Inhibitory and structural studies of novel coenzyme-substrate analogs of human histidine decarboxylase.
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 microM 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
Fang
F
Dept. of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Yu
Jing
J
Gehring
Heinz
H
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003067:Coenzymes / Q000737:chemistry*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006639:Histidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011735:Pyridoxic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013552:Swine
D003067:Coenzymes; D004791:Enzyme Inhibitors; C527806:pyridoxyl-histidine methyl ester; D006639:Histidine; D011735:Pyridoxic Acid; D006640:Histidine Decarboxylase