DOPA decarboxylase activity

Reith, J., Benkelfat, C., Sherwin, A. et al. Elevated dopa decarboxylase activity in living brain of patients with psychosis. Proc. Natl Acad. Sci. USA 91 11651-11654,1994. 

Ernst, M., Zametkin, A.J., Matochik, J.A., Jons, P.H., and Cohen, R.M. (1998) DOPA decarboxylase activity in attention deficit disorder adults. A [fluorine-18]fluorodopa positron emission tomographic study. / Neurosci 18 5901-5907. 

HTP and DOPA decarboxylase activities of partially purified extracts of hog kidney it has been stated that these compounds do not also inhibit histidine decarboxylase. This statement is misleading, however, as it refers to results obtained by earlier workers using a histidine decarboxylase of bacterial origin . ... 

Carbidopa. This drug inhibits peripheral dopa decarboxylase activity. 

Fears have been expressed [510, 511] that long-term administration of L-dopa may induce a state of pyridoxine deficiency, since excess dietary pyridoxine, which is rapidly converted in vivo to the decarboxylase coenzyme pyridoxine-5 -phosphate [512], can nullify the beneficial effects of the amino acid [513-515]. Pyridoxine apparently both complexes with L-dopa and produces an accelerated decarboxylation of the amino acid in extracerebral tissues, both processes effectively reducing the amount of available dopamine in the striatum [512, 516]. The decarboxylase inhibitor MK-485 (37) prevents this reversal of the therapeutic effect by pyridoxine [517] and, more significantly, pyridoxine actually enhances the effects of L-dopa when given in conjunction with such an inhibitor [518]. The mechanism involved in this potentiation reflects enhancement by pyridoxine of dopa decarboxylase activity within the striatum in the presence of complete inhibition of extracerebral decarboxylase. The use of combinations of L-dopa, pyridoxine, and inhibitors of aromatic L-amino-acid decarboxylase, may lead to a more... 

A large number of inhibitors of DOPA decarboxylase have been described a few of the most imtent compounds are listed in Table 7. Inhibitors include DOPA analogues such as a-methylDOPA. cinnamic acid derivatives and hydrazino compounds. Although many of these compounds are effective inhibitors of the enzyme in vivo, there is such a Mgh DOPA-decarboxylase activity in most tissues that it has proved very difficult to produce any significant inhibition of catechohunine bio-... 

The chronology of the effects of ecdysone is also quite compatible with the model The hormone penetrates the epidermis cells within IS to 30 min after its injection, reaching a maximum concentration after 1 hr. Stimulation of messenger-RNA synthesis is seen within 1 to 2 hr. increase in labelling of microsomal RNA within 3 to 4 hr, and the enhancement of DOPA decarboxylase activity begins after 6 to 8 hr. 

According to the fourth criterion, the model implies that (1) the acetyldopamine supply limits the sclerotization process (2) the DOPA decarboxylase activity limits acetyldopamine supply (3) the activity of DOPA decarboxylase is limited by the concentration (Le. in this case by the synthesis) of the enzyme (4) DOPA... 

Decarboxylation of histidine to histamine is catalyzed by a broad-specificity aromatic L-amino acid decarboxylase that also catalyzes the decarboxylation of dopa, 5-hy-droxytryptophan, phenylalanine, tyrosine, and tryptophan. a-Methyl amino acids, which inhibit decarboxylase activity, find appfication as antihypertensive agents. Histidine compounds present in the human body include ergothioneine, carnosine, and dietary anserine (Figure 31-2). Urinary levels of 3-methylhistidine are unusually low in patients with Wilson s disease. 

FIGURE 29-2. Levodopa absorption and metabolism. Levodopa is absorbed in the small intestine and is distributed into the plasma and brain compartments by an active transport mechanism. Levodopa is metabolized by dopa decarboxylase, monoamine oxidase, and catechol-O-methyltransferase. Carbidopa does not cross the blood-brain barrier. Large, neutral amino acids in food compete with levodopa for intestinal absorption (transport across gut endothelium to plasma). They also compete for transport across the brain (plasma compartment to brain compartment). Food and anticholinergics delay gastric emptying resulting in levodopa degradation in the stomach and a decreased amount of levodopa absorbed. If the interaction becomes a problem, administer levodopa 30 minutes before or 60 minutes after meals. 

Baylin, S. B., Abeloff, M. D., Goodwin, G., Carney, D. M and Gazdar, A. F. (1980). Activities of L-dopa decarboxylase and diamine oxidase (histaminase) in human lung cancers and decarboxylase as a marker for small (oat) cell cancer in cell culture. Cancer Res. 40 1990-1994. 

Mastick, G. S., and Scholnick, S. B. (1992). Repression and activation of the Drosophila dopa decarboxylase gene in glia. Mol. Cell. Biol. 12 5659-5666. 

Rahman, M. K Nagatsu, T., and Kato, T. (1981). Aromatic L-amino acid decarboxylase activity in central and peripheral tissues and serum of rats with L-DOPA and L-5-hydroxytryptophan as substrates. Biochem. Pharmacol. 30 645-649. 

