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  • 1.
    Engelmark Cassimjee, Karim
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Manta, Bianca
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Himo, Fahmi
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    A quantum chemical study of the ω-transaminase reaction mechanism2015In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 13, no 31, p. 8453-8464Article in journal (Refereed)
    Abstract [en]

    ω-Transaminases are valuable tools in biocatalysis due to their stereospecificity and their broad substrate range. In the present study, the reaction mechanism of Chromobacterium violaceum ω-transaminase is investigated by means of density functional theory calculations. A large active site model is designed based on the recent X-ray crystal structure. The detailed energy profile for the half-transamination of (S)-1-phenylethylamine to acetophenone is calculated and the involved transition states and intermediates are characterized. The model suggests that the amino substrate forms an external aldimine with the coenzyme pyridoxal-5′-phosphate (PLP), through geminal diamine intermediates. The external aldimine is then deprotonated in the rate-determining step, forming a planar quinonoid intermediate. A ketimine is then formed, after which a hemiaminal is produced by the addition of water. Subsequently, the ketone product is obtained together with pyridoxamine-5′-phosphate (PMP). In the studied half-transamination reaction the ketone product is kinetically favored. The mechanism presented here will be valuable to enhance rational and semi-rational design of engineered enzyme variants in the development of ω-transaminase chemistry.

  • 2.
    Manta, Bianca
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Engelmark Cassimjee, Karim
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Himo, Fahmi
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Quantum Chemical Study of Dual-Substrate Recognition in ω-Transaminase2017In: ACS Omega, E-ISSN 2470-1343, Vol. 2, no 3, p. 890-898Article in journal (Refereed)
    Abstract [en]

    ω-Transaminases are attractive biocatalysts for the production of chiral amines. These enzymes usually have a broad substrate range. Their substrates include hydrophobic amines as well as amino acids, a feature referred to as dual-substrate recognition. In the present study, the reaction mechanism for the half-transamination of L-alanine to pyruvate in (S)-selective Chromobacterium violaceum ω-transaminase is investigated using density functional theory calculations. The role of a flexible arginine residue, Arg416, in the dual-substrate recognition is investigated by employing two active-site models, one including this residue and one lacking it. The results of this study are compared to those of the mechanism of the conversion of (S)-1-phenylethylamine to acetophenone. The calculations suggest that the deaminations of amino acids and hydrophobic amines follow essentially the same mechanism, but the energetics of the reactions differ significantly. It is shown that the amine is kinetically favored in the half-transamination of L-alanine/pyruvate, whereas the ketone is kinetically favored in the half-transamination of (S)-1-phenylethylamine/acetophenone. The calculations further support the proposal that the arginine residue facilitates the dual-substrate recognition by functioning as an arginine switch, where the side chain is positioned inside or outside of the active site depending on the substrate. Arg416 participates in the binding of L-alanine by forming a salt bridge to the carboxylate moiety, whereas the conversion of (S)-1-phenylethylamine is feasible in the absence of Arg416, which here represents the case in which the side chain of Arg416 is positioned outside of the active site.

  • 3.
    Manta, Bianca
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Himo, Fahmi
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Insights from Quantum Chemical Calculations into Active Site Structure and Reaction Mechanism of Manganese-Dependent Dinitrogenase Reductase-Activating GlycohydrolaseManuscript (preprint) (Other academic)
  • 4.
    Manta, Bianca
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Raushel, Frank M.
    Himo, Fahmi
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Reaction Mechanism of Zinc-Dependent Cytosine Deaminase from Escherichia coli: A Quantum-Chemical Study2014In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, no 21, p. 5644-5652Article in journal (Refereed)
    Abstract [en]

    The reaction mechanism of cytosine deaminase from Escherichia coli is studied using density functional theory. This zinc-dependent enzyme catalyzes the deamination of cytosine to form uracil and ammonia. The calculations give a detailed description of the catalytic mechanism and establish the role of important active-site residues. It is shown that Glu217 is essential for the initial deprotonation of the metal-bound water nucleophile and the subsequent protonation of the substrate. It is also demonstrated that His246 is unlikely to function as a proton shuttle in the nucleophile activation step, as previously proposed. The steps that follow are nucleophilic attack by the metal-bound hydroxide, protonation of the leaving group assisted by Asp313, and C-N bond cleavage. The calculated overall barrier is in good agreement with the experimental findings. Finally, the calculations reproduce the experimentally determined inverse solvent deuterium isotope effect, which further corroborates the suggested reaction mechanism.

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