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

Abstract

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.

Synthesis and Deployment of an Elusive Fluorovinyl Cation Equivalent: Access to Quaternary α-(1′-Fluoro)vinyl Amino Acids as Potential PLP Enzyme Inactivators

“…The pyruvamide-dependent AADCs include S-adenosylmethionine (SAM) DC 74 from all three kingdoms of life (also central to the polyamine biosynthetic pathway), aspartate α-DC 75 (key step in coenzyme A biosynthesis, potential antibiotic target), phosphatidyl serine DC 76 (phospholipid biosynthesis) as well as other variants of both histidine DC 77 and arginine DC. 78 In this context, the methodology/protection strategy reported here shows real promise for building potential new inhibitors for ODC (lysine chemistry here) and for aromatic AADC (tyrosine and tryptophan side chains established here vs. the DOPA and 5-hydroxytryptophan side chains that presumably would target this active site).…”

Poisoning Pyridoxal 5-Phosphate-Dependent Enzymes: A New Strategy to Target the Malaria Parasite Plasmodium falciparum

“…Wu et al [14] showed that the pyridoxyl-histidine methyl ester (PHME) acts as a potent transition-state inhibitor of histidine decarboxylase (hHDC) in human cells. When PHME was applied to cultured P. falciparum no significant growth inhibition was observed; similar to the result obtained with the pyridoxine analog deoxypyridoxine, although the latter was previously reported to be an effective inhibitor in a different system [21].…”

“…The active site model of Pf ODC with PPT3 and PPT5 was generated on the basis of the known 3D coordinates of the complex of Pf ODC with PLP-DFMO followed by energy minimization with the InsightII/Built module (steepest descents, up to a maximum derivative of 20 kcal/mol, consistent valence force field, CVFF). The structures were further optimized by energy minimization using the InsightII/Discover module (conjugation gradient, until a maximum derivative of 0.01 kcal/mol was reached, CVFF) according to Wu et al [14].…”

“…Recently, a new analog, the BOC-protected pyridoxyl-ornithine conjugate (POB), was shown to inhibit human ODC in cells as well as the growth of various tumor and transformed cells effectively, whereas non-tumorigenic cells were less affected [13]. Another analog, pyridoxyl-histidine methyl ester (PHME), was able to inhibit human histidine decarboxylase in human mastocytoma cells without affecting proliferation [14].…”

Structural Study Reveals That Ser-354 Determines Substrate Specificity on Human Histidine Decarboxylase

“…However, neither agent has been clinically used. Epigallocatechin gallate from green tea (20) and pyridoxyl histidine methyl ester (21) were recently found to act as potent HDC inhibitors; however, the possibility of side effects, in vivo efficiency, and specificity for HDC of these inhibitors have not been assessed, making them unavailable for clinical use. Detailed information on the structure of HDC would facilitate the development of HDC inhibitors with high affinity and specificity.…”