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MetaCyc Pathway: L-phenylalanine degradation IV (mammalian, via side chain)
Traceable author statement to experimental support

Pathway diagram: L-phenylalanine degradation IV (mammalian, via side chain)

If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.

Superclasses: Degradation/Utilization/AssimilationAmino Acids DegradationProteinogenic Amino Acids DegradationL-phenylalanine Degradation

Some taxa known to possess this pathway include : Bos taurus, Cavia porcellus, Homo sapiens, Macaca fuscata, Macaca mulatta, Rattus norvegicus

Expected Taxonomic Range: Metazoa

General Background

L-phenylalanine is an essential amino acid in humans and must be obtained in the diet. The major pathway of mammalian L-phenylalanine degradation is via hydroxylation to L-tyrosine in the liver, followed by complete oxidation of L-tyrosine (see pathway L-phenylalanine degradation I (aerobic) and associated pathway link). However, a minor pathway of L-phenylalanine side chain degradation by transamination or decarboxylation also occurs (this pathway). Metabolites formed in this alternative pathway include 2-oxo-3-phenylpropanoate, phenyllactate, phenylacetate, 2-hydroxyphenylacetate (o-hydroxyphenylacetate), 2-phenylethylamine and α-N-phenylacetyl-L-glutamine or phenylacetylglycine, which can be identified in urine. In individuals with hyperphenylalaninemia, such as phenylketonuria patients, these minor metabolites are increased in urine (in [Williams08, Wada04, Bier03, Kuhara07] and [Kaufman99]).

About This Pathway

The enzyme involved in transamination of L-phenylalanine to 2-oxo-3-phenylpropanoate was hypothesized to be mitochondrial aspartate aminotransferase (EC This was supported by later work that showed a narrow substrate specificity for human tyrosine aminotransfrase (EC, making this enzyme an unlikely candidate [Sivaraman06]. 2-oxo-3-phenylpropanoate may be oxidized to 2-hydroxyphenylacetate, or reduced to phenyllactate. Note that pathway diagrams in the literature also suggest that 2-oxo-3-phenylpropanoate can be metabolized to phenylacetate (in [Williams08] and in [Kaufman99]) (not shown) although the reaction, or route, was not given. A microbial route for this conversion is shown in L-phenylalanine degradation II (anaerobic).

The enzyme involved in the decarboxylation of L-phenylalanine is aromatic L-amino acid decarboxylase (in [Zhu92]). The decarboxylation product 2-phenylethylamine (β-phenylethylamine) is a trace amine in the mammalian central nervous system and is hypothesized to function as a neuromodulator, enhancing dopaminergic transmission. It is metabolized by mitochondrial monoamine oxidase B to phenylacetaldehyde. This compound is dehydrogenated to phenylacetate by mitochondrial aldehyde dehydrogenase (EC and possibly also by aldehyde oxidase (EC and xanthine oxidase ( phenylacetate may subsequently be activated and conjugated to amino acids (see below) [Geha01, Panoutsopoulos04, Panoutsopoulos04a, Klyosov96, Young82, Bergman01, Boulton90, Yang73] and reviewed in [Berry04].

An enzymatic activity in extracts from human and bovine liver mitochondria that catalyzed the activation of phenylacetate to its coenzyme A derivative was characterized early [Moldave57]. It is now known that many endogenous and xenobiotic substrates are metabolized in liver and kidney mitochondria via the formation of acyl-CoA derivatives in reactions catalyzed by ATP-dependent acid-CoA ligases (AMP-forming) (EC through EC (note that EC is a microbial enzyme). The mitochondrial medium-chain CoA ligase EC is associated with metabolism via amino acid conjugates (reviewed in [Knights98] and [Testa08]) and is a candidate enzyme for this pathway. Different forms of this enzyme have been purified and characterized from human and bovine sources, although species differences may exist as to which ligases function in a given reaction (in [Vessey03]). Two of these enzymes from human liver mitochondria, HXM-A and HXM-B, have been purified and characterized and were shown in vitro to have phenylacetate-CoA ligase activity, although highest activity was found with benzoate and hexanoate, respectively [Vessey99, Vessey03].

