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

• Type of Material: Article
• Authors: John Horton, Emory University; Ken Sawada, Emory University; Masahiro Nishibori, Okayama University; Xiaodong Cheng, Emory University
• Language: English
• Date: 2005-10-21
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2005 Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 2.5 Generic
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jmb.2005.08.040
• Title of Journal or Parent Work: Journal of Molecular Biology
• ISSN: 0022-2836
• Volume: 353
• Issue: 2
• Start Page: 334
• End Page: 344
• Grant/Funding Information: The study was partly supported by the US National Science Foundation (INT-0003815), Emory University Research Committee, Georgia Research Alliance Eminent Scholar Challenge Grand Awards (No. RGA.CG04.300.D and No. GRA.CG05.F).; Financial support for the beamlines comes principally from the Offices of Biological and Environmental Research and of Basic Energy Sciences of the US Department of Energy, and from the National Center for Research Resources of the National Institutes of Health.; The Cheng laboratory is currently supported by the National Institutes of Health grant GM068680.
• Keywords: diphenhydramine; metoprine; amodiaquine; HNMT inhibitors; tacrine
• Research Categories: Chemistry, Biochemistry; Health Sciences, Pharmacology

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 10–100 nM. 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.