Deamination of serotonin

Carbolines exert a variety of pharmacological effects, including sedation, catalepsy, inhibition of convulsion, hallucination, and inhibition of monoamine oxidases (MAO) and of monoamine uptake (104a,b). Extensively investigated was the inhibition of MAO by /3-carbolines, which is probably responsible for their antidepressant effects in man (5d). p-Caibolines inhibit the oxidative deamination of serotonin at micromolar... 

Serotonin is not a substrate for COMT and follows simpler pathways of metabolism than those for catecholamines (Figure 29-6). Deamination of serotonin to the aldehyde intermediate is preferentially followed by oxidation to 5-hydroxyindoleacetic acid (5-HIAA) catalyzed by... 

In the same year that the description of the unique behavior of (-)-deprenyl was published, Johnston described a substance, later named clorgyline, that came into world-wide use as an experimental tool in MAO research. Johnston realized that clorgyline preferentially inhibits the deamination of serotonin. He proposed the existence of two forms of MAO, type A and type B, the former being selectively inhibited by clorgyline and the latter relatively insensitive to it. Johnston s nomenclature has become widely accepted and is still in use (Johnston 1968). 

Whether MAO is one enzyme or a myriad of them, it is now apparent that certain compounds which inhibit the enzymatic oxidative deamination of serotonin and other amines in vitro are capable of inhibiting this action in vivo. When such compounds are administered to animals or patients, levels of serotonin and other amines are increased in the tissues. The increase in brain serotonin level is now widely used as an index of the ability of various drugs to produce MAO inhibition in vivo in animals. 

Most mammalian tissues display the presence of MAO-A and MAO-B isoforms with different substrate specificities. For example, MAO-A catalyses the oxidative deamination of serotonin, whereas MAO-B displays higher specificity for benzylamine and P-phenylethylamine. Noradrenaline, adrenaline, tyramine, tryptamine and dopamine are deaminated by both isozymes. In the human brain the hypothalamus and basal ganglia (striatum) show high MAO activity and it has been observed that... 

Monoamine Oxidase Inhibitors. MAOIs inactivate the enzyme MAO, which is responsible for the oxidative deamination of a variety of endogenous and exogenous substances. Among the endogenous substances are the neurotransmitters, norepinephrine, dopamine, and serotonin. The prototype MAOI is iproniazid [54-92-2] (25), originally tested as an antitubercular dmg and a close chemical relative of the effective antitubercular, isoniazid [54-85-3] (26). Tubercular patients exhibited mood elevation, although no reHef of their tuberculosis, following chronic administration of iproniazid. In... 

Ubiquitous mitochondrial monoamine oxidase [monoamine oxygen oxidoreductase (deaminating) (flavin-containing) EC 1.4.3.4 MAO] exists in two forms, namely type A and type B [ monoamine oxidase (MAO) A and B]. They are responsible for oxidative deamination of primary, secondary, and tertiary amines, including neurotransmitters, adrenaline, noradrenaline, dopamine (DA), and serotonin and vasoactive amines, such as tyramine and phenylethylamine. Their nonselec-tive and selective inhibitors ( selective MAO-A and -B inhibitors) are employed for the treatment of depressive illness and Parkinson s disease (PD). 

Warbritton, J. D., Ill, Stewart, R. M., and Baldessarini, R. J. (1980) Increased sensitivity to intracerebroventricular infusion of serotonin and deaminated indoles after lesioning rat with dihydroxytryptamine. Brain Res., 183 355-366. 

Monoamine oxidase (MAO) inhibitors block the oxidative deamination of monoamines, i.e. norepinephrine and serotonin by inhibiting monoamine oxidase type A (MAO-A) and dopamine also by monoamine oxidase type B (MAO-B) inhibition, thereby increasing these neurotransmittors at their receptors in the brain and in the periphery. MAO-A... 

Monoamine oxidases (MAOs) are mitochondrial membrane enzymes. These flavin-dependent enzymes are responsible for the oxidative deamination of numerous endogenic and exogenic amines (norepinephrine, serotonin, dopamine, etc.). MAO A and B take part in the regulation of these amines in many organs, such as the brain. The essential physiological role of these amines, especially in the central nervous system, has motivated the search for inhibitors of their catabolism in order to enhance the synaptic concentration of neuroamines. 

Most SSRls inhibit cytochrome P450 (CYP) isoenzymes, a family of about 30 enzymes that catalyze the oxidase metabolism of multiple dmgs in humans. They are eliminated mostly through hepatic metabolism by oxidase demethylation or oxidative deamination. SSRls generally act by inhibiting the pumps that send serotonin across synapses, thus locally increasing the levels of serotonin in those synapse spaces. However, it is important to point out from the onset that the responses... 

