If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Degradation/Utilization/Assimilation → Amino Acids Degradation → 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 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 126.96.36.199). This was supported by later work that showed a narrow substrate specificity for human tyrosine aminotransfrase (EC 188.8.131.52), 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 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 184.108.40.206) and possibly also by aldehyde oxidase (EC 220.127.116.11) and xanthine oxidase (18.104.22.168). 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 22.214.171.124 through EC 126.96.36.199) (note that EC 188.8.131.52 is a microbial enzyme). The mitochondrial medium-chain CoA ligase EC 184.108.40.206 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 [Watson92]. 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
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