L-Dopa decarboxylase

Ando-Yamamoto, M., Hayashi, H., Sugiyama, T., Fukui, H., Watanabe, T., and Wada, H. (1987). Purification of L-dopa decarboxylase from rat liver and production of polyclonal and monoclonal antibodies against it. J. Biochem. 101 405-414. 

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. 

Coge, F., Krieger-Poullet, M., Guillemot, J. C., Ferrara, P., Gros, F., and Thibault, J. C. (1989). Purification and partial sequencing of L-dopa decarboxylase from pheo-chromocytoma in rats. C. R. Acad. Sci. Ser. 3 309 587-592. 

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. 

Catechol O-methyltransferase inhibition represents therefore a valuable adjuvant to the L-DOPA decarboxylase inhibition. Unfortunately, tolcapone exhibited... 

A.F. Gazdar et al.. Expression of neuroendocrine cell markers L-dopa decarboxylase, chromogranin A, and dense core granules in human tumors of endocrine and nonendocrine origin. Cancer Res. 48 (1988)4078-4082. 

Catechol O-methyltransferase inhibition therefore represents a valuable adjuvant to L-DOPA decarboxylase... 

Papaver Alkaloids.—Biosynthesis of benzylisoquinoline alkaloids involves the amino-acid dopa, which is in part implicated through decarboxylation to dopamine. The presence of L-dopa decarboxylase in Papaver orientale latex has recently been demonstrated. ... 

Dopamine is a key intermediate in the plant BIA biosynthesis pathway. It condenses with 4-HPAA, and forms a BIA scaffold. In plants, tyrosine/ DOPA decarboxylases catalyze the decarboxylation of L-tyrosine and l-DOPA to tyramine and dopamine, respectively [49]. T3Tamine is an undesirable product for bacterial BIA synthetic pathways because its MAO product (i.e., 4-HPAA) combines with dopamine to form norcoclaurine, which needs CYP80B to be converted to reticuline. l-DOPA decarboxylase (PpDODC) from the Pseudomonas putida strain KT2440 exhibited a more than 10 -fold preference for l-DOPA compared with other aromatic amino acids [unpublished data]. Therefore, conversion of l-DOPA with PpDODC is expected to reduce the formation of undesirable by-products, 4-HPAA, and the resultant norcoclaurine (Fig. 1.4). Using an L-DOPA-produdng E. coli strain that overexpresses PpDODC, dopamine production reached 1.05 g. The conversion efficiency from L-tyrosine to dopamine was 29.1 % [24]. 

DOPA (dihydroxyphenylalanine) is a drug used to treat the neurodegenerative condition known as Parkinson s disease. It is of particular interest in this context as the form that is active in the body is actually achiral. However, one of the chiral forms - the D-isomer -causes harmful side effects and so the compound must be administered as the L-enantiomer. This is then converted to the active achiral form in the brain by the enzyme, l-DOPA decarboxylase (Figure 20.80). 

Roberts MF, Antoun MD (1978) The relationship between L-DOPA decarboxylase in the latex of Papaver somniferum and alkaloid formation. Ph3rtochemistry 17 1083-1087 Roberts MF, McCarthy D, Kutchan TM, Coscia CJ (1983) Localization of enzyme and alkaloidal metabolites in Papaver latex. Arch Biochem Biophys 222 599-609 Rueffer M, El-Shagi H, Nagakura N, Zenk MH (1981) (S)-Norlaudanosoline synthetase the first enzyme in the benzylisoquinoline biosynthetic pathway. FEBS Lett 129 5-9 Sasse F, Backs-Hiisemann D, Barz W (1979) Isolation and characterization of vacuoles from cell suspension cultures of Daucus carota. Z Naturforsch 34 848-853 Schuchmann R, Wellmann E (1983) Somatic embryogenesis of tissue cultures of Papaver somniferum and Papaver orientate and its relationship to alkaloid and lipid metabolism. Plant Cell Rep 2 88-91... 

The neurotransmitter must be present in presynaptic nerve terminals and the precursors and enzymes necessary for its synthesis must be present in the neuron. For example, ACh is stored in vesicles specifically in cholinergic nerve terminals. It is synthesized from choline and acetyl-coenzyme A (acetyl-CoA) by the enzyme, choline acetyltransferase. Choline is taken up by a high affinity transporter specific to cholinergic nerve terminals. Choline uptake appears to be the rate-limiting step in ACh synthesis, and is regulated to keep pace with demands for the neurotransmitter. Dopamine [51 -61-6] (2) is synthesized from tyrosine by tyrosine hydroxylase, which converts tyrosine to L-dopa (3,4-dihydroxy-L-phenylalanine) (3), and dopa decarboxylase, which converts L-dopa to dopamine. 