Amino acid conjugation of phenylacetyl-CoA with L-glutamine or glycine is catalyzed by mitochondrial arylacetyl acyl-CoA:amino acid N-acyltransferase of liver and kidney. The α-N-phenylacetyl-L-glutamine conjugate has been shown to occur in humans and monkeys, whose enzyme is L-glutamine-specific. In other mammals the phenylacetylglycine conjugate is predominantly formed ( [Moldave57, Nandi79, Webster76] in [Vessey98], in [Davis91] and in [Sabelli83]).

Although not shown here, it should also be noted that 2-hydroxyphenylacetate may also be formed from the biogenic amine o-tyramine and has been identified in aqueous humor of the human eye [Watson92a]. o-tyramine is formed by decarboxylation of 2-hydroxyphenylalanine, which is formed from L-phenylalanine by oxygen radicals under conditions of oxidative stress [Molnar05, Huggins93] . Normal L-tyrosine (p-tyrosine) can be similarly decarboxylated to tyramine which is found in tissues and urine [Brier91, Bowsher83, Nishimura66] and further oxidative metabolism of tyramine has also been shown [Benedetti83, Suzuki79] and reviewed in [Berry04].

Variants: L-phenylalanine degradation I (aerobic), L-phenylalanine degradation II (anaerobic), L-phenylalanine degradation III, L-phenylalanine degradation V

Unification Links: KEGG:map00360

Created 20-Aug-2009 by Fulcher CA, SRI International


Benedetti83: Benedetti MS, Boucher T, Carlsson A, Fowler CJ (1983). "Intestinal metabolism of tyramine by both forms of monoamine oxidase in the rat." Biochem Pharmacol 32(1);47-52. PMID: 6830619

Bergman01: Bergman J, Yasar S, Winger G (2001). "Psychomotor stimulant effects of beta-phenylethylamine in monkeys treated with MAO-B inhibitors." Psychopharmacology (Berl) 159(1);21-30. PMID: 11797065

Berry04: Berry MD (2004). "Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators." J Neurochem 90(2);257-71. PMID: 15228583

Bier03: Bier DM (2003). "Amino acid pharmacokinetics and safety assessment." J Nutr 133(6 Suppl 1);2034S-2039S. PMID: 12771361

Boulton90: Boulton AA, Juorio AV, Paterson IA (1990). "Phenylethylamine in the CNS: effects of monoamine oxidase inhibiting drugs, deuterium substitution and lesions and its role in the neuromodulation of catecholaminergic neurotransmission." J Neural Transm Suppl 29;119-29. PMID: 2193105

Bowsher83: Bowsher RR, Henry DP (1983). "Decarboxylation of p-tyrosine: a potential source of p-tyramine in mammalian tissues." J Neurochem 40(4);992-1002. PMID: 6131938

Brier91: Brier ME, Bowsher RR, Mayer PR, Henry DP (1991). "Conversion of p-tyrosine to p-tyramine in the isolated perfused rat kidney: modulation by perfusate concentrations of p-tyrosine." Life Sci 48(9);901-7. PMID: 1997791

Davis91: Davis BA, O'Reilly RL, Placatka CL, Paterson IA, Yu PH, Durden DA (1991). "Effect of dietary phenylalanine on the plasma concentrations of phenylalanine, phenylethylamine and phenylacetic acid in healthy volunteers." Prog Neuropsychopharmacol Biol Psychiatry 15(5);611-23. PMID: 1956990

Geha01: Geha RM, Rebrin I, Chen K, Shih JC (2001). "Substrate and inhibitor specificities for human monoamine oxidase A and B are influenced by a single amino acid." J Biol Chem 276(13);9877-82. PMID: 11134050

Huggins93: Huggins TG, Wells-Knecht MC, Detorie NA, Baynes JW, Thorpe SR (1993). "Formation of o-tyrosine and dityrosine in proteins during radiolytic and metal-catalyzed oxidation." J Biol Chem 268(17);12341-7. PMID: 8509373

