<i>N</i><sup>1</sup>‐acetyl‐5‐methoxykynuramine contrasts with other tryptophan metabolites by a peculiar type of NO scavenging: cyclization to a cinnolinone prevents formation of unstable nitrosamines

Hardeland, Ruediger; Backhaus, Claudia; Fadavi, Azadeh; Hess, M L

doi:10.1111/j.1600-079x.2007.00431.x

Cited by 32 publications

(40 citation statements)

References 8 publications

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“…These compounds were (i) N 1 ‐acetyl‐5‐methoxy‐3‐nitrokynuramine (AMNK or 3‐nitro‐AMK) produced by reactions with carbonate and NO 2 radicals deriving from the peroxynitrite‐CO 2 adduct [7], and (ii) 3‐acetamidomethyl‐6‐methoxycinnolinone (AMMC; Fig. 1), formed by nitrosation [7–9], reactions in which any of the three NO congeners or derivatives thereof can be involved [1, 9].…”

Section: Introductionmentioning

confidence: 99%

Reactions of the melatonin metabolite N¹‐acetyl‐5‐methoxykynuramine with carbamoyl phosphate and related compounds

Kuesel

Hardeland

Pfoertner

et al. 2009

Journal of Pineal Research

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N-[2-(6-methoxyquinazolin-4-yl)-ethyl] acetamide (MQA) is a compound formed from the melatonin metabolite N(1)-acetyl-5-methoxykynuramine (AMK). We followed MQA production in reaction systems containing various putative reaction partners, in the absence and presence of hydrogen peroxide and/or copper(II). Although MQA may be formally described as a condensation product of either N(1)-acetyl-N(2)-formyl-5-methoxykynuramine (AFMK) with ammonia, or AMK with formamide, none of these combinations led to substantial quantities of MQA. However, MQA formation was observed in mixtures containing AMK, hydrogen peroxide, hydrogen carbonate and ammonia, or AMK, hydrogen peroxide, copper(II) and potentially carbamoylating agents, such as potassium cyanate or, more efficiently, carbamoyl phosphate. In the presence of hydrogen peroxide, copper(II) and carbamoyl phosphate, MQA was the major product obtained from AMK, but the omission of copper(II) mainly led to another metabolite, 3-acetamidomethyl-6-methoxycinnolinone (AMMC). This was caused by nitric oxide (NO) generated under oxidative conditions from carbamoyl phosphate, as shown by an NO spin trap. MQA formation with carbamoyl phosphate was not due to the possible decomposition product, formamide. The reaction of AMK with carbamoyl phosphate under oxidative conditions, in which inorganic phosphate and water are released and which differs from the typical process of carbamoylation via isocyanate, may be considered as a new physiological route of MQA formation.

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Section: Introductionmentioning

confidence: 99%

Reactions of the melatonin metabolite N¹‐acetyl‐5‐methoxykynuramine with carbamoyl phosphate and related compounds

Kuesel

Hardeland

Pfoertner

et al. 2009

Journal of Pineal Research

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“…This last pathway has been reported for other tryptophan metabolites, 3-hydroxykynurenine and 3-hydroxyanthranilic acid. However, Nnitrosation of AMK leads, by formation of a second ring, to the stable compound AMMC, which does not spontaneously re-donate NO [43].…”

Section: The Kynuramine Pathwaymentioning

confidence: 99%

“…AMK is of high interest because of several properties. It is a potent antioxidant [110], effective scavenger of reactive nitrogen species [36,42,43], protecting agent against mitochondrial damage [1,38,40,41], downregulator of cyclooxygenase-2 [24,86], cyclooxygenase inhibitor by far more potent than aspirin [62], and antagonist of neuronal [71] and inducible NO synthases [24,143].…”

