If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Degradation/Utilization/Assimilation → Amino Acids Degradation → Proteinogenic Amino Acids Degradation → L-phenylalanine Degradation|
Expected Taxonomic Range: Metazoa
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 184.108.40.206). This was supported by later work that showed a narrow substrate specificity for human tyrosine aminotransfrase (EC 220.127.116.11), 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 18.104.22.168) and possibly also by aldehyde oxidase (EC 22.214.171.124) and xanthine oxidase (126.96.36.199). 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 188.8.131.52 through EC 184.108.40.206) (note that EC 220.127.116.11 is a microbial enzyme). The mitochondrial medium-chain CoA ligase EC 18.104.22.168 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].
Unification Links: KEGG:map00360
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
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
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
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
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
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
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
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
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
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
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
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
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
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