Kaufman99: Kaufman S (1999). "A model of human phenylalanine metabolism in normal subjects and in phenylketonuric patients." Proc Natl Acad Sci U S A 96(6);3160-4. PMID: 10077654

Klyosov96: Klyosov AA (1996). "Kinetics and specificity of human liver aldehyde dehydrogenases toward aliphatic, aromatic, and fused polycyclic aldehydes." Biochemistry 35(14);4457-67. PMID: 8605195

Knights98: Knights KM (1998). "Role of hepatic fatty acid:coenzyme A ligases in the metabolism of xenobiotic carboxylic acids." Clin Exp Pharmacol Physiol 25(10);776-82. PMID: 9784915

Kuhara07: Kuhara T (2007). "Noninvasive human metabolome analysis for differential diagnosis of inborn errors of metabolism." J Chromatogr B Analyt Technol Biomed Life Sci 855(1);42-50. PMID: 17467347

Moldave57: Moldave K, Meister A (1957). "Synthesis of phenylacetylglutamine by human tissue." J Biol Chem 229(1);463-76. PMID: 13491597

Molnar05: Molnar GA, Nemes V, Biro Z, Ludany A, Wagner Z, Wittmann I (2005). "Accumulation of the hydroxyl free radical markers meta-, ortho-tyrosine and DOPA in cataractous lenses is accompanied by a lower protein and phenylalanine content of the water-soluble phase." Free Radic Res 39(12);1359-66. PMID: 16298866

Nandi79: Nandi DL, Lucas SV, Webster LT (1979). "Benzoyl-coenzyme A:glycine N-acyltransferase and phenylacetyl-coenzyme A:glycine N-acyltransferase from bovine liver mitochondria. Purification and characterization." J Biol Chem 254(15);7230-7. PMID: 457678

Nishimura66: Nishimura T, Gjessing LR (1966). "Studies on urinary phenolic compounds in man. 3. excretion of o-tyramine." Scand J Clin Lab Invest 18(2);217-20. PMID: 5914747

Panoutsopoulos04: Panoutsopoulos GI, Kouretas D, Gounaris EG, Beedham C (2004). "Metabolism of 2-phenylethylamine and phenylacetaldehyde by precision-cut guinea pig fresh liver slices." Eur J Drug Metab Pharmacokinet 29(2);111-8. PMID: 15230339

Panoutsopoulos04a: Panoutsopoulos GI, Kouretas D, Gounaris EG, Beedham C (2004). "Enzymatic oxidation of 2-phenylethylamine to phenylacetic acid and 2-phenylethanol with special reference to the metabolism of its intermediate phenylacetaldehyde." Basic Clin Pharmacol Toxicol 95(6);273-9. PMID: 15569272

Sabelli83: Sabelli HC, Fawcett J, Gusovsky F, Javaid J, Edwards J, Jeffriess H (1983). "Urinary phenyl acetate: a diagnostic test for depression?." Science 220(4602);1187-8. PMID: 6857245

Sivaraman06: Sivaraman S, Kirsch JF (2006). "The narrow substrate specificity of human tyrosine aminotransferase--the enzyme deficient in tyrosinemia type II." FEBS J 273(9);1920-9. PMID: 16640556

Suzuki79: Suzuki O, Oya M, Katsumata Y (1979). "Oxidation of p-, m- and o-tyramine by type A and type B monoamine oxidase." Biochem Pharmacol 28(17);2682-4. PMID: 518681

Testa08: Testa B, Kramer SD (2008). "The biochemistry of drug metabolism--an introduction: part 4. reactions of conjugation and their enzymes." Chem Biodivers 5(11);2171-336. PMID: 19035562

Vessey03: Vessey DA, Lau E, Kelley M, Warren RS (2003). "Isolation, sequencing, and expression of a cDNA for the HXM-A form of xenobiotic/medium-chain fatty acid:CoA ligase from human liver mitochondria." J Biochem Mol Toxicol 17(1);1-6. PMID: 12616642

