Amino acids L-DOPA

At the level of the small intestine we have already encountered the case of the amino-acid L-dopa, which has to compete with dietary amino-acids for uptake through an active transporter system in the intestinal wall. 

Although L-Dopa is not a proteinogenic a-amino acid, L-/ -Dopa 10 is discussed here, because of its close structural and biosynthetic relationship with L-/ -Tyr 9 and L-yS-Phe 8. 

Biosynthesis of norepinephrine takes piace within adrenergic neurons near the terminus of the axon and junction with the effector cell. The biosynthetic pathway (Fig. 13,1) begins with the active transport of the amino acid L-tyrosine into the adrenergic neuron cell (1). In the first step within the cytoplasm, the enzyme tyrosine hydroxylase (tyrosine-3-monooxygenase) oxidizes the 3 position of tyrosine to form the catechol amino acid L-dopa. This is the rate-limiting step in norepinephrine biosynthesis, and the activity of tyrosine hydroxylase is carefully controlled (3). The enzyme is under feedback inhibition control by product catecholamines and is... 

Knowles developed other catalysts capable of much higher enantiomeric excess, and he then set out to use asymmetric catalytic hydrogenation to develop an industrial synthesis of the amino acid L-dopa ... 

Figure 1. Comparison of the oxidation products of the free amino acid L-DOPA and peptidyl DOPA. Ri and R2 represent peptide chains attached by amide linkages on either side of the DOPA residue.

In 1968, Knowles at Monsanto Company showed that a chiral transition metal based catalyst could transfer chirality to a nonchiral substrate resulting in a chiral product with one of the enantiomers in excess. The aim of Knowles was to develop an industrial synthesis process for the rare amino acid l-DOPA, which had proved useful in the treatment of Parkinson s disease. Knowles and co-workers at Monsanto discovered that a cationic rhodium complex containing DiPAMP (Fig. 2.5A), a chelating diphosphine with... 

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. 

Chiral catalysis is employed in several industrial processes leading to enan-tiomerically pure products, such as the amino acid L-dihydroxyphenylalanine (L-DOPA) required for the treatment of Parkinson s disease, L-menthol, and car-bapenems.7 8 The hydrogenation of prochiral functionalized alkenes, notably a-acetamidocinnamic esters, has attracted particular attention ... 

Tyrosine phenol lyase (p-tyrosinase) has been shown to catalyze the efficient synthesis of the L-amino acids L-tyrosine and L-dopa from pyruvate, ammonia and phenol, or catechol, respectively (87-89). 

The LAT system has been used for the transport of various compounds to the brain. Variations in the cerebellum to plasma ratio at late times in 6-[18F]fluoro-L-DOPA studies are consistent with competitive binding of large neutral amino acids (LNAAs) for the LAT at the BBB (117). In addition, it was shown that oral administration of phenylalanine inhibited the uptake of an artificial amino acid [(1 lC)-aminocyclohexanecarboxylate] in human brain (118). Melphalan, a nitrogen mustard derivative of the neutral amino acid L-phenylalanine, was transported to the brain via the LAT system at the rat BBB. In addition, it was shown that melphalan competed with phenylalanine for the LAT system (119). 

The synthesis of dopamine originates from the precursor the amino acid L-tyrosine, which must be transported across the blood-brain barrier into the dopaminergic neuron. The rate limiting step in the synthesis is the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) by the enzyme tyrosine hydroxylase (TH). L-DOPA is subsequently converted to dopamine by aromatic L-amino acid decarboxylase. The latter enzyme turns over so rapidly that L-DOPA levels in the brain are negligible under normal conditions.1... 

L-Dopa is normally a trace intermediary metabolite in the biosynthesis of catecholamines, formed from L-tyrosine in a rate-limiting hydroxylation step by tyrosine hydroxylase, a phosphorylation-activated cytoplasmic mono-oxygenase. L-Dopa is readily decar-boxy ated by the cytoplasmic enzyme L-aro-matic amino acid decarboxylase ("dopa decarboxylase ) to form DA (2). The effects observed after systemic administration of l-... 

The catecholamines are biosynthesized from the amino acid L-tyrosine as outhned in Figure 7.1. The known biochemical events leading to catecholamine metabolism and urinary excretion are also summarized in Figure 7.1. There is evidence that functioning pheochromocytomas have the various enzymes necessary for the conversion of tyrosine to catecholamines, and the level of activity of some of these enzymes (tyrosine hydroxylase, Dopa decarboxylase and dopamine p-hydroxylase) is higher than in normal adrenal tissue." ... 

Tyrosine is actively transported into nerve endings and is converted to dihydroxyphenylalanine DOPA) via tyrosine hydroxylase 1). This step is rate limiting in the synthesis of NE. DOPA is converted to dopamine (DA) via L-aromatic amino acid decarboxylase (DOPA decarboxylase). DA in turn is metabolized to NE via DA beta hydroxylase and is taken up and stored in granules (6). Inactivation ofNE via monoamine oxidase (MAO) (2) may regulate prejunctional levels of transmitter in the mobile pool (3) but not the NE stored in granules. 

The aromatic amino acid L-methyl DOPA (Di Hydroxy PhenylAlanine) 80 is used to make an antihypertensive compound. Synthesis by the Strecker method clearly requires the aromatic ketone 77, and the synthesis follows the pattern below.18 The intermediates and final product have been resolved in various ways. 

The L-stereospecificity is often incorporated into the names of drugs derived from amino acids either as "L" or "levo" for the direction in which L amino acids rotate polarized light. For example, patients with Parkinson s disease are treated with L-DOPA (a derivative of the amino acid L-tyrosine), and hypothyroid patients are treated with levothyroxine (a different derivative of L-tyrosine)... 

Mechanisms Because dopamine has low bioavaUability and does not readily cross the blood-brain barrier, its precursor, t-dopa (levodopa), is used. This amino acid is converted to dopamine by the enzyme aromatic L-amino acid decarboxylase (DOPA decarboxylase), which is present in many body tissues, including the brain. Levodopa is usually given with carhidopa, a drug that does not cross the blood-brain barrier but inhibits DOPA decarboxylase in peripheral tissues. With this combination, lower doses of levodopa are effective, and there are fewer peripheral side effects. 

The classic example of enantioselective synthesis of amino acids concerns the enantioselective hydrogenation of an aminocinnamic acid derivative for the preparation of the unnatural amino acid (L)-3,4-dihydroxyphenylalanine (L-DOPA). This is a very convincing and instructive case, because for the first time a particularly high enantiomeric excess was achieved, and here some fundamental aspects of enantioselective catalysis can be demonstrated. 

Hokfelt T, Fuxe K., and Goldstein M (1973) Immunohistochemical localization of aromatic L-amino acid decarboxylase (DOPA decarboxylase) in central dopamine and 5-hydroxytryptamme nerve cell bodies of the rat. Brain Res 53, 175-180. 

FIGURE 16.7 Tyrosine hydroxylase (1) and dopa decarboxylase (2) catalyze the synthesis of dopamine from the amino acid L-tyrosine. 

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