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discounted EARLY registration ends Dec 31, 2014
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discounted EARLY registration ends Dec 31, 2014
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discounted EARLY registration ends Dec 31, 2014
Metabolic Modeling Tutorial
discounted EARLY registration ends Dec 31, 2014
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MetaCyc Pathway: L-dopa degradation

Enzyme View:

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

Some taxa known to possess this pathway include ? : Homo sapiens , Rattus norvegicus , Sus scrofa

Expected Taxonomic Range: Vertebrata

Summary:
General Background

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 2.1.1.6 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 2.6.1.5 [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).

Credits:
Created 18-Sep-2009 by Fulcher CA , SRI International


References

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

Allen09: Allen GF, Land JM, Heales SJ (2009). "A new perspective on the treatment of aromatic L-amino acid decarboxylase deficiency." Mol Genet Metab 97(1);6-14. PMID: 19231266

Bonifacio07: Bonifacio MJ, Palma PN, Almeida L, Soares-da-Silva P (2007). "Catechol-O-methyltransferase and its inhibitors in Parkinson's disease." CNS Drug Rev 13(3);352-79. PMID: 17894650

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

Hauser09: Hauser RA (2009). "Levodopa: past, present, and future." Eur Neurol 62(1);1-8. PMID: 19407449

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

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Axelrod58: Axelrod J, Tomchick R (1958). "Enzymatic O-methylation of epinephrine and other catechols." J Biol Chem 233(3);702-5. PMID: 13575440

Belarbi77: Belarbi A, Bollack C, Befort N, Beck JP, Beck G (1977). "Purification and characterization of rat liver tyrosine aminotransferase." FEBS Lett 75(1);221-5. PMID: 15865

Belarbi79: Belarbi A, Beck G, Bergmann C, Bollack C (1979). "Intrinsic forms of soluble and mitochondrial tyrosine aminotransferase from rat tissues." FEBS Lett 104(1);59-65. PMID: 39002

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

Borchardt78: Borchardt R, Cheng CF (1978). "Purification and characterization of rat heart and brain catechol methyltransferase." Biochim Biophys Acta 522(1);49-62. PMID: 413582

Hargrove80: Hargrove JL, Granner DK (1980). "Purification of the native form of tyrosine aminotransferase from rat liver." Anal Biochem 104(1);231-5. PMID: 6104456

Hargrove81: Hargrove JL, Granner DK (1981). "Physical properties, limited proteolysis, and acetylation of tyrosine aminotransferase from rat liver." J Biol Chem 256(15);8012-7. PMID: 6114952

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

Hargrove90: Hargrove JL (1990). "Stabilization and purification of tyrosine aminotransferase from rat liver." Prep Biochem 20(1);11-22. PMID: 1973296

Karhunen94: Karhunen T, Tilgmann C, Ulmanen I, Julkunen I, Panula P (1994). "Distribution of catechol-O-methyltransferase enzyme in rat tissues." J Histochem Cytochem 42(8);1079-90. PMID: 8027527

Latendresse13: Latendresse M. (2013). "Computing Gibbs Free Energy of Compounds and Reactions in MetaCyc."

Lee79: Lee KL, Roberson LE, Kenney FT (1979). "Properties of tyrosine aminotransferase from rat liver." Anal Biochem 95(1);188-93. PMID: 40452

Lu03a: 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

Miller71b: Miller JE, Litwack G (1971). "Purification, properties, and identity of liver mitochondrial tyrosine aminotransferase." J Biol Chem 246(10);3234-40. PMID: 4396841

Overbye09: Overbye A, Seglen PO (2009). "Phosphorylated and non-phosphorylated forms of catechol O-methyltransferase in rat liver, brain and other tissues." Biochem J 417(2);535-45. PMID: 18831714

Roewekamp77: Roewekamp W, Sekeris CE (1977). "Purification and subunit structure of tyrosine aminotransferase from rat liver cytosol." FEBS Lett 73(2);225-8. PMID: 14026

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

Tenhunen93: Tenhunen J, Ulmanen I (1993). "Production of rat soluble and membrane-bound catechol O-methyltransferase forms from bifunctional mRNAs." Biochem J 296 ( Pt 3);595-600. PMID: 8280056

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Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Sun Nov 23, 2014, BIOCYC14B.