An In Vitro Characterization of γ‐Glutamylhistamine Synthetase: A Novel Enzyme Catalyzing Histamine Metabolism in the Central Nervous System of the Marine Mollusk, Aplysia californica

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Abstract
The properties of the histamine metabolizing enzyme, .gamma.-glutamylhistamine synthetase (.gamma.-GHA synthetase), were studied in A. ganglia in vitro. This enzyme catalyzes the incorporation of histamine into peptide linkage with L-glutamate to form a peptidoamine, .gamma.-glutamylhistamine (.gamma.-GHA). .gamma.-GHA synthetase is a soluble enzyme with an apparent Km of 653 .mu.M for histamine and 10.6 mM for L-glutamate. Synthesis of .gamma.-GHA is energy-dependent, having an absolute requirement for ATP. Mg ions and dithiothreitol are also essential for activity. Of a variety of .gamma.-glutamyl compounds and glutamate analogs tested, only L-glutamate was effectively incorporated into peptide linkage with histamine. The enzyme has a higher affinity for histamine than for numerous imidazole analogs. In addition, dopamine, 5-hydroxytryptamine, octopamine and several other amines tested are effective inhibitors of .gamma.-GHA synthesis. Ganglia, nerve trunks and the capsule surrounding the ganglion had the highest synthetase activity. The specific activity of the enzyme in muscle, heart and hemolymph was < 10% of that in ganglia. Differences in substrate, specificity and effect of inhibitors distinguish .gamma.-GHA synthetase from .gamma.-glutamyl transpeptidase, glutamine synthetase and carnosine synthetase.