View source for Tyrosine aminotransferase

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{{Short description|Mammalian protein found in Homo sapiens}}
{{infobox enzyme
| Name       = Tyrosine transaminase
| EC_number  = 2.6.1.5
| CAS_number = 9014-55-5
| GO_code    = 0080130
| image      = 3DYD.png
| width      =
| caption    = Human tyrosine aminotransferase (rainbow colored, [[N-terminus]] = blue, [[C-terminus]] = red) complexed with [[pyridoxal phosphate]] ([[space-filling model]]).<ref name="Karlberg">{{PDB|3DYD}}; {{cite journal  |vauthors=Karlberg T, Moche M, Andersson J |display-authors=etal| title =Human tyrosine aminotransferase | journal =  Protein Data Bank | year = 2008 |doi=10.2210/pdb3dyd/pdb }}</ref> 
}}
{{Infobox_gene}}

'''Tyrosine aminotransferase''' (or '''tyrosine transaminase''') is an enzyme present in the liver and catalyzes the conversion of [[tyrosine]] to [[4-hydroxyphenylpyruvate]].<ref name="pmid1349265">{{cite journal | author = Dietrich JB | title = Tyrosine aminotransferase: a transaminase among others? | journal = Cellular and Molecular Biology | volume = 38 | issue = 2 | pages = 95–114 |date=April 1992 | pmid = 1349265 }}</ref>

[[File:Tyrosine aminotransferase.svg|600px|center]]

<div align=center>[[L-tyrosine]] + [[2-oxoglutarate]] <math>\rightleftharpoons</math> [[4-hydroxyphenylpyruvate]] + [[L-glutamate]]</div>

In humans, the tyrosine aminotransferase protein is encoded by the ''TAT'' [[gene]].<ref>{{cite journal |last1=Zea-Rey |first1=Alexandra V. |last2=Cruz-Camino |first2=Héctor |last3=Vazquez-Cantu |first3=Diana L. |last4=Gutiérrez-García |first4=Valeria M. |last5=Santos-Guzmán |first5=Jesús |last6=Cantú-Reyna |first6=Consuelo |title=The Incidence of Transient Neonatal Tyrosinemia Within a Mexican Population |journal=Journal of Inborn Errors of Metabolism and Screening |date=27 November 2017 |volume=5 |pages=232640981774423 |doi=10.1177/2326409817744230|doi-access=free }}</ref>  A deficiency of the enzyme in humans can result in what is known as [[Tyrosinemia type II|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.<ref name="pmid1973834">{{cite journal | vauthors = Rettenmeier R, Natt E, Zentgraf H, Scherer G | title = Isolation and characterization of the human tyrosine aminotransferase gene | journal = Nucleic Acids Res. | volume = 18 | issue = 13 | pages = 3853–61 |date=July 1990 | pmid = 1973834 | pmc = 331086 | doi = 10.1093/nar/18.13.3853 }}</ref>

== Mechanism ==

Structures of the three main molecules involved in chemical reaction catalyzed by the tyrosine aminotransferase enzyme are shown below: the amino acid [[tyrosine]] (left), the [[prosthetic group]] [[pyridoxal phosphate]] (right), and the resulting product [[4-hydroxyphenylpyruvic acid|4-hydroxyphenylpyruvate]] (center).

:[[Image:3strucfinal.svg|thumb|left|400px]]{{clear left}}

[[Image:DimerTAT.jpg|thumb|right|Ribbon diagram of the tyrosine aminotransferase [[protein dimer|dimer]].  The prosthetic group PLP is visible in both [[monomer]]s.<ref name="Peterson">{{cite journal |author1 = Pettersen, E.F. |author2 =Goddard, T.D. |author3 =Huang, C.C. |author4 =Couch, G.S. |author5 =Greenblatt, D.M. |author6 =Meng, E.C. |author7 =Ferrin, T.E. | title =UCSF Chimera - A Visualization System for Exploratory Research and Analysis |  journal =  Journal of Computational Chemistry| volume = 25 | issue = 13 | pages = 1605–1612 | year = 2004 | pmid = 15264254| doi = 10.1002/jcc.20084|citeseerx =10.1.1.456.9442 |s2cid =8747218 }}</ref>]]

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.

[[Image:Lys280plp.jpg|thumb|right|Ball & stick diagram of the TAT amino acid Lys280 linked to PLP.<ref name="Karlberg"/>]]

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.

[[Image:ReactionTAT.jpg]]

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.

==Active site==

[[Image:Pancakejpeg.jpg|thumb|right|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 site.  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:
[[Image:TATActivesite.jpg]]

==Pathology==

[[Tyrosinemia]] is the most common metabolic disease associated with tyrosine aminotransferase.  The disease results from a deficiency in hepatic tyrosine aminotransferase.<ref name="pmid1357662">{{cite journal | vauthors = Natt E, Kida K, Odievre M, Di Rocco M, Scherer G | title = Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 89 | issue = 19 | pages = 9297–301 |date=October 1992 | pmid = 1357662 | pmc = 50113 | doi = 10.1073/pnas.89.19.9297| bibcode = 1992PNAS...89.9297N | doi-access = free }}</ref> 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.<ref name="pmid1357662"/>  Keratitis in Tyrosinemia type II patients is caused by the deposition of tyrosine crystals in the cornea and results in corneal inflammation.<ref name="pmid7648039">{{cite journal | vauthors = al-Hemidan AI, al-Hazzaa SA | title = Richner-Hanhart syndrome (tyrosