This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: dihydroxy-L-phenylalanine degradation
|Superclasses:||Degradation/Utilization/Assimilation → Amino Acids Degradation → Other Amino Acids Degradation|
Expected Taxonomic Range:
The major pathway of L-dopa metabolism involves its role as a precursor metabolite in the biosynthesis of the catecholamines dopamine, (R)-noradrenaline and (R)-adrenaline (see pathway catecholamine biosynthesis). The pathway shown here is a relatively minor catabolic pathway for L-dopa that has been demonstrated in rat liver. It involves methylation of L-dopa to 3-O-methyldopa and final conversion to 3-methoxy-4-hydroxyphenyllactate (vanillactate) which is excreted in urine [Maeda76, Maeda78] . Early studies also described 3-O-methyldopa as a quantitatively minor precursor of L-dopa (not shown), although details of this O-demethylation reaction remain to be established and data suggested that it does not occur in liver ([Maeda76] and in [Goodwin78]).
L-dopa is used as a pro-drug for dopamine in the therapy of central nervous system disorders such as Parkinson's disease because dopamine cannot cross the blood-brain barrier. Because L-dopa is decarboxylated to dopamine in peripheral tissues by aromatic L-amino acid decarboxylase (dopa decarboxylase) and can also be methylated to 3-O-methyldopa by catechol-O-methyltransferase, combination therapies with L-dopa and inhibitors of these enzymes are used (reviewed in [Hauser09, Bonifacio07, Allen09]).
About This Pathway
The degradation of L-dopa has been studied in rat liver homogenates [Maeda76]] and in a rat liver mitochondrial fraction [Maeda78]. Urinary metabolites have been analyzed after L-dopa administration to rats [Goodwin78]. The catabolism of L-dopa is initiated by catechol O-methyltransferase EC 220.127.116.11 which methylates L-dopa in a S-adenosyl-L-methionine-dependent reaction. The 3-O-methyldopa formed is transaminated to 3-methoxy-4-hydroxyphenylpyruvate (vanilpyruvate). The identity of the transaminase was suggested to be tyrosine aminotransferase EC 18.104.22.168 [Maeda76], although this remains to be confirmed. Unlike L-dopa, 3-O-methyldopa is not easily decarboxylated, so the equilibrium is shifted to 3-methoxy-4-hydroxyphenylpyruvate formation [Maeda78]. 3-methoxy-4-hydroxyphenylpyruvate undergoes NADH-dependent reduction to 3-methoxy-4-hydroxyphenyllactate (vanillactate) predominantly by aromatic α-keto acid reductase, and also by lactate dehydrogenase [Maeda78].
It was also suggested that 3-methoxy-4-hydroxyphenylpyruvate may be oxidatively decarboxylated to homovanillate as evidenced by identification of a small amount of this compound by thin layer chromatography [Maeda76]. Analysis of urinary excretion patterns of L-dopa metabolites also suggested this reaction [Goodwin78].
In humans, the urinary metabolite N-acetyl-vanilalanine was identified in a patient with aromatic L-amino acid decarboxylase deficiency. This metabolite was postulated to be derived from 3-O-methyldopa (vanilalanine) by acetylation [Abdenur06] (not shown).
Abdenur06: Abdenur JE, Abeling N, Specola N, Jorge L, Schenone AB, van Cruchten AC, Chamoles NA (2006). "Aromatic l-aminoacid decarboxylase deficiency: unusual neonatal presentation and additional findings in organic acid analysis." Mol Genet Metab 87(1);48-53. PMID: 16288991
Goodwin78: Goodwin BL, Ruthven CR, King GS, Sandler M (1978). "Metabolism of 3, 4-dihydroxyphenylalanine, its metabolites and analogues in vivo in the rat: urinary excretion pattern." Xenobiotica 8(10);629-51. PMID: 716472
Maeda76: Maeda T, Shindo H (1976). "Metabolic pathway of L-3-methoxy,4-hydroxyphenylalanine (3-O-methylDOPA)-participation of tyrosine aminotransferase and lactate dehydrogenase." Chem Pharm Bull (Tokyo) 24(5);1104-6. PMID: 14789
Maeda78: Maeda T, Shindo H (1978). "Metabolic difference between 3,4-dihydroxyphenylpyruvic acid (DHPP) and 3-methoxy-4-hydroxyphenylpyruvic acid (MHPP)." Chem Pharm Bull (Tokyo) 26(7);2054-7. PMID: 28856
Bonifacio01: Bonifacio MJ, Vieira-Coelho MA, Soares-da-Silva P (2001). "Expression and characterization of rat soluble catechol-O-methyltransferase fusion protein." Protein Expr Purif 23(1);106-12. PMID: 11570851
Hargrove84: Hargrove JL, Mackin RB (1984). "Organ specificity of glucocorticoid-sensitive tyrosine aminotransferase. Separation from aspartate aminotransferase isoenzymes." J Biol Chem 259(1);386-93. PMID: 6142885
Lu03: Lu H, Meng X, Yang CS (2003). "Enzymology of methylation of tea catechins and inhibition of catechol-O-methyltransferase by (-)-epigallocatechin gallate." Drug Metab Dispos 31(5);572-9. PMID: 12695345
Lundstrom92: Lundstrom K, Tilgmann C, Peranen J, Kalkkinen N, Ulmanen I (1992). "Expression of enzymatically active rat liver and human placental catechol-O-methyltransferase in Escherichia coli; purification and partial characterization of the enzyme." Biochim Biophys Acta 1129(2);149-54. PMID: 1730052
Salminen90: Salminen M, Lundstrom K, Tilgmann C, Savolainen R, Kalkkinen N, Ulmanen I (1990). "Molecular cloning and characterization of rat liver catechol-O-methyltransferase." Gene 93(2);241-7. PMID: 2227437
Sapico74: Sapico V, Shear L, Litwack G (1974). "Translocation of inducible tyrosine aminotransferase to the mitochondrial fraction. Facilitation by acute uremia and other conditions." J Biol Chem 249(7);2122-9. PMID: 4150471
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