| Tyrosine transaminase |
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Human tyrosine aminotransferase (rainbow colored, N-terminus = blue, C-terminus = red) complexed with pyridoxal phosphate (space-filling model).[1]
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| Identifiers |
| EC number |
2.6.1.5 |
| CAS number |
9014-55-5 |
| Databases |
| IntEnz |
IntEnz view |
| BRENDA |
BRENDA entry |
| ExPASy |
NiceZyme view |
| KEGG |
KEGG entry |
| MetaCyc |
metabolic pathway |
| PRIAM |
profile |
| PDB structures |
RCSB PDB PDBe PDBsum |
| Gene Ontology |
AmiGO / EGO |
| Search |
| PMC |
articles |
| PubMed |
articles |
| NCBI |
proteins |
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| Tyrosine aminotransferase |
| Available structures |
| PDB |
Ortholog search: PDBe, RCSB |
| List of PDB id codes |
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3DYD
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| Identifiers |
| Symbol |
TAT |
| External IDs |
OMIM: 613018 HomoloGene: 37293 GeneCards: TAT Gene |
| EC number |
2.6.1.5 |
| Gene ontology |
| Molecular function |
• L-tyrosine:2-oxoglutarate aminotransferase activity
• amino acid binding
• pyridoxal phosphate binding
• L-phenylalanine:2-oxoglutarate aminotransferase activity
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| Cellular component |
• cellular_component
• mitochondrion
• cytosol
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| Biological process |
• 2-oxoglutarate metabolic process
• glutamate metabolic process
• L-phenylalanine catabolic process
• tyrosine catabolic process
• response to oxidative stress
• biosynthetic process
• cellular nitrogen compound metabolic process
• small molecule metabolic process
• response to mercury ion
• response to glucocorticoid
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| Sources: Amigo / QuickGO |
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| Orthologs |
| Species |
Human |
Mouse |
| Entrez |
6898 |
234724 |
| Ensembl |
ENSG00000198650 |
ENSMUSG00000001670 |
| UniProt |
P17735 |
Q8QZR1 |
| RefSeq (mRNA) |
NM_000353 |
NM_146214 |
| RefSeq (protein) |
NP_000344 |
NP_666326 |
| Location (UCSC) |
Chr 16:
71.57 – 71.58 Mb |
Chr 8:
109.99 – 110 Mb |
| PubMed search |
[1] |
[2] |
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Tyrosine aminotransferase (or tyrosine transaminase) is an enzyme present in the liver and catalyzes the conversion of tyrosine to 4-hydroxyphenylpyruvate.[2] In humans, the tyrosine aminotransferase protein is encoded by the TAT gene. A deficiency of the enzyme in humans can result in what is known as Type II Tyrosinemia, wherein there is an abundance of tyrosine as a result of tyrosine failing to undergo an aminotransferase reaction to form 4-hydroxyphenylpyruvate.[3]
Contents
- 1 Mechanism
- 2 Active Site
- 3 Pathology
- 4 References
- 5 External links
Mechanism
Structures of the three main molecules involved in chemical reaction catalyzed by the tyrosine aminotransferase enzyme are shown below: the amino acid tyrosine, the prosthetic group pyridoxal phosphate, and the resulting product 4-hydroxyphenylpyruvate.
Ribbon diagram of the tyrosine aminotransferase dimer. The prosthetic group PLP is visible in both monomers.
[4]
Each side of the dimer protein includes pyridoxal phosphate (PLP) bonded to the Lys280 residue of the tyrosine aminotransferase molecule. The amine group of tyrosine attacks the alpha carbon of the imine bonded to Lys280, forming a tetrahedral complex and then kicking off the LYS-ENZ. This process is known as transimination by the act of switching out the imine group bonded to PLP. The newly formed PLP-TYR molecule is then attacked by a base.
Ball & stick diagram of the TAT amino acid Lys280 linked to PLP.
[1]
A possible candidate for the base in the mechanism could be Lys280 that was just pushed off of PLP, which sequesters the newly formed amino group of the PLP-TYR molecule. In a similar mechanism of aspartate transaminase, the lysine that forms the initial imine to PLP later acts as the base that attacks the tyrosine in transimination. The electrons left behind from the loss of the proton move down to form a new double bond to the imine, which in turn pushes the already double bonded electrons through PLP and end up as a lone pair on the positively charged nitrogen in the six-membered ring of the molecule. Water attacks the alpha carbon of the imine of PLP-TYR and through acyl substitution kicks off the nitrogen of PLP and forming pyridoxamine phosphate (PMP) and 4-hydroxyphenylpyruvate.
PMP is then regenerated into PLP by transferring its amine group to alpha-ketoglutarate, reforming it's aldehyde functional group. This is followed by another substitution reaction with the Lys280 residue to reform its imine linkage to the enzyme, forming ENZ-PLP.
Active Site
Space filling model depicting non-polar amino acid side chains Phe169 and Ile249. Notice sandwich effect of the two groups to hold PLP in the correct orientation
Tyrosine Aminotransferase as a dimer has two identical active sights. Lys280 is attached to PLP, which is held in place via two nonpolar amino acid side chains; phenylalanine and isoleucine (see thumbnail on right). The PLP is also held in place by hydrogen bonding to surrounding molecules mainly by its phosphate group.
Shown below is one active site at three different magnifications:
Pathology
Tyrosinemia is the most common metabolic disease associated with tyrosine aminotransferase. The disease results from a deficiency in hepatic tyrosine aminotransferase.[5] Tyrosinemia type II (Richner-Hanhart syndrome, RHS) is a disease of autosomal recessive inheritance characterized by keratitis, palmoplantar hyperkeratosis, mental retardation, and elevated blood tyrosine levels.[5] Keratitis in Tyrosinemia type II patients is caused by the deposition of tyrosine crystals in the cornea and results in corneal inflammation.[6] The TAT gene is located on human chromosome 16q22-24 and extends over 10.9 kilobases (kb) containing 12 exons, and its 3.0 kb mRNA codes for a 454-amino acid protein of 50.4 kDa.[7] Twelve different TAT gene mutations have been reported.[7]
References
- ^ a b PDB: 3DYD ; Karlberg T, Moche M, Andersson J et al. (2008). "Human tyrosine aminotransferase". To be Published.
- ^ Dietrich JB (April 1992). "Tyrosine aminotransferase: a transaminase among others?". Cellular and molecular biology 38 (2): 95–114. PMID 1349265.
- ^ Rettenmeier R, Natt E, Zentgraf H, Scherer G (July 1990). "Isolation and characterization of the human tyrosine aminotransferase gene". Nucleic Acids Res. 18 (13): 3853–61. doi:10.1093/nar/18.13.3853. PMC 331086. PMID 1973834.
- ^ Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E.C., and Ferrin, T.E. (2004). "UCSF Chimera - A Visualization System for Exploratory Research and Analysis.". Comput. Chem. 25 (13): 1605–1612. doi:10.1002/jcc.20084. PMID 15264254.
- ^ a b Natt E, Kida K, Odievre M, Di Rocco M, Scherer G (October 1992). "Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II". Proc. Natl. Acad. Sci. U.S.A. 89 (19): 9297–301. doi:10.1073/pnas.89.19.9297. PMC 50113. PMID 1357662.
- ^ al-Hemidan AI, al-Hazzaa SA (March 1995). "Richner-Hanhart syndrome (tyrosinemia type II). Case report and literature review". Ophthalmic Genet. 16 (1): 21–6. doi:10.3109/13816819509057850. PMID 7648039.
- ^ a b Minami-Hori M, Ishida-Yamamoto A, Katoh N, Takahashi H, Iizuka H (January 2006). "Richner-Hanhart syndrome: report of a case with a novel mutation of tyrosine aminotransferase". J. Dermatol. Sci. 41 (1): 82–4. doi:10.1016/j.jdermsci.2005.10.007. PMID 16318910.
Molecular graphics images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR-01081).
External links
- Tyrosine aminotransferase at the US National Library of Medicine Medical Subject Headings (MeSH)
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Transferase: nitrogenous groups (EC 2.6)
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| 2.6.1: Transaminases |
- Aspartate transaminase
- Alanine transaminase
- GABA transaminase
- Tyrosine aminotransferase
- Ornithine aminotransferase
- Branched chain aminotransferase
- Alanine—glyoxylate transaminase
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| 2.6.3: Oximinotransferases |
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| 2.6.99: Other |
- Pyridoxine 5'-phosphate synthase
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- Biochemistry overview
- Enzymes overview
- By EC number: 1.1
- 2
- 3
- 4
- 5
- 6
- 7
- 8
- 10
- 11
- 13
- 14
- 15-18
- 2.1
- 3.1
- 4.1
- 5.1
- 6.1-3
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Metabolism: Protein metabolism, synthesis and catabolism enzymes
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Essential amino acids are in Capitals
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| K→acetyl-CoA |
| LYSINE→ |
- Saccharopine dehydrogenase
- Glutaryl-CoA dehydrogenase
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| LEUCINE→ |
- Branched chain aminotransferase
- Branched-chain alpha-keto acid dehydrogenase complex
- Isovaleryl coenzyme A dehydrogenase
- Methylcrotonyl-CoA carboxylase
- Methylglutaconyl-CoA hydratase
- 3-hydroxy-3-methylglutaryl-CoA lyase
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| TRYPTOPHAN→ |
- Indoleamine 2,3-dioxygenase/Tryptophan 2,3-dioxygenase
- Arylformamidase
- Kynureninase
- 3-hydroxyanthranilate oxidase
- Aminocarboxymuconate-semialdehyde decarboxylase
- Aminomuconate-semialdehyde dehydrogenase
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| PHENYLALANINE→tyrosine→ |
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| G |
G→pyruvate
→citrate |
| glycine→serine→ |
- Serine hydroxymethyltransferase
- Serine dehydratase
- glycine→creatine: Guanidinoacetate N-methyltransferase
- Creatine kinase
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| alanine→ |
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| cysteine→ |
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| threonine→ |
- L-threonine dehydrogenase
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G→glutamate→
α-ketoglutarate |
| HISTIDINE→ |
- Histidine ammonia-lyase
- Urocanate hydratase
- Formiminotransferase cyclodeaminase
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| proline→ |
- Proline oxidase
- Pyrroline-5-carboxylate reductase
- 1-Pyrroline-5-carboxylate dehydrogenase/ALDH4A1
- PYCR1
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| arginine→ |
- Ornithine aminotransferase
- Ornithine decarboxylase
- Agmatinase
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| →alpha-ketoglutarate→TCA |
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| Other |
- cysteine+glutamate→glutathione: Gamma-glutamylcysteine synthetase
- Glutathione synthetase
- Gamma-glutamyl transpeptidase
- glutamate→glutamine: Glutamine synthetase
- Glutaminase
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G→propionyl-CoA→
succinyl-CoA |
| VALINE→ |
- Branched chain aminotransferase
- Branched-chain alpha-keto acid dehydrogenase complex
- Enoyl-CoA hydratase
- 3-hydroxyisobutyryl-CoA hydrolase
- 3-hydroxyisobutyrate dehydrogenase
- Methylmalonate semialdehyde dehydrogenase
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| ISOLEUCINE→ |
- Branched chain aminotransferase
- Branched-chain alpha-keto acid dehydrogenase complex
- 3-hydroxy-2-methylbutyryl-CoA dehydrogenase
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| METHIONINE→ |
- generation of homocysteine: Methionine adenosyltransferase
- Adenosylhomocysteinase
- regeneration of methionine: Methionine synthase/Homocysteine methyltransferase
- Betaine-homocysteine methyltransferase
- conversion to cysteine: Cystathionine beta synthase
- Cystathionine gamma-lyase
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| THREONINE→ |
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| →succinyl-CoA→TCA |
- Propionyl-CoA carboxylase
- Methylmalonyl CoA epimerase
- Methylmalonyl-CoA mutase
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| G→fumarate |
| PHENYLALANINE→tyrosine→ |
- Phenylalanine hydroxylase
- Tyrosine aminotransferase
- 4-Hydroxyphenylpyruvate dioxygenase
- Homogentisate 1,2-dioxygenase
- Fumarylacetoacetate hydrolase
- tyrosine→melanin: Tyrosinase
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| G→oxaloacetate |
| asparagine→aspartate→ |
- Asparaginase/Asparagine synthetase
- Aspartate transaminase
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Index of inborn errors of metabolism
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| Description |
- Metabolism
- Enzymes and pathways: citric acid cycle
- pentose phosphate
- glycoproteins
- glycosaminoglycans
- phospholipid
- cholesterol and steroid
- sphingolipids
- eicosanoids
- amino acid
- urea cycle
- nucleotide
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| Disorders |
- Citric acid cycle and electron transport chain
- Glycoprotein
- Proteoglycan
- Fatty-acid
- Phospholipid
- Cholesterol and steroid
- Eicosanoid
- Amino acid
- Purine-pyrimidine
- Heme metabolism
- Symptoms and signs
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| Treatment |
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