Evidence for a single catalytic binding site on human brain type B monoamine oxidase.
The tricyclic antidepressant drug, amitriptyline, inhibited the B form of human brain mitochondrial monoamine oxidase (MAO) under normal atmospheric conditions in a noncompetitive manner when phenylethylamine (PEA) was used as substrate and competitively when benzylamine (BzNH2) was employed as substrate. In addition, it was also found that PEA and BzNH2 inhibited each other's degradation noncompetitively. Similar results have previously been reported with human platelet MAO. These data suggest that the catalytic binding sites for PEA and BzNH2 on the B form of human brain MAO may be different. Attempts were made to further distinguish these catalytic binding sites on the brain oxidase using the irreversible MAO inhibitors, pargyline and clorgyline. Though these drugs have considerably different affinities for the B form of the oxidase, the degree to which either compound inhibited PEA or BzNH2 deamination was essentially identical. When incubations were performed at elevated oxygen concentrations PEA and BzNH2 became mutually competitive inhibitors of each other's metabolism. Also at the higher levels of oxygen, amitriptyline inhibition of PEA deamination approached a competitive fashion. These results suggest that PEA and BzNH2 share a common catalytic binding site on the B form of MAO and, in addition, bind to an inhibitory site on the reduced form of the oxidase. Accordingly, the data indicate that amitriptyline also binds to both the oxidized and reduced forms of this human brain oxidase.
Roth
J A
JA
Department of Anesthesiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
D001596:Benzylamines / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry; D002384:Catalysis / Q000187:drug effects; D003010:Clorgyline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005625:Frontal Lobe / Q000201:enzymology; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology; D010293:Pargyline / Q000494:pharmacology; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology
D001596:Benzylamines; D008996:Monoamine Oxidase Inhibitors; D010627:Phenethylamines; D010293:Pargyline; C030796:benzylamine; D008995:Monoamine Oxidase; D003010:Clorgyline; D010100:Oxygen