's substrate and inhibitors with coenzyme

Taha-Nejad, F.

doi:10.1016/s0223-5234(00)90170-3

Cited by 5 publications

(3 citation statements)

References 21 publications

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“…All the active TSase models prepared in the previous section were solvated using a TIP3P, type of water molecules within a minimum radius of 12 Å from the surface of the enzyme. Hydrogen atoms were added to the model using SANDER from AMBER12 package…”

Section: Methodsmentioning

confidence: 99%

Solving the Catalytic Mechanism of Tryptophan Synthase: an Emergent Drug Target in the Treatment of Tuberculosis

et al. 2019

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Tryptophan Synthase (TSase) is an emergent therapeutic target in the treatment of tuberculosis. Interest in TSase as a drug target arose from the fact that this enzyme is not present in humans, while in bacteria, like M. tuberculosis, it catalyses the last two steps in the tryptophan biosynthetic pathway. Several inhibitors of TSase have recently been developed, with promising results. However, the exact catalytic mechanism of this enzyme has remained unexplained at the atomic level. The fact that TSase is a multifunctional enzyme, with two dimers, each one with two independent active sites, interconnected by a 25 Å tunnel, has made it a challenging enzyme, from the catalytic point of view. QM/MM calculations were used to analyze and explain the two steps catalyzed by this enzyme. The results provide an atomic‐level clarification of the full catalytic mechanism of this enzyme, offering also important clues for the development of new inhibitors against tuberculosis.

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Section: Methodsmentioning

confidence: 99%

Solving the Catalytic Mechanism of Tryptophan Synthase: an Emergent Drug Target in the Treatment of Tuberculosis

et al. 2019

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“…The protein and the external aldimine or quinonoid intermediate were solvated by using TIP3P type water molecules. The water box was constructed allowing a minimum distance of 12 Å from protein to each face of the box.…”

Section: Computational Detailsmentioning

confidence: 99%

The Catalytic Mechanism of the Pyridoxal‐5′‐phosphate‐Dependent Enzyme, Histidine Decarboxylase: A Computational Study

Fernandes

Ramos

Cerqueira

2017

Chemistry A European J

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The catalytic mechanism of histidine decarboxylase (HDC), a pyridoxal-5'-phosphate (PLP)-dependent enzyme, was studied by using a computational QM/MM approach following the scheme M06-2X/6-311++G(3df,2pd):Amber. The reaction involves two sequential steps: the decarboxylation of l-histidine and the protonation of the generated intermediate from which results histamine. The rate-limiting step is the first one (ΔG =17.6 kcal mol ; ΔG =13.7 kcal mol ) and agrees closely with the available experimental k (1.73 s ), which corresponds to an activation barrier of 17.9 kcal mol . In contrast, the second step is very fast (ΔG =1.9 kcal mol ) and exergonic (ΔG =-33.2 kcal mol ). Our results agree with the available experimental data and allow us to explain the role played by several active site residues that are considered relevant according to site-directed mutagenesis studies, namely Tyr334B, Asp273A, Lys305A, and Ser354B. These results can provide insights regarding the catalytic mechanism of other enzymes belonging to family II of PLP-dependent decarboxylases.

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“…Although the prokaryotic HDC enzymes are mainly pyruvoyl-dependent (with the exception of a few Gram-negative bacteria such as Morganella morganii together with some Enterobacter and Klebsiella species), the eukaryotic, and thus the mammalian and human, enzymes are PLP-dependent. E. E. Snell and co-workers cloned, purified, and characterized the prokaryotic PLP HDCs. − Today, apart from a few mechanistic papers, these prokaryotic decarboxylases are mainly studied for their role in contamination of food, especially fish, to find possible inhibitors that could prevent histamine accumulation. − …”

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confidence: 99%

Cysteine 180 Is a Redox Sensor Modulating the Activity of Human Pyridoxal 5′-Phosphate Histidine Decarboxylase

Rossignoli

Grottesi²,

Bisello

et al. 2018

Biochemistry

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Histidine decarboxylase is a pyridoxal 5′-phosphate enzyme catalyzing the conversion of histidine to histamine, a bioactive molecule exerting its role in many modulatory processes. The human enzyme is involved in many physiological functions, such as neurotransmission, gastrointestinal track function, cell growth, and differentiation. Here, we studied the functional properties of the human enzyme and, in particular, the effects exerted at the protein level by two cysteine residues: Cys-180 and Cys-418. Surprisingly, the enzyme exists in an equilibrium between a reduced and an oxidized form whose extent depends on the redox state of Cys-180. Moreover, we determined that (i) the two enzymatic redox species exhibit modest structural changes in the coenzyme microenvironment and (ii) the oxidized form is slightly more active and stable than the reduced one. These data are consistent with the model proposed by bioinformatics analyses and molecular dynamics simulations in which the Cys-180 redox state could be responsible for a structural transition affecting the C-terminal domain reorientation leading to active site alterations. Furthermore, the biochemical properties of the purified C180S and C418S variants reveal that C180S behaves like the reduced form of the wild-type enzyme, while C418S is sensitive to reductants like the wild-type enzyme, thus allowing the identification of Cys-180 as the redox sensitive switch. On the other hand, Cys-418 appears to be a residue involved in aggregation propensity. A possible role for Cys-180 as a regulatory switch in response to different cellular redox conditions could be suggested.

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Quantum mechanical study of the intermediates formed following the reaction of the histidine decarboxylase's substrate and inhibitors with coenzyme

Cited by 5 publications

References 21 publications

Solving the Catalytic Mechanism of Tryptophan Synthase: an Emergent Drug Target in the Treatment of Tuberculosis

Solving the Catalytic Mechanism of Tryptophan Synthase: an Emergent Drug Target in the Treatment of Tuberculosis

The Catalytic Mechanism of the Pyridoxal‐5′‐phosphate‐Dependent Enzyme, Histidine Decarboxylase: A Computational Study

Cysteine 180 Is a Redox Sensor Modulating the Activity of Human Pyridoxal 5′-Phosphate Histidine Decarboxylase

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