Section: The Kynuramine Pathwaymentioning

confidence: 99%

Melatonin Metabolism in the Central Nervous System

Hardeland¹

2010

114

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Abstract:The metabolism of melatonin in the central nervous system is of interest for several reasons. Melatonin enters the brain either via the pineal recess or by uptake from the blood. It has been assumed to be also formed in some brain areas. Neuroprotection by melatonin has been demonstrated in numerous model systems, and various attempts have been undertaken to counteract neurodegeneration by melatonin treatment. Several concurrent pathways lead to different products. Cytochrome P 450 subforms have been demonstrated in the brain. They either demethylate melatonin to Nacetylserotonin, or produce 6-hydroxymelatonin, which is mostly sulfated already in the CNS. Melatonin is deacetylated, at least in pineal gland and retina, to 5-methoxytryptamine. N 1 -acetyl-N 2 -formyl-5-methoxykynuramine is formed by pyrrole-ring cleavage, by myeloperoxidase, indoleamine 2,3-dioxygenase and various non-enzymatic oxidants. Its product, N 1 -acetyl-5-methoxykynuramine, is of interest as a scavenger of reactive oxygen and nitrogen species, mitochondrial modulator, downregulator of cyclooxygenase-2, inhibitor of cyclooxygenase, neuronal and inducible NO synthases. Contrary to other nitrosated aromates, the nitrosated kynuramine metabolite, 3-acetamidomethyl-6-methoxycinnolinone, does not re-donate NO. Various other products are formed from melatonin and its metabolites by interaction with reactive oxygen and nitrogen species. The relative contribution of the various pathways to melatonin catabolism seems to be influenced by microglia activation, oxidative stress and brain levels of melatonin, which may be strongly changed in experiments on neuroprotection. Many of the melatonin metabolites, which may appear in elevated concentrations after melatonin administration, possess biological or pharmacological properties, including N-acetylserotonin, 5-methoxytryptamine and some of its derivatives, and especially the 5-methoxylated kynuramines.

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“…AMMC is generated by all three different NO congeners, ·NO, NO + and HNO, although the reaction with NO + is physiologically less likely, because of the short half-life of the cation in aqueous solution at pH 7.4 [126]. AMMC represents a stable compound, contrary to the majority of other Nnitrosated substances [127], including N-nitrosomelatonin, which easily redonate NO. AMNK was found to be produced by the combination of peroxynitrite and CO 2 , a physiological nitrating mixture leading to carbonate radicals (CO 3 · À ) and ·NO 2 [125].…”

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confidence: 99%

Melatonin, hormone of darkness and more – occurrence, control mechanisms, actions and bioactive metabolites

Hardeland

2008

Cell. Mol. Life Sci.

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222

202

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In its role as a pineal hormone, melatonin is a pleiotropic, nocturnally peaking and systemically acting chronobiotic. These effects are largely explained by actions via G protein-coupled membrane receptors found in the suprachiasmatic nucleus, but also in numerous other sites. Nuclear (ROR/RZR), cytoplasmic (quinone reductase-2, calmodulin, calreticulin) and mitochondrial binding sites and radical-scavenging properties contribute to the actions of melatonin. Regulation of pineal melatonin biosynthesis is largely explained by control mechanisms acting on arylalkylamine N-acetyltransferase, at the levels of gene expression and/or enzyme stability influenced by phosphorylation and interaction with 14-3-3 proteins. Melatonin is not only a hormone but is also synthesized in numerous extrapineal sites, in which it sometimes attains much higher quantities than in the pineal and the circulation. It is also present in many taxonomically distant groups of organisms, including bacteria, fungi, and plants. Moreover, melatonin is a source of bioactive metabolites, such as 5-methoxytryptamine, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine and N(1)-acetyl-5-methoxykynuramine.

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N¹‐acetyl‐5‐methoxykynuramine contrasts with other tryptophan metabolites by a peculiar type of NO scavenging: cyclization to a cinnolinone prevents formation of unstable nitrosamines

Cited by 32 publications

References 8 publications

Reactions of the melatonin metabolite N¹‐acetyl‐5‐methoxykynuramine with carbamoyl phosphate and related compounds

Reactions of the melatonin metabolite N¹‐acetyl‐5‐methoxykynuramine with carbamoyl phosphate and related compounds

Melatonin Metabolism in the Central Nervous System

Melatonin, hormone of darkness and more – occurrence, control mechanisms, actions and bioactive metabolites

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N1‐acetyl‐5‐methoxykynuramine contrasts with other tryptophan metabolites by a peculiar type of NO scavenging: cyclization to a cinnolinone prevents formation of unstable nitrosamines

Cited by 32 publications

References 8 publications

Reactions of the melatonin metabolite N1‐acetyl‐5‐methoxykynuramine with carbamoyl phosphate and related compounds

Reactions of the melatonin metabolite N1‐acetyl‐5‐methoxykynuramine with carbamoyl phosphate and related compounds

Melatonin Metabolism in the Central Nervous System

Melatonin, hormone of darkness and more – occurrence, control mechanisms, actions and bioactive metabolites

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Product

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N¹‐acetyl‐5‐methoxykynuramine contrasts with other tryptophan metabolites by a peculiar type of NO scavenging: cyclization to a cinnolinone prevents formation of unstable nitrosamines

Reactions of the melatonin metabolite N¹‐acetyl‐5‐methoxykynuramine with carbamoyl phosphate and related compounds

Reactions of the melatonin metabolite N¹‐acetyl‐5‐methoxykynuramine with carbamoyl phosphate and related compounds