Together with dopamine, adrenaline and noradrenaline belong to the endogenous catecholamines that are synthesized from the precursor amino acid tyrosine (Fig. 1). In the first biosynthetic step, tyrosine hydroxylase generates l-DOPA which is further converted to dopamine by the aromatic L-amino acid decarboxylase ( Dopa decarboxylase). Dopamine is transported from the cytosol into synaptic vesicles by a vesicular monoamine transporter. In sympathetic nerves, vesicular dopamine (3-hydroxylase generates the neurotransmitter noradrenaline. In chromaffin cells of the adrenal medulla, approximately 80% of the noradrenaline is further converted into adrenaline by the enzyme phenylethanolamine-A-methyltransferase. 

The main clinical use of COMT inhibitors is as adjunct (or additional adjunct) in the therapy of Parkinson s disease. The standard therapy of Parkinson s disease is oral L-dopa (as a drug levodopa) given with a dopa decarboxylase (DDC) inhibitor (e.g. carbidopa and benserazide), which does not reach the brain. When the peripheral DDC is inhibited, the concentration of 3-O-methyldopa (3-OMD), a product of COMT, in plasma is many times that of L-dopa. Since the half-life of 3-OMD is about 15 h, compared to about 1 h for L-dopa, the concentration of 3-OMD remains particularly high during chronic therapy, especially if new slow release L-dopa preparations are used. A triple therapy (L-dopa plus DDC inhibitor plus COMT-inhibitor) will... 

The immediate metabolic precursor to dopamine, l-DOPA (L-dihydroxphenylalanine) is converted to the active neurotransmitter dopamine by the action of the enzyme aromatic amine acid decarboxylase (AADC). l-DOPA (INN name Levodopa) is the main diug used to treat Parkinson s disease. 

Dopa decarboxylase is an enzyme catalyzing the synthesis of dopamine from l-DOPA or of serotonin (= 5-hydroxytryptamine) from L-tryptophan. Inhibitors of this enzyme, which do not pass through the... 

L-DOPA/Levodopa Dopa Decarboxylase Dopamine System Dopamine- 3-hydroxylase Dopaminergic Neurotoxicity Dose... 

By contrast, the cytoplasmic decarboxylation of dopa to dopamine by the enzyme dopa decarboxylase is about 100 times more rapid (Am 4x 10 " M) than its synthesis and indeed it is difficult to detect endogenous dopa in the CNS. This enzyme, which requires pyridoxal phosphate (vitamin B6) as co-factor, can decarboxylate other amino acids (e.g. tryptophan and tyrosine) and in view of its low substrate specificity is known as a general L-aromatic amino-acid decarboxylase. 

Konrad, K. D and Marsh, J. L. (1987). Developmental expression and spatial distribution of dopa decarboxylase in Drosophila. Dev. Biol. 722 172-185. 

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. 

L-dopa is effective in the treatment of Parkinson s disease, a disorder characterised by low levels of dopamine, since L-dopa is metabolised into dopamine. However, this biosynthesis normally occurs in both the peripheral nervous system (PNS) and the central nervous system CNS. The related drug carbidopa inhibits aromatic L-amino acid decarboxylase only in the periphery, since it does not cross the blood-brain barrier. So, when carbidopa is given with L-dopa, it reduces the biosynthesis of L-dopa to dopamine in the periphery and, thus, increases the bioavailability of L-dopa for the dopaminergic neurons in the brain. Hence, carbidopa increases the clinical efficacy of L-dopa for Parkinsonian patients. 

Carbidopa An inhibitor of aromatic L-amino acid decarboxylase used with L-dopa in the treatment of Parkinson s disease. 

Decarboxylase Decarboxylation of amino adds and simple phenolic adds, primarily p-hydroxylated L-dopa, tyrosine... 

Although the absence of paracellular transport across the BBB impedes the entry of small hydrophilic compounds into the brain, low-molecular-weight lipophilic substances may pass through the endothelial cell membranes and cytosol by passive diffusion [7]. While this physical barrier cannot protect the brain against chemicals, the metabolic barrier formed by the enzymes from the endothelial cell cytosol may transform these chemicals. Compounds transported through the BBB by carrier-mediated systems may also be metabolized. Thus, l-DOPA is transported through the BBB and then decarboxylated to dopamine by the aromatic amino acid decarboxylase [7]. 

The answer is c. (idardman, p 510.) Carbidopa is an inhibitor of aromatic L-amino acid decarboxylase. It cannot readily penetrate the central nervous system (CNS) and, thus, decreases the decarboxylation of L-clopa in the peripheral tissues. This promotes an increased concentration of L-clopa in the nigrostriatum, where it is converted to dopamine. In addition, the effective dose of L-dopa can be reduced... 

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