Histamine N-methyltransferase: inhibition by monoamine oxidase inhibitors.
Histamine N-methyltransferase (HNMT) catalyzes the N tau-methylation of histamine. N tau-Methylhistamine can then undergo oxidation catalyzed by the mitochondrial enzyme monoamine oxidase (MAO). Addition of an MAO inhibitor such as pargyline to tissue preparations can increase the HNMT activity assayed --presumably as a result of inhibition of N tau-methylhistamine metabolism by MAO. However, pargyline-dependent "activation" of HNMT may also occur in tissue preparations that lack mitochondria. Our experiments were performed to determine whether MAO inhibitors, like many other amine compounds, could directly increase the activity of partially purified HNMT, and, if so, to study the mechanism of activation. Human kidney HNMT was partially purified by sequential ion exchange and gel filtration chromatography. The activity of the purified HNMT was increased approximately 50% in the presence of pargyline. However, enzyme kinetic experiments showed that pargyline, like many other amines, was a competitive inhibitor of HNMT. Apparent activation of the enzyme resulted from sequential shifts of histamine substrate curves to higher Vmax values in the presence of increasing concentrations of pargyline. Other acetylenic MAO inhibitors, clorgyline and the two stereoisomers of deprenyl, were also competitive inhibitors of purified human kidney HNMT. Inhibition kinetic experiments performed in the presence of varying concentrations of histamine demonstrated that Kis values for pargyline, clorgyline, (R)-deprenyl and (S)-deprenyl were 0.126, 0.144, 0.217, and 0.627 mM, respectively. When the concentration of the cosubstrate for the reaction, S-adenosyl-L-methionine, was varied in the presence of variable concentrations of pargyline, inhibition of HNMT by pargyline was noncompetitive with regard to the methyl donor, with Kii and Kis values of 1.23 and 0.95 mM, respectively. Finally, several amine compounds related structurally to pargyline were also found to be inhibitors of HNMT.
Boudíková-Girard
B
B
Department of Pharmacology, Mayo Medical School/Mayo Clinic/Mayo Foundation, Rochester, MN 55905.
Scott
M C
MC
Weinshilboum
R
R
D004789:Enzyme Activation / Q000187:drug effects; D006637:Histamine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010293:Pargyline / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D008996:Monoamine Oxidase Inhibitors; D011506:Proteins; D010293:Pargyline; D008995:Monoamine Oxidase; D006637:Histamine N-Methyltransferase