Vessey98: Vessey DA, Lau E (1998). "Determination of the sequence of the arylacetyl acyl-CoA:amino acid N-acyltransferase from bovine liver mitochondria and its homology to the aralkyl acyl-CoA:amino acid N-acyltransferase." J Biochem Mol Toxicol 12(5);275-9. PMID: 9664233

Vessey99: Vessey DA, Kelley M, Warren RS (1999). "Characterization of the CoA ligases of human liver mitochondria catalyzing the activation of short- and medium-chain fatty acids and xenobiotic carboxylic acids." Biochim Biophys Acta 1428(2-3);455-62. PMID: 10434065

Wada04: Wada M (2004). "Measurement of hepatic phenylalanine metabolism in children using the [(13)C]-phenylalanine breath test and gas chromatography-mass spectrometry." J Chromatogr B Analyt Technol Biomed Life Sci 806(1);5-10. PMID: 15149604

Watson92a: Watson DG, McGhee CN, Midgley JM, Zhou P, Doig WM (1992). "Determination of acidic metabolites of biogenic amines in human aqueous humour by gas chromatography--negative ion chemical ionisation mass spectrometry." J Neurochem 58(1);116-20. PMID: 1727423

Webster76: Webster LT, Siddiqui UA, Lucas SV, Strong JM, Mieyal JJ (1976). "Identification of separate acyl- CoA:glycine and acyl-CoA:L-glutamine N-acyltransferase activities in mitochondrial fractions from liver of rhesus monkey and man." J Biol Chem 251(11);3352-8. PMID: 931988

Williams08: Williams RA, Mamotte CD, Burnett JR (2008). "Phenylketonuria: an inborn error of phenylalanine metabolism." Clin Biochem Rev 29(1);31-41. PMID: 18566668

Yang73: Yang HY, Neff NH (1973). "Beta-phenylethylamine: a specific substrate for type B monoamine oxidase of brain." J Pharmacol Exp Ther 187(2);365-71. PMID: 4748552

Young82: Young SN, Davis BA, Gauthier S (1982). "Precursors and metabolites of phenylethylamine, m and p-tyramine and tryptamine in human lumbar and cisternal cerebrospinal fluid." J Neurol Neurosurg Psychiatry 45(7);633-9. PMID: 6181210

Zhu92: Zhu MY, Juorio AV, Paterson IA, Boulton AA (1992). "Regulation of aromatic L-amino acid decarboxylase by dopamine receptors in the rat brain." J Neurochem 58(2);636-41. PMID: 1729407

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

Aarenstrup02: Aarenstrup L, Falch AM, Jakobsen KK, Neve S, Henriksen L LO, Tommerup N, Leffers H, Kristiansen K (2002). "Expression and post-translational modification of human 4-hydroxy-phenylpyruvate dioxygenase." Cell Biol Int 26(7);615-25. PMID: 12127941

Agarwal87: Agarwal DP, Goedde HW (1987). "Human aldehyde dehydrogenase isozymes and alcohol sensitivity." Isozymes Curr Top Biol Med Res 16;21-48. PMID: 3610592

Albert92: Albert VR, Lee MR, Bolden AH, Wurzburger RJ, Aguanno A (1992). "Distinct promoters direct neuronal and nonneuronal expression of rat aromatic L-amino acid decarboxylase." Proc Natl Acad Sci U S A 89(24);12053-7. PMID: 1465439

Arias08: Arias S, Olivera ER, Arcos M, Naharro G, Luengo JM (2008). "Genetic analyses and molecular characterization of the pathways involved in the conversion of 2-phenylethylamine and 2-phenylethanol into phenylacetic acid in Pseudomonas putida U." Environ Microbiol 10(2);413-32. PMID: 18177365

Asaoka91: Asaoka K (1991). "Enzymes that metabolize acyl-coenzyme A in the monkey--their distribution, properties and roles in an alternative pathway for the excretion of nitrogen." Int J Biochem 23(4);429-34. PMID: 1673104