These reactions, which have provided a means of inhibiting the flavin-linked monoamine oxidases, enable us to end on a clinical note. The monoamine oxidases are responsible for the deamination of monoamines such as adrenaline, noradrenaline, dopamine, and serotonin, which act as neurotransmitters. Imbalances in the levels of monoamines cause various psychiatric and neurological disorders Parkinson s disease is associated with lowered levels of dopamine, and low levels of other monoamines are associated with depression. Inhibitors of monoamine oxidases may consequently be used to treat Parkinson s disease and depression. The flavin moiety is covalently bound to the enzyme by the thiol group of a cysteine residue (equation 9.17). The acetylenic suicide inhibitor N,N-dimethyl-propargylamine inactivates monoamine oxidases by alkylating the flavin on N-5.25 A likely mechanism for the reaction is the Michael addition of the N-5 of the reduced flavin to the acetylenic carbon 2... 

Flavin-containing mitochondrial MAO-A and MAO-B catalyze the oxidative deamination of neurotransmitters, such as dopamine, serotonin, and norepinephrine in the central nervous system and peripheral tissues. The enzymes share 73% sequence homology and follow the same kinetic and chemical mechanism but have different substrate and inhibitor specificities. Chemical modification experiments provide evidence that a histidine residue is essential for the catalysis. There is also strong evidence that two cysteine residues are present in the active site of MAO. 

The biological function of amine oxidases involves the oxidation of biogenic amines formed during normal biological processes. In mammals, the monoamine oxidases are involved in the control of the serotonin catecholamine ratios in the brain, which in turn influence sleep and EEG patterns, body temperature, and mental depression. Two groups of amine oxidases are involved in the oxidative deamination of naturally occurring amines as well as foreign compounds. 

MAOs are mitochondrial flavoproteins containing one covalently bound FAD cofactor. Two isozymes, termed as MAO-A and MAO-B, are known for the MAO enzyme family. They catalyze the oxidative deamination of structurally diverse amines including neurotransmitters dopamine, norepinephrine, serotonin, tyramine, and 2-phenylethylamine, and some drugs and xenobiotics that contain cyclic and acyclic alkylamine functional groups [67, 68]. The MAO reaction cycle involves two half reactions, as shown in equations 1.3a and 1.3c ... 

MAO catalyzes the oxidative deamination of catecholamines, 5-hydroxytryptamine (serotonin), and other monoamines, both primary such as NE, and secondary such as EP. It is one of several oxidase-type enzymes whose coenzyme is the flavin-adenine-dinucleotide (FAD) covalently bound as a prosthetic group (Fig. 9-3). The isoalloxazine ring system is viewed as the catalytically functional component of the enzyme. In a narrow view N-5 and C-4a is where the redox reaction takes place (i.e., +H+, +le or -H+, -le), although the whole chromophoric N-5-C-4a-C-4-N-3-C-2-N-l region undoubtedly participates. Figure 9-3 is a proposed structure of MAO isolated from pig brain (Salach et al., 1976).4... 

Monoamine oxidase (MAO) is an enzyme present in the outer mitochondrial membrane of neuronal and non-neuronal cells. Two isoforms of MAO exist MAO-A and MAO-B. The MAO enzymes are responsible for the oxidative deamination of endogenous and xenobiotic amines, and have different substrate preferences, inhibitor specificities, and tissue distributions. MAO inhibition allows endogenous and exogenous substrates to accumulate, and may thereby alter the dynamics of regular monoamine transmitters, such as norepinephrine, serotonin, and dopamine. Specifically, MAO-A deaminates serotonin, norepinephrine, and dopamine, and MAO-B deaminates dopamine, [3-phenylethylamine, and benzylamine. In the human brain, about 75% of MAO is of the B subtype. Hence, the primary effect of MAO inhibitors (MAOIs) is to increase the availability of these neurotransmitters at the nerve terminal. 

Harmaline is reported to be an inhibitor of MAO A. MAO A mainly deaminates neurotransmitters serotonin, dopamine, tyramine, noradrenaiin, and octopamine (Barbeau 1978). The molecule possesses antibacterial activity (Coulthard 1933). Synthetic preparation see (Manske 1927) (Spenser 1959). Harmaline is excreted in the urine of rats as the giucuronide conjugate (Ho 1971). In human subjects the molecule produces numbness of hands and feet (paresthesias) at the onset of the effect. Individuals noted that there was discomfort in the chest, pressure in the head, and dizziness and general malaise which would alternately appear and disappear throughout the session. The dizziness and malaise were associated with certain thoughts or associations (Naranjo 1967). There is a pronouced decrease in neurotic symptoms in many of the subjects who took this molecule,... 

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