Structural Basis for Inhibition of Histamine N-Methyltransferase by Diverse Drugs

Abstract

In mammals, histamine action is terminated through metabolic inactivation by histamine N-methyltransferase (HNMT) and diamine oxidase. In addition to three well-studied pharmacological functions, smooth muscle contraction, increased vascular permeability, and stimulation of gastric acid secretion, histamine plays important roles in neurotransmission, immunomodulation, and regulation of cell proliferation. The histamine receptor H1 antagonist diphenhydramine, the antimalarial drug amodiaquine, the antifolate drug metoprine, and the anticholinesterase drug tacrine (an early drug for Alzheimer's disease) are surprisingly all potent HNMT inhibitors, having inhibition constants in the range of 10-100nM. We have determined the structural mode of interaction of these four inhibitors with HNMT. Despite their structural diversity, they all occupy the histamine-binding site, thus blocking access to the enzyme's active site. Near the N terminus of HNMT, several aromatic residues (Phe9, Tyr15, and Phe19) adopt different rotamer conformations or become disordered in the enzyme-inhibitor complexes, accommodating the diverse, rigid hydrophobic groups of the inhibitors. The maximized shape complementarity between the protein aromatic side-chains and aromatic ring(s) of the inhibitors are responsible for the tight binding of these varied inhibitors.

The Histamine N-Methyltransferase T105I Polymorphism Affects Active Site Structure and Dynamics

“…However, the histamine-binding domain becomes slightly more disrupted in the 105T HNMT simulations, reaching a Cα-RMSD of 5.2 ± 0.7 Å compared to 3.7 ± 1.3 Å in the 105I protein. Figure 2 shows the average Cα-root-mean square fluctuations (Cα-RMSF) about the mean structure for the 37°C simulations, along with the crystallographic B-factors of HNMT (2AOT, (28)). The fluctuations during the simulations are of the same magnitude and follow a pattern similar to the B-factors.…”

Modulation of Fgfr1a Signaling in Zebrafish Reveals a Genetic Basis for the Aggression–Boldness Syndrome

“…We treated homozygous spd mutants with a nonsedative dose (see Fig. 8b) of the Hnmt inhibitor tacrine hydrochloride (Horton et al, 2005) and observed an increase in HA levels in the brain (Fig. 6b).…”

“…7c). At low concentrations, tacrine hydrochloride is specific for hnmt, whereas at high concentrations it can also inhibit the acetylcholine breakdown enzyme acetylcholinesterase (Horton et al, 2005). To rule out a contribution of acetylcholine signaling to the spd behavioral phenotype, we treated homozygous spd mutants with a nonsedative dose (Fig.…”

Quinoline Ring Derivatives Protect Against Aminoglycoside-Induced Hair Cell Death in the Zebrafish Lateral Line

“…Mefloquine, amodiaquine, and tacrine are known inhibitors of histamine N-methyltransferase (HNMT), which metabolizes and breaks down histamine (Harle and Baldo 1988;Cumming et al 1990;Horton et al 2005). Inhibition of HNMT and enhancement of the effects of histamine thus were hypothesized as a possible mechanism of protection.…”

“…Six of these drugs are antimalarial drugs-other known functions include antineoplastics and anticholinesterases. In addition, some members of the quinoline ring family are known to inhibit histamine N-methyltransferase (Harle and Baldo 1988;Cumming et al 1990;Horton et al 2005). In this study, we examined and characterized the protective profile of this group of protective drugs.…”