Ashibe07: Ashibe B, Hirai T, Higashi K, Sekimizu K, Motojima K (2007). "Dual subcellular localization in the endoplasmic reticulum and peroxisomes and a vital role in protecting against oxidative stress of fatty aldehyde dehydrogenase are achieved by alternative splicing." J Biol Chem 282(28);20763-73. PMID: 17510064

Awata94: Awata H, Endo F, Matsuda I (1994). "Structure of the human 4-hydroxyphenylpyruvic acid dioxygenase gene (HPD)." Genomics 23(3);534-9. PMID: 7851880

Bach88: Bach AW, Lan NC, Johnson DL, Abell CW, Bembenek ME, Kwan SW, Seeburg PH, Shih JC (1988). "cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties." Proc Natl Acad Sci U S A 85(13);4934-8. PMID: 3387449

Beltrametti97: Beltrametti F, Marconi AM, Bestetti G, Colombo C, Galli E, Ruzzi M, Zennaro E (1997). "Sequencing and functional analysis of styrene catabolism genes from Pseudomonas fluorescens ST." Appl Environ Microbiol 63(6);2232-9. PMID: 9172343

Binda02: Binda C, Newton-Vinson P, Hubalek F, Edmondson DE, Mattevi A (2002). "Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders." Nat Struct Biol 9(1);22-6. PMID: 11753429

Binda04: Binda C, Hubalek F, Li M, Herzig Y, Sterling J, Edmondson DE, Mattevi A (2004). "Crystal structures of monoamine oxidase B in complex with four inhibitors of the N-propargylaminoindan class." J Med Chem 47(7);1767-74. PMID: 15027868

Binda04a: Binda C, Hubalek F, Li M, Edmondson DE, Mattevi A (2004). "Crystal structure of human monoamine oxidase B, a drug target enzyme monotopically inserted into the mitochondrial outer membrane." FEBS Lett 564(3);225-8. PMID: 15111100

Braun87: Braun T, Bober E, Singh S, Agarwal DP, Goedde HW (1987). "Evidence for a signal peptide at the amino-terminal end of human mitochondrial aldehyde dehydrogenase." FEBS Lett 215(2);233-6. PMID: 3582651

BRENDA14: BRENDA team (2014). Imported from BRENDA version existing on Aug 2014.

Burkhard01: Burkhard P, Dominici P, Borri-Voltattorni C, Jansonius JN, Malashkevich VN (2001). "Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase." Nat Struct Biol 8(11);963-7. PMID: 11685243

Cechetto02: Cechetto JD, Sadacharan SK, Berk PD, Gupta RS (2002). "Immunogold localization of mitochondrial aspartate aminotransferase in mitochondria and on the cell surface in normal rat tissues." Histol Histopathol 17(2);353-64. PMID: 11962739

Cesura90: Cesura AM, Imhof R, Muggli-Maniglio D, Picotti GB, Da Prada M (1990). "Characterization of [3H]Ro 16-6491 binding to digitonin solubilized monoamine oxidase-B and purification of the enzyme from human platelets by affinity chromatography." Biochem Pharmacol 39(1);216-20. PMID: 2297358

Chang97a: Chang C, Yoshida A (1997). "Human fatty aldehyde dehydrogenase gene (ALDH10): organization and tissue-dependent expression." Genomics 40(1);80-5. PMID: 9070922

Christenson72: Christenson JG, Dairman W, Udenfriend S (1972). "On the identity of DOPA decarboxylase and 5-hydroxytryptophan decarboxylase (immunological titration-aromatic L-amino acid decarboxylase-serotonin-dopamine-norepinephrine)." Proc Natl Acad Sci U S A 69(2);343-7. PMID: 4536745

Chuang74: Chuang HY, Patek DR, Hellerman L (1974). "Mitochondrial monoamine oxidase. Inactivation by pargyline. Adduct formation." J Biol Chem 249(8);2381-4. PMID: 4822497

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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