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Issue 31, 2015
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A quantum chemical study of the ω-transaminase reaction mechanism

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Abstract

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.

Graphical abstract: A quantum chemical study of the ω-transaminase reaction mechanism

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Publication details

The article was received on 07 Apr 2015, accepted on 30 Jun 2015 and first published on 30 Jun 2015


Article type: Paper
DOI: 10.1039/C5OB00690B
Citation: Org. Biomol. Chem., 2015,13, 8453-8464
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    A quantum chemical study of the ω-transaminase reaction mechanism

    K. E. Cassimjee, B. Manta and F. Himo, Org. Biomol. Chem., 2015, 13, 8453
    DOI: 10.1039/C5OB00690B

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