Two polymorphic forms of human histamine methyltransferase: Structural, thermal, and kinetic comparisons

John R. Horton, Ken Sawada, Masahiro Nishibori, Xing Zhang, Xiaodong Cheng

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Background: Histamine plays important biological roles in cell-to-cell communication; it is a mediator in allergic responses, a regulator of gastric acid secretion, a messenger in bronchial asthma, and a neurotransmitter in the central nervous system. Histamine acts by binding to histamine receptors, and its local action is terminated primarily by methylation. Human histamine N-methyltransferase (HNMT) has a common polymorphism at residue 105 that correlates with the high- (Thr) and low- (Ile) activity phenotypes. Results: Two ternary structures of human HNMT have been determined: the Thr105 variant complexed with its substrate histamine and reaction product AdoHcy and the Ile105 variant complexed with an inhibitor (quinacrine) and AdoHcy. Our steady-state kinetic data indicate that the recombinant Ile105 variant shows 1.8- and 1.3-fold increases in the apparent KM for AdoMet and histamine, respectively, and slightly (16%) but consistently lower specific activity as compared to that of the Thr105 variant. These differences hold over a temperature range of 25°C-45°C in vitro. Only at a temperature of 50°C or higher is the Ile105 variant more thermolabile than the Thr105 enzyme. Conclusions: HNMT has a 2 domain structure including a consensus AdoMet binding domain, where the residue 105 is located on the surface, consistent with the kinetic data that the polymorphism does not affect overall protein stability at physiological temperatures but lowers KM values for AdoMet and histamine. The interactions between HNMT and quinacrine provide the first structural insights into a large group of pharmacologic HNMT inhibitors and their mechanisms of inhibition.

Original languageEnglish
Pages (from-to)837-849
Number of pages13
JournalStructure
Volume9
Issue number9
DOIs
Publication statusPublished - 2001

Fingerprint

Histamine N-Methyltransferase
Histamine
Hot Temperature
S-Adenosylmethionine
Quinacrine
Temperature
Histamine Receptors
Protein Stability
Gastric Acid
Cell Communication
Methylation
Neurotransmitter Agents
Asthma
Central Nervous System
Phenotype
Enzymes

Keywords

  • Antimalarial drug quinacrine
  • Histamine
  • Methylation
  • Polymorphism
  • Thermal stability

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Two polymorphic forms of human histamine methyltransferase : Structural, thermal, and kinetic comparisons. / Horton, John R.; Sawada, Ken; Nishibori, Masahiro; Zhang, Xing; Cheng, Xiaodong.

In: Structure, Vol. 9, No. 9, 2001, p. 837-849.

Research output: Contribution to journalArticle

Horton, John R. ; Sawada, Ken ; Nishibori, Masahiro ; Zhang, Xing ; Cheng, Xiaodong. / Two polymorphic forms of human histamine methyltransferase : Structural, thermal, and kinetic comparisons. In: Structure. 2001 ; Vol. 9, No. 9. pp. 837-849.
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N2 - Background: Histamine plays important biological roles in cell-to-cell communication; it is a mediator in allergic responses, a regulator of gastric acid secretion, a messenger in bronchial asthma, and a neurotransmitter in the central nervous system. Histamine acts by binding to histamine receptors, and its local action is terminated primarily by methylation. Human histamine N-methyltransferase (HNMT) has a common polymorphism at residue 105 that correlates with the high- (Thr) and low- (Ile) activity phenotypes. Results: Two ternary structures of human HNMT have been determined: the Thr105 variant complexed with its substrate histamine and reaction product AdoHcy and the Ile105 variant complexed with an inhibitor (quinacrine) and AdoHcy. Our steady-state kinetic data indicate that the recombinant Ile105 variant shows 1.8- and 1.3-fold increases in the apparent KM for AdoMet and histamine, respectively, and slightly (16%) but consistently lower specific activity as compared to that of the Thr105 variant. These differences hold over a temperature range of 25°C-45°C in vitro. Only at a temperature of 50°C or higher is the Ile105 variant more thermolabile than the Thr105 enzyme. Conclusions: HNMT has a 2 domain structure including a consensus AdoMet binding domain, where the residue 105 is located on the surface, consistent with the kinetic data that the polymorphism does not affect overall protein stability at physiological temperatures but lowers KM values for AdoMet and histamine. The interactions between HNMT and quinacrine provide the first structural insights into a large group of pharmacologic HNMT inhibitors and their mechanisms of inhibition.

AB - Background: Histamine plays important biological roles in cell-to-cell communication; it is a mediator in allergic responses, a regulator of gastric acid secretion, a messenger in bronchial asthma, and a neurotransmitter in the central nervous system. Histamine acts by binding to histamine receptors, and its local action is terminated primarily by methylation. Human histamine N-methyltransferase (HNMT) has a common polymorphism at residue 105 that correlates with the high- (Thr) and low- (Ile) activity phenotypes. Results: Two ternary structures of human HNMT have been determined: the Thr105 variant complexed with its substrate histamine and reaction product AdoHcy and the Ile105 variant complexed with an inhibitor (quinacrine) and AdoHcy. Our steady-state kinetic data indicate that the recombinant Ile105 variant shows 1.8- and 1.3-fold increases in the apparent KM for AdoMet and histamine, respectively, and slightly (16%) but consistently lower specific activity as compared to that of the Thr105 variant. These differences hold over a temperature range of 25°C-45°C in vitro. Only at a temperature of 50°C or higher is the Ile105 variant more thermolabile than the Thr105 enzyme. Conclusions: HNMT has a 2 domain structure including a consensus AdoMet binding domain, where the residue 105 is located on the surface, consistent with the kinetic data that the polymorphism does not affect overall protein stability at physiological temperatures but lowers KM values for AdoMet and histamine. The interactions between HNMT and quinacrine provide the first structural insights into a large group of pharmacologic HNMT inhibitors and their mechanisms of inhibition.

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