<i>Trans</i>-urocanic acid (UCA) is an endogenous ultraviolet photoprotectant and involved in the highly controlled desquamation process. It is one of the products of the nonoxidative deamination of substrate histidine. The deamination of histidine is catalyzed by the enzyme histidine ammonia-lyase (HAL) converting the substrate to α,β-unsaturated <i>trans</i>-urocanate in the first step. The mechanism of the deamination is still unclear, posing a mechanistic hurdle to understand the deamination of histidine for the last couple of decades. Two mechanisms were reported, one proposed a direct attack by the α-amino group on the electrophilic group 4-methylidene-imidazol-5-one (MIO), enhancing the leaving ability of the amino group. This mechanism is unable to answer how the β-hydrogen of the substrate is activated. The other proposed an attack by the imidazole ring of histidine to MIO, however, our calculations suggest that this mechanism is energetically unfavorable. In this work, a comprehensive mechanistic study on the deamination of histidine by HAL was performed at the Density Functional Theory level. Possible mechanisms were investigated. Our results demonstrate that the deamination of histidine adopts an alternative path where the β-carbon of histidine attacks MIO. Our proposed mechanism satisfactorily interprets experimental observations.

Plausible reaction mechanism of the deamination of histidine catalyzed by histidine-ammonia lyase

253rd National Meeting (2017)

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