An interesting example of the above difference is l-DOPA 4, which is used in the treatment of Parkinson s disease. The active drug is the achiral compound dopamine formed from 4 via in vivo decarboxylation. As dopamine cannot cross the blood-brain barrier to reach the required site of action, the prodrug 4 is administered. Enzyme-catalyzed in vivo decarboxylation releases the drug in its active form (dopamine). The enzyme l-DOPA decarboxylase, however, discriminates the stereoisomers of DOPA specifically and only decarboxylates the L-enantiomer of 4. It is therefore essential to administer DOPA in its pure L-form. Otherwise, the accumulation of d-DOPA, which cannot be metabolized by enzymes in the human body, may be dangerous. Currently l-DOPA is prepared on an industrial scale via asymmetric catalytic hydrogenation. 

L-Dopa. Dopamine itself cannot penetrate the blood-brain barrier however, its natural precursor, L-dihydroxy-phenylalanine (levodopa), is effective in replenishing striatal dopamine levels, because it is transported across the blood-brain barrier via an amino acid carrier and is subsequently decarboxy-lated by DOPA-decarboxylase, present in striatal tissue. Decarboxylation also takes place in peripheral organs where dopamine is not needed, likely causing undesirable effects (tachycardia, arrhythmias resulting from activation of Pi-adrenoceptors [p. 114], hypotension, and vomiting). Extracerebral production of dopamine can be prevented by inhibitors of DOPA-decarboxylase (car-bidopa, benserazide) that do not penetrate the blood-brain barrier, leaving intracerebral decarboxylation unaffected. Excessive elevation of brain dopamine levels may lead to undesirable reactions, such as involuntary movements (dyskinesias) and mental disturbances. 

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

Synthesis of norepinephrine begins with the amino acid tyrosine, which enters the neuron by active transport, perhaps facilitated by a permease. In the neuronal cytosol, tyrosine is converted by the enzyme tyrosine hydroxylase to dihydroxyphenylalanine (dopa), which is converted to dopamine by the enzyme aromatic L-amino acid decarboxylase, sometimes termed dopa-decarboxylase. The dopamine is actively transported into storage vesicles, where it is converted to norepinephrine (the transmitter) by dopamine (3-hydroxylase, an enzyme within the storage vesicle. 

Carbidopa (4.75), a hydrazine analog of a-methyldopa, is an important DOPA decarboxylase inhibitor. It is used to protect the DOPA that is administered in large doses in Parkinson s disease (section 4.4.4) from peripheral decarboxylation. DOPA concentrations in the CNS will therefore increase without requiring the administration of extremely high, toxic doses of DOPA. The exclusive peripheral mode of action of carbidopa is due to its ionic character and inability to cross the blood-brain barrier. Because of this effect, carbidopa is co-administered with DOPA in a single tablet formulation as a first-line therapy for Parkinson s disease. Benserazide (4.76) has similar activity. 

As a result of a high index of clinical suspicion and, on occasion, supporting biochemical data from other investigations, one of the first specialist investigations to ascertain whether a patient has an inborn error of biogenic amine metabolism is, as mentioned above, analysis of the CSF concentrations of HVA and 5HIAA. This is often performed in conjunction with the measurement of 3-methyldopa (3-MD), also known as 3-methoxytyrosine. 3-MD is formed from L-dopa via COMT activity and accumulates in conditions where aromatic amino acid decarboxylase activity is impaired. The chemical structures of HVA, 5HIAA and 3-MD are shown in Fig. 6.2.1. 

Depression. Depression is our most common mental problem. One in four women and one in ten men will have a major depression during their lifetime.1095 More than 15 million people in the United States are affected by severe depression in any given year and more than 30,000 may commit suicide.1096 1097 Worldwide psychiatric problems, mostly depression, account for 28% of all disabilities.1098 The biogenic amine hypothesis states that depression results from the depletion of neurotransmitters in the areas of the brain involved in sleep, arousal, appetite, sex drive, and psychomotor activity. An excess of transmitters is proposed to give rise to the manic phase of the bipolar (manic-depressive) cycle that is sometimes observed. In support of this hypothesis is the observation that administration of reserpine precipitates depression, which may be serious in 15-20% of hypertensive patients receiving the drug. Similar effects are observed with the dopa decarboxylase inhibitor a-methyldopa... 

Noradrenergic neurons. The noradrenergic neuron uses NE for its neurotransmitter. Monoamine neurotransmitters are synthesized by means of enzymes, which assemble neurotransmitters in the cell body or nerve terminal. For the noradrenergic neuron, this process starts with tyrosine, the amino acid precursor of NE, which is transported into the nervous system from the blood by means of an active transport pump (Fig. 5 — 17). Once inside the neuron, the tyrosine is acted on by three enzymes in sequence, the first of which is tyrosine hydroxylase (TOH), the rate-limiting and most important enzyme in the regulation of NE synthesis. Tyrosine hydroxylase converts the amino acid tyrosine into dihydroxyphenylalanine (DOPA). The second enzyme DOPA decarboxylase (DDC), then acts, converting DOPA into dopamine (DA), which itself is a neurotransmitter in some neurons. However, for NE neurons, DA is just a precursor of NE. In fact, the third and final NE synthetic enzyme, dopamine beta-hydroxylase (DBH), converts DA into NE. The NE is then stored in synaptic packages called vesicles until released by a nerve impulse (Fig. 5—17). 

FIGURE 5—31. Dopamine (DA) is produced in dopaminergic neurons from the precursor tyrosine (tyr), which is transported into the neuron by an active transport pump, called the tyrosine transporter, and then converted into DA by two of the same three enzymes that also synthesize norepinephrine (Fig. 5-17). The DA-synthesizing enzymes are tyrosine hydroxylase (TOH), which produces DOPA, and DOPA decarboxylase (DDC), which produces DA. 

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