Cysteine 180 is a redox sensor modulating activity of human pyridoxal 5'-phosphate histidine decarboxylase

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 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 proposed model by bioinformatics analyses and molecular dynamics simulations that 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 similarly to the reduced form of wild-type enzyme, while C418S is sensitive to reductants as the wild-type enzyme, thus allowing the identification of Cys-180 as the redox sensitive switch. On the other hand, Cys-418 appears as 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.