An Unrecognized Fundamental Relationship between Neurotransmitters: Glutamate Protects against Catecholamine Oxidation

Neurotransmitter catecholamines (dopamine, epinephrine, and norepinephrine) are liable to undergo oxidation, which copper is deeply involved in. Catecholamine oxidation-derived neurotoxicity is recognized as a pivotal pathological mechanism in neurodegenerative diseases. Glutamate, as an excitatory neurotransmitter, is enriched in the brain at extremely high concentrations. However, the chemical biology relationship of these two classes of neurotransmitters remains largely unknown. In the present study, we assessed the influences of glutamate on the autoxidation of catecholamines, the copper- and copper-containing ceruloplasmin-mediated oxidation of catecholamines, the catecholamine-induced formation of quinoprotein, catecholamine/copper-induced hydroxyl radicals, and DNA damage in vitro. The results demonstrate that glutamate, at a physiologically achievable molar ratio of glutamate/catecholamines, has a pronounced inhibitory effect on catecholamine oxidation, catecholamine oxidation-evoked hydroxyl radicals, quinoprotein, and DNA damage. The protective mechanism of glutamate against catecholamine oxidation could be attributed to its restriction of the redox activity of copper via chelation. This previously unrecognized link between glutamate, catecholamines, and copper suggests that neurodegenerative disorders may occur and develop once the built-in equilibrium is disrupted and brings new insight into developing more effective prevention and treatment strategies for neurodegenerative diseases.

Catecholamine Oxidative Products, but Not Melanin, Are Produced by Cryptococcus neoformans during Neuropathogenesis in Mice

ABSTRACT Melanin has been proposed as a virulence factor inCryptococcus neoformans, but its presence has not been shown unambiguously in vivo. Validated methods used previously to show production of cryptococcal eumelanin pigment in vitro (P. R. Williamson, K. Wakamatsu, and S. Ito, J. Bacteriol. 180:1570–1572, 1998) were used to assess for production of laccase-derived products in mouse brain of the Lacc+ strains, 2E-TUC, H99 (serotype A), and ATCC 34873 (serotype D), and the Lacc− strain, 2E-TU. Pyrrole-2,3,5-tricarboxylic and pyrrole-2,3-dicarboxylic acid, specific degradation products of catecholamine derivatives such as melanin, were found in all Lacc+ strains, but not in the Lacc− strain, 2E-TU. However, the presence of melanin pigment itself could not be demonstrated in the same cells. Lack of the specific degradation products aminohydroxyphenylalanine and aminohydroxyphenylethylamine in Lacc+ strains upon hydriodic acid hydrolysis showed that pheomelanin was also not produced by the fungus in vivo. These are the first data to support the generation of catecholamine oxidation products by C. neoformans in vivo, but they do not support postenzymatic polymerization of these products to form typical eumelanin, as previously proposed.

Melanin Biosynthesis in Cryptococcus neoformans

ABSTRACT Pigment production by Cryptococcus neoformans is virulence associated. Dopamine- and 3,4-dihydroxyphenylalanine–melanin products were identified after acidic permanganate oxidation, alkaline hydrogen peroxide oxidation, or hydrolysis with hydriodic acid. These data provide direct chemical evidence for the formation of eumelanin polymers by catecholamine oxidation by laccase alone followed by oxidative coupling of dihydroxyindole.