Phenylalanine and tyrosine metabolism (Homo sapiens)

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9, 10, 12, 1411, 15164, 51, 6, 20132, 73, 8, 17, 2119, 2218cytosolHPD PXLP-KYAT1 dimer4MAAH+PAH:Fe2+ tetramerASRGL1 heterodimerHPPYRAFUMAO2NH33IN-PYRA4FAAQDPR qDHBPCBD1 tetramerkPPVFAH HGTAFAD TAT dimerAscH- Fe2+ L-TyrO2H2OL-GluO2QDPR dimerMeOHaspartamePYR4aOH-BH42OGFe2+ L-AspH2OH2O2L-PheIL4I1 H2OBH4ACAPXLP-K280-TAT O2CO2GSTZ1 ASRGL1(1-167) HGD hexamerHPD:AscH-:Fe2+ dimerL-AlaPCBD1 ASRGL1(168-308) GSH NADHHGD IL4I1:FADFe2+ PXLP-K247-KYAT1 PAH H2ONAD+FAH dimerL-PheGSTZ1 dimer1, 629, 149, 10, 142, 7151916


Description

The hydroxylation of phenylalanine, an essential amino acid, to form tyrosine is a major source of the latter amino acid in the body under normal conditions and is also the first step in phenylalanine catabolism. To continue the catabolic process, tyrosine is transaminated to 3-(4-hydroxyphenyl)pyruvate which is broken down to fumarate and acetoacetate (Blau et al. 2001; Mitchell et al. 2001). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8963691
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Jassal, Bijay

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Bibliography

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  1. Hauer CR, Rebrin I, Thöny B, Neuheiser F, Curtius HC, Hunziker P, Blau N, Ghisla S, Heizmann CW.; ''Phenylalanine hydroxylase-stimulating protein/pterin-4 alpha-carbinolamine dehydratase from rat and human liver. Purification, characterization, and complete amino acid sequence.''; PubMed Europe PMC Scholia
  2. Su Y, Varughese KI, Xuong NH, Bray TL, Roche DJ, Whiteley JM.; ''The crystallographic structure of a human dihydropteridine reductase NADH binary complex expressed in Escherichia coli by a cDNA constructed from its rat homologue.''; PubMed Europe PMC Scholia
  3. Li W, Cantor JR, Yogesha SD, Yang S, Chantranupong L, Liu JQ, Agnello G, Georgiou G, Stone EM, Zhang Y.; ''Uncoupling intramolecular processing and substrate hydrolysis in the N-terminal nucleophile hydrolase hASRGL1 by circular permutation.''; PubMed Europe PMC Scholia
  4. Fernández-Cañón JM, Granadino B, Beltrán-Valero de Bernabé D, Renedo M, Fernández-Ruiz E, Peñalva MA, Rodríguez de Córdoba S.; ''The molecular basis of alkaptonuria.''; PubMed Europe PMC Scholia
  5. Titus GP, Mueller HA, Burgner J, Rodríguez De Córdoba S, Peñalva MA, Timm DE.; ''Crystal structure of human homogentisate dioxygenase.''; PubMed Europe PMC Scholia
  6. Ficner R, Sauer UH, Stier G, Suck D.; ''Three-dimensional structure of the bifunctional protein PCD/DCoH, a cytoplasmic enzyme interacting with transcription factor HNF1.''; PubMed Europe PMC Scholia
  7. Lockyer J, Cook RG, Milstien S, Kaufman S, Woo SL, Ledley FD.; ''Structure and expression of human dihydropteridine reductase.''; PubMed Europe PMC Scholia
  8. Cantor JR, Stone EM, Chantranupong L, Georgiou G.; ''The human asparaginase-like protein 1 hASRGL1 is an Ntn hydrolase with beta-aspartyl peptidase activity.''; PubMed Europe PMC Scholia
  9. Rossi F, Han Q, Li J, Li J, Rizzi M.; ''Crystal structure of human kynurenine aminotransferase I.''; PubMed Europe PMC Scholia
  10. Baran H, Okuno E, Kido R, Schwarcz R.; ''Purification and characterization of kynurenine aminotransferase I from human brain.''; PubMed Europe PMC Scholia
  11. Lindblad B, Lindstedt G, Lindstedt S.; ''The mechanism of enzymic formation of homogentisate from p-hydroxyphenylpyruvate.''; PubMed Europe PMC Scholia
  12. Perry S, Harries H, Scholfield C, Lock T, King L, Gibson G, Goldfarb P.; ''Molecular cloning and expression of a cDNA for human kidney cysteine conjugate beta-lyase.''; PubMed Europe PMC Scholia
  13. Labelle Y, Phaneuf D, Leclerc B, Tanguay RM.; ''Characterization of the human fumarylacetoacetate hydrolase gene and identification of a missense mutation abolishing enzymatic activity.''; PubMed Europe PMC Scholia
  14. Han Q, Robinson H, Cai T, Tagle DA, Li J.; ''Structural insight into the inhibition of human kynurenine aminotransferase I/glutamine transaminase K.''; PubMed Europe PMC Scholia
  15. Rüetschi U, Cerone R, Pérez-Cerda C, Schiaffino MC, Standing S, Ugarte M, Holme E.; ''Mutations in the 4-hydroxyphenylpyruvate dioxygenase gene (HPD) in patients with tyrosinemia type III.''; PubMed Europe PMC Scholia
  16. Polekhina G, Board PG, Blackburn AC, Parker MW.; ''Crystal structure of maleylacetoacetate isomerase/glutathione transferase zeta reveals the molecular basis for its remarkable catalytic promiscuity.''; PubMed Europe PMC Scholia
  17. Nomme J, Su Y, Lavie A.; ''Elucidation of the specific function of the conserved threonine triad responsible for human L-asparaginase autocleavage and substrate hydrolysis.''; PubMed Europe PMC Scholia
  18. Boulland ML, Marquet J, Molinier-Frenkel V, Möller P, Guiter C, Lasoudris F, Copie-Bergman C, Baia M, Gaulard P, Leroy K, Castellano F.; ''Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation.''; PubMed Europe PMC Scholia
  19. Fusetti F, Erlandsen H, Flatmark T, Stevens RC.; ''Structure of tetrameric human phenylalanine hydroxylase and its implications for phenylketonuria.''; PubMed Europe PMC Scholia
  20. Citron BA, Kaufman S, Milstien S, Naylor EW, Greene CL, Davis MD.; ''Mutation in the 4a-carbinolamine dehydratase gene leads to mild hyperphenylalaninemia with defective cofactor metabolism.''; PubMed Europe PMC Scholia
  21. Nomme J, Su Y, Konrad M, Lavie A.; ''Structures of apo and product-bound human L-asparaginase: insights into the mechanism of autoproteolysis and substrate hydrolysis.''; PubMed Europe PMC Scholia
  22. Guldberg P, Mallmann R, Henriksen KF, Güttler F.; ''Phenylalanine hydroxylase deficiency in a population in Germany: mutational profile and nine novel mutations.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114751view16:23, 25 January 2021ReactomeTeamReactome version 75
113195view11:26, 2 November 2020ReactomeTeamReactome version 74
112796view17:50, 9 October 2020DeSlOntology Term : 'phenylalanine metabolic pathway' added !
112795view17:50, 9 October 2020DeSlOntology Term : 'tyrosine metabolic pathway' added !
112747view16:15, 9 October 2020ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
2OGMetaboliteCHEBI:16810 (ChEBI)
3IN-PYRAMetaboliteCHEBI:29750 (ChEBI)
4FAAMetaboliteCHEBI:18034 (ChEBI)
4MAAMetaboliteCHEBI:17105 (ChEBI)
4aOH-BH4MetaboliteCHEBI:15374 (ChEBI)
ACAMetaboliteCHEBI:13705 (ChEBI)
ASRGL1 heterodimerComplexR-HSA-5696373 (Reactome)
ASRGL1(1-167) ProteinQ7L266 (Uniprot-TrEMBL)
ASRGL1(168-308) ProteinQ7L266 (Uniprot-TrEMBL)
AscH- MetaboliteCHEBI:38290 (ChEBI)
BH4MetaboliteCHEBI:15372 (ChEBI)
CO2MetaboliteCHEBI:16526 (ChEBI)
FAD MetaboliteCHEBI:16238 (ChEBI)
FAH ProteinP16930 (Uniprot-TrEMBL)
FAH dimerComplexR-HSA-71175 (Reactome)
FUMAMetaboliteCHEBI:37154 (ChEBI)
Fe2+ MetaboliteCHEBI:29033 (ChEBI)
GSH MetaboliteCHEBI:16856 (ChEBI)
GSTZ1 ProteinO43708 (Uniprot-TrEMBL)
GSTZ1 dimerComplexR-HSA-71166 (Reactome)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HGD ProteinQ93099 (Uniprot-TrEMBL)
HGD hexamerComplexR-HSA-71076 (Reactome)
HGTAMetaboliteCHEBI:16169 (ChEBI)
HPD ProteinP32754 (Uniprot-TrEMBL)
HPD:AscH-:Fe2+ dimerComplexR-HSA-71161 (Reactome)
HPPYRAMetaboliteCHEBI:15999 (ChEBI)
IL4I1 ProteinQ96RQ9 (Uniprot-TrEMBL)
IL4I1:FADComplexR-HSA-2160485 (Reactome)
L-AlaMetaboliteCHEBI:57972 (ChEBI)
L-AspMetaboliteCHEBI:29991 (ChEBI)
L-GluMetaboliteCHEBI:29985 (ChEBI)
L-PheMetaboliteCHEBI:58095 (ChEBI)
L-TyrMetaboliteCHEBI:58315 (ChEBI)
MeOHMetaboliteCHEBI:17790 (ChEBI)
NAD+MetaboliteCHEBI:57540 (ChEBI)
NADHMetaboliteCHEBI:57945 (ChEBI)
NH3MetaboliteCHEBI:16134 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PAH ProteinP00439 (Uniprot-TrEMBL)
PAH:Fe2+ tetramerComplexR-HSA-71068 (Reactome)
PCBD1 ProteinP61457 (Uniprot-TrEMBL)
PCBD1 tetramerComplexR-HSA-71132 (Reactome)
PXLP-K247-KYAT1 ProteinQ16773 (Uniprot-TrEMBL)
PXLP-K280-TAT ProteinP17735 (Uniprot-TrEMBL)
PXLP-KYAT1 dimerComplexR-HSA-893603 (Reactome)
PYRMetaboliteCHEBI:15361 (ChEBI)
QDPR ProteinP09417 (Uniprot-TrEMBL)
QDPR dimerComplexR-HSA-71120 (Reactome)
TAT dimerComplexR-HSA-71153 (Reactome)
aspartameMetaboliteCHEBI:2877 (ChEBI)
kPPVMetaboliteCHEBI:18005 (ChEBI)
qDHBMetaboliteCHEBI:20680 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2OGArrowR-HSA-517444 (Reactome)
2OGR-HSA-71155 (Reactome)
3IN-PYRAArrowR-HSA-893593 (Reactome)
4FAAArrowR-HSA-71173 (Reactome)
4FAAR-HSA-71181 (Reactome)
4MAAArrowR-HSA-71164 (Reactome)
4MAAR-HSA-71173 (Reactome)
4aOH-BH4ArrowR-HSA-71118 (Reactome)
4aOH-BH4R-HSA-71146 (Reactome)
ACAArrowR-HSA-71181 (Reactome)
ASRGL1 heterodimermim-catalysisR-HSA-5696365 (Reactome)
BH4ArrowR-HSA-71130 (Reactome)
BH4R-HSA-71118 (Reactome)
CO2ArrowR-HSA-71163 (Reactome)
FAH dimermim-catalysisR-HSA-71181 (Reactome)
FUMAArrowR-HSA-71181 (Reactome)
GSTZ1 dimermim-catalysisR-HSA-71173 (Reactome)
H+R-HSA-71130 (Reactome)
H2O2ArrowR-HSA-2160492 (Reactome)
H2OArrowR-HSA-71146 (Reactome)
H2OR-HSA-2160492 (Reactome)
H2OR-HSA-5696365 (Reactome)
H2OR-HSA-71181 (Reactome)
HGD hexamermim-catalysisR-HSA-71164 (Reactome)
HGTAArrowR-HSA-71163 (Reactome)
HGTAR-HSA-71164 (Reactome)
HPD:AscH-:Fe2+ dimermim-catalysisR-HSA-71163 (Reactome)
HPPYRAArrowR-HSA-71155 (Reactome)
HPPYRAR-HSA-517444 (Reactome)
HPPYRAR-HSA-71163 (Reactome)
IL4I1:FADmim-catalysisR-HSA-2160492 (Reactome)
L-AlaArrowR-HSA-893593 (Reactome)
L-AspArrowR-HSA-5696365 (Reactome)
L-GluArrowR-HSA-71155 (Reactome)
L-GluR-HSA-517444 (Reactome)
L-PheArrowR-HSA-5696365 (Reactome)
L-PheR-HSA-2160492 (Reactome)
L-PheR-HSA-71118 (Reactome)
L-PheR-HSA-893593 (Reactome)
L-TyrArrowR-HSA-517444 (Reactome)
L-TyrArrowR-HSA-71118 (Reactome)
L-TyrR-HSA-71155 (Reactome)
MeOHArrowR-HSA-5696365 (Reactome)
NAD+ArrowR-HSA-71130 (Reactome)
NADHR-HSA-71130 (Reactome)
NH3ArrowR-HSA-2160492 (Reactome)
O2R-HSA-2160492 (Reactome)
O2R-HSA-71118 (Reactome)
O2R-HSA-71163 (Reactome)
O2R-HSA-71164 (Reactome)
PAH:Fe2+ tetramermim-catalysisR-HSA-71118 (Reactome)
PCBD1 tetramermim-catalysisR-HSA-71146 (Reactome)
PXLP-KYAT1 dimermim-catalysisR-HSA-893593 (Reactome)
PYRR-HSA-893593 (Reactome)
QDPR dimermim-catalysisR-HSA-71130 (Reactome)
R-HSA-2160492 (Reactome) Extracellular L-amino-acid oxidase (IL4I1) catalyzes the reaction of phenylalanine, water, and molecular oxygen to form keto-phenylpyruvate, ammonia, and hydrogen peroxide. IL4I1, inferred to form a complex with FAD, has L-amino acid oxidase activity and with a strong preference for phenylalanine. The enzyme, found both in lysosomes and secreted into the extracellular space, is produced in the body by myeloid and dedritic cells (Boulland et al. 2007).
R-HSA-517444 (Reactome) Cytosolic tyrosine aminotransferase (TAT) catalyzes the reversible reaction of 3-(4-hydroxyphenyl)pyruvate and glutamate to form tyrosine and alpha-keto (2-oxo) glutarate (Mitchell et al. 2001). The enzymatic activity of the protein encoded by the cloned human TAT cDNA is inferred from the biochemical properties of its rat homologue. Unpublished crystallographic studies (PDB 3DYD) have shown TAT to be a homodimer with a pyridoxal phosphate moity attached to lysine-280 in each monomer.
R-HSA-5696365 (Reactome) The human isoaspartyl peptidase/L-asparaginase (ASRGL1) is an N-terminal nucleophile (Ntn) hydrolase superfamily member that catalyses the hydrolysis of l-asparagine and beta-aspartyl-dipeptides and their methyl esters such as aspartame (beta-L-Asp-L-Phe methyl ester) (Cantor et al. 2009, Li et al. 2012, Nomme et al. 2014). ASRGL1 is a cytosolic enzyme that is active as a heterodimer of alpha and beta chains, formed by autocleavage between Gly167 and Thr168 (Nomme et al. 2012). ASRGL1 is expressed in brain, kidney, testis and the gastrointestinal tract. Aspartame is an artificial sweetner used as a sugar substitute in some drinks. Sufferers of phenylketonuria (PKU) are advised to avoid aspartame as one of its breakdown products, phenylalanine, could contribute to the excess pool of phenylalanine that PKU sufferers cannot metabolise from the body.
R-HSA-71118 (Reactome) Inactivating mutations of cytosolic phenylalanine hydroxylase (PAH) block the normal reaction of phenylalanine, molecular oxygen and tetrahydrobiopterin to form tyrosine, water, and 4 alpha-hydroxytetrahydrobiopterin. Excess phenylalanine accumulates as a result, driving the formation of abnormally high levels of phenylpyruvate, and phenyllactate (Guldberg et al. 1996; Mitchell et al. 2011) in reactions not annotated here.
R-HSA-71130 (Reactome) Cytosolic dihydropteridine reductase (QDPR) catalyzes the reaction of q-dihydrobiopterin with NADH + H+to form tetrahydrobiopterin and NAD+. The enzyme is a homodimer (Lockyer et al. 1987; Su et al. 1993).
R-HSA-71146 (Reactome) Cytosolic pterin-4-alpha-carbinolamine dehydratase (PCDB1) catalyzes the reaction of 4a-hydroxytetrahydrobiopterin to form q-dihydrobiopterin and water (Hauer et al. 1993. The active enzyme is a homotetramer (Ficner et al. 1995); mutations in the PCDB1 gene are associated with mild hyperphenylalanemia in vivo (Citron et al. 1993).
R-HSA-71155 (Reactome) Cytosolic tyrosine aminotransferase (TAT) catalyzes the reversible reaction of tyrosine and alpha-keto (2-oxo) glutarate to form 3-(4-hydroxyphenyl)pyruvate and glutamate (Mitchell et al. 2001). The enzymatic activity of the protein encoded by the cloned human TAT cDNA is inferred from the biochemical properties of its rat homologue. Unpublished crystallographic studies (PDB 3DYD) have shown TAT to be a homodimer with a pyridoxal phosphate moity attached to lysine-280 in each monomer.
R-HSA-71163 (Reactome) Cytosolic 4-hydroxyphenylpyruvate dioxygenase (HPD) catalyzes the reaction of 3-(4-Hydroxyphenyl)pyruvate with molecular oxygen to form homogentisate and CO2 (Ruetschi et al. 2000, Lindblad et al. 1970). Unpublished crystallographic data indicate that the enzyme is a homodimer (PDB 3ISQ) utilising Fe2+ and ascorbate (AscH-).
R-HSA-71164 (Reactome) Cytosolic homogentisate 1,2-dioxygenase (HGD) catalyzes the reaction of homogentisate and molecular oxygen to form 4-maleylacetoacetate. The activity of human HGD is inferred from the phenotype of alkaptonuria patients, in whom HGD activity is defective (Fernandez-Canon et al. 1996). HGD is a homohexamer (Titus et al. 2000).
R-HSA-71173 (Reactome) Cytosolic maleylacetoacetic acid isomerase (GSTZ1) catalyzes the conversion of 4-maleylacetoacetate to 4-fumarylacetoacetate. The enzyme is a homodimer (Polekhina et al. 2001).
R-HSA-71181 (Reactome) This is the final step of tyrosine degradation. Fumarylacetoacetase catalyzes the hydrolysis of 4-fumarylacetoacetate to form fumarate and acetoacetate (Labelle et al. 1993).
R-HSA-893593 (Reactome) CCBL1 (KAT 1) catalyzes the reaction of phenylalanine and pyruvate to form 3-(indol-3-yl)pyruvate and alanine. The active form of CCBL1 is a homodimer with one molecule of pyridoxal phosphate bound to each monomer (Baran et al. 1994; Han et al. 2009; Rossi et al. 2004). The enzyme's cytosolic localization is inferred from that of recombinant protein overexpressed in transfected cells (Perry et al. 1995).
TAT dimermim-catalysisR-HSA-517444 (Reactome)
TAT dimermim-catalysisR-HSA-71155 (Reactome)
aspartameR-HSA-5696365 (Reactome)
kPPVArrowR-HSA-2160492 (Reactome)
qDHBArrowR-HSA-71146 (Reactome)
qDHBR-HSA-71130 (Reactome)
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