| Tyrosine transaminase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Human tyrosine aminotransferase (rainbow colored,N-terminus = blue,C-terminus = red) complexed withpyridoxal phosphate (space-filling model).[1] | |||||||||
| Identifiers | |||||||||
| EC no. | 2.6.1.5 | ||||||||
| CAS no. | 9014-55-5 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDBPDBePDBsum | ||||||||
| Gene Ontology | AmiGO /QuickGO | ||||||||
| |||||||||
Tyrosine aminotransferase (ortyrosine transaminase) is an enzyme present in the liver and catalyzes the conversion oftyrosine to4-hydroxyphenylpyruvate.[6]
In humans, the tyrosine aminotransferase protein is encoded by theTATgene.[7] A deficiency of the enzyme in humans can result in what is known astype II tyrosinemia, wherein there is an abundance of tyrosine as a result of tyrosine failing to undergo an aminotransferase reaction to form 4-hydroxyphenylpyruvate.[8]
Tyrosine aminotransferase (TAT) is apyridoxal phosphate (PLP)-dependent enzyme that catalyzes the first and rate-limiting step in the degradation of the amino acidtyrosine, transferring its amino group toα-ketoglutarate to produce4-hydroxyphenylpyruvate andglutamate.[9] This reaction is essential for tyrosine catabolism and energy production, as the resulting products feed into thecitric acid cycle.[10] TAT is predominantly expressed in the liver but is also present in other tissues, where it maintains narrow substrate specificity, favoring tyrosine over other aromatic amino acids such as phenylalanine.[9] Structurally, TAT contains a central catalytic core and a PLP-binding site critical for its enzymatic function.[11]
Tyrosine aminotransferase is a dimeric enzyme composed of two identical subunits, each containing a central catalytic core and a smaller domain formed by both amino- and carboxyl-terminal regions.[11] The enzyme's active site features a lysine residue (Lys280 in humans) that forms a Schiff base with the pyridoxal phosphate (PLP) cofactor, which is essential for its transaminase activity.[11] Structural studies, including crystallography, reveal that the PLP cofactor is stabilized within the active site through interactions with nonpolar amino acid side chains and hydrogen bonding, facilitating precise substrate positioning and catalysis.[13] Additionally, the carboxyl terminus contains hydrophilic, glutamate-rich segments resembling PEST sequences, which may contribute to the enzyme's rapid degradation rate.[11] The overall architecture of tyrosine aminotransferase aligns it with the aminotransferase superfamily, sharing conserved residues critical for function and substrate specificity.[11]
Structures of the three main molecules involved in chemical reaction catalyzed by the tyrosine aminotransferase enzyme are shown below: the amino acidtyrosine (left), theprosthetic grouppyridoxal phosphate (right), and the resulting product4-hydroxyphenylpyruvate (center).
Each side of the dimer protein includes pyridoxal phosphate (PLP) bonded to theLys280 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.
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 ofaspartate 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 throughacyl 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 its 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.
Deficiency of TAT activity leads to tyrosinemia type II, a metabolic disorder marked by elevated blood tyrosine levels and symptoms including keratitis, skin lesions, and neurological impairment.[14]
Tyrosinemia is the most common metabolic disease associated with tyrosine aminotransferase. The disease results from a deficiency in hepatic tyrosine aminotransferase.[15] 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.[15] Keratitis in Tyrosinemia type II patients is caused by the deposition of tyrosine crystals in the cornea and results in corneal inflammation.[16] 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.[17] Twelve different TAT gene mutations have been reported.[17]
