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Inhibitory and structural studies of novel coenzyme-substrate analogs of human histidine decarboxylase

Fang Wu^*, Jing Yu and Heinz Gehring^*,1

^* Department of Biochemistry, University of Zurich, Zurich, Switzerland; and

Institute of Molecular Pharmacy, University of Basel, Basel, Switzerland

¹Correspondence: Dept. of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. E-mail: gehring{at}bioc.uzh.ch

Histamine, a biogenic amine with important biological functions, is produced from histidine by histidine decarboxylase (HDC), a pyridoxal 5'-phosphate-dependent enzyme. HDC is thus a potential target to attenuate histamine production in certain pathological states. Targeting mammalian HDC with novel inhibitors and elucidating the structural basis of their specificity for HDC are challenging tasks, because the three-dimensional structure of mammalian HDC is still unknown. In the present study, we designed, synthesized, and tested potentially membrane-permeable pyridoxyl-substrate conjugates as inhibitors for human (h) HDC and modeled an active site of hHDC, which is compatible with the experimental data. The most potent inhibitory compound among nine tested structural variants was the pyridoxyl-histidine methyl ester conjugate (PHME), indicating that the binding site of hHDC does not tolerate groups other than the imidazole side chain of histidine. PHME inhibited 60% of the fraction of 12-O-tetradecanoylphorbol-13-acetate-induced newly synthesized HDC in human HMC-1 cells at 200 µM and was also inhibitory in cell extracts. The proposed model of hHDC, containing phosphopyridoxyl-histidine in the active site, revealed the binding specificity of HDC toward its substrate and the structure-activity relationship of the designed and investigated compounds.—Wu, F., Yu, J., Gehring, H. Inhibitory and structural studies of novel coenzyme-substrate analogs of hHDC.

Key Words: mammalian histidine decarboxylase • pyridoxyl-substrate analogs • binding specificity of histidine decarboxylase • histamine