engleski

Nonenzymatic modifications of tryptophan and its metabolites with methylglyoxal into beta-carbolines

beta-Carbolines represent a large group of alkaloids widely distributed in nature, including plants, marine organisms and insects, foodstuffs as well as in human tissues and body fluids. These compounds are of great interest due to their diverse biological activities such as the inhibition of topoisomerase and monoamine oxidase, binding to benzodiazepine and 5-hydroxy serotonin receptors and intercalating into DNA. In addition, these compounds also demonstrate a broad spectrum of pharmacological properties including sedative, anxiolytic, hypnotic, anticonvulsant, antitumor and antimicrobial activities. Nonenzymatic modifications of tryptophan (1) and its metabolites with aldehydes, via the Pictet-Spengler reaction, lead to beta-carboline formation. Here we demonstrate that methylglyoxal (MGO, 2) generates biologically active 1-acetyl-beta-carbolines from tryptophan (1), from its methyl ester (3) and from tryptamine (4). Surprisingly, MGO (2) does not generate 1-(1-hydroxyethyl)-beta-carboline derivates like phenylglyoxal. HPLC analysis of model reaction systems showed the formation of 1-acety-beta-carboline-3-acetic acid (5) and 1-acetyl-beta-carboline (6) during incubation of 1 and 2 at pH 5.7 and 7.4 at 100 °C and 5 at 37 °C at the same pH values under a limited amount of oxygen. Aerobic conditions influenced significantly higher formation of 6 at 37 °C at both pH values, while at higher temperature the same effect was only observed at lower pH. Lack of oxygen did not significantly impact the generation of 5 or 6 at both pH and temperature values, in comparison with the formation at limited amounts of oxygen. Incubation of 2 and 3 generated 3-methyl-1-acetyl-beta-carboline-3-carboxylate (7) together with 5 and 6 as a result of hydrolysis of 3 into 1 and 7 into 5, while in incubation mixtures of 2 and 4 only unstable 1-acety-3, 4-dihydro-β -carboline (8) was observed. In addition, MGO (2) showed higher reactivity toward tryptophan (1) and its metabolites in comparison with glyoxal and 2, 3-butandion under mildly acidic and basic conditions as well as at 37 and 100 °C, while amine reactivity toward MGO (2) decreased in this order: methyl ester of tryptophan (3) > tryptophan (1) > tryptamine (4).

glycation; Maillard; methylglyoxal; tryptophan

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