Catecholamine Catabolism
Two enzymes are responsible for the catabolism of catecholamines: monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT).
Monoamine Oxidase
MAO catalyzes the oxidative deamination of amines and is a major enzyme in the metabolism of the biogenic amines (ie, norepinephrine, dopamine, and serotonin). MAO is found throughout the CNS. It is present in both glia and neurons. Studies on the subcellular distribution of the enzyme indicate that it is principally associated with the mitochondrial fraction, although it is also present in a microsomal fraction. In the mitochondrial fraction, the enzyme is present in the outer membrane. The enzyme requires flavin adenine dinucleotide as a cofactor.
MAO exists in two forms: MAO-A, whic!h oxidatively deaminates serotonin, norepinephrine, and epinephrine; and MAO-B, which catalyzes the oxidation of benzylamine, phenylethylamine, and phenylethanolamine. Tyramine and dopamine are substrates for both forms. MAO-A seems to be the predominant form in neurons.
Catechol-O-Methyl Transferase
COMT methylates the hydroxyl group meta to the side chain of catecholamines. The methyl donor is S-adenosylmethionine. COMT has a requirement for divalent cations such as Mg++, Mn++, Zn++, Fe++, CO++, and Cd++.
Monoamine Oxidase Inhibitors
MAO inhibitors have antidepressant effects; however, their interaction with the sympathomimetic amines and tyramine causes many side effects. Many drugs act as antidepressants by increasing the content of the neurotransmitters at their respective postsynaptic receptors. An MAO-A inhibitor effectively increases the content of both norepinephrine and serotonin through an inhibition of their degradation.
In human brain, the major MAO is type B, for which dopamine is a good substrate. In the treatment of Parkinson’s disease, L -dopa is used to replace the deficient dopamine. A large fraction of L -dopa is decarboxylated by peripheral tissues to dopamine, and because dopamine doesn’t traverse the blood-brain barrier, L -dopa is administered in combination with a peripheral decarboxylase inhibitor. A specific MAO-B inhibitor, (-) deprenyl, lacks many of the untoward side effects of other MAO inhibitors that block both A and B forms.
Serotonin
Serotonin Biosynthesis & Metabolism
Brain serotonin (5-HT) is synthesized in neurons that contain the enzyme tryptophan hydroxylase. Hydroxylation of tryptophan by this enzyme is the initial and rate-limiting step in the synthesis of 5-HT. L -Tryptophan is converted to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase, and 5-HTP is converted to 5-HT by the aromatic-L -amino acid decarboxylase. Tryptophan hydroxylase requires oxygen and the reduced cofactor pterin (Figure 3-6).
Psychotropic drugs can influence 5-HT by (1) decreasing the storage capacity of the serotonergic neuron, (2) inhibiting the synthesis of 5-HT, (3) inhibiting the enzyme (MAO) that metabolizes 5-HT, or (4) inhibiting the reuptake transporter. Many drugs affect the various sites where 5-HT and norepinephrine are synthesized, stored, released, and recaptured.
Practical Applications
Theoretical and technical advances in molecular biology have provided neuropharmacology with powerful tools to develop new psychoactive drugs. The receptors of most of the neurotransmitters have been cloned and sequenced. We are now obtaining information as to where and how neurotransmitters and drugs bind to these receptors. The proteins that transport neurotransmitters are also being cloned and sequenced, so that psychoactive drugs can be designed to affect the transport system. We now know the genes and enzymes involved in the synthesis of neurotransmitters, and these sites too are amenable to manipulation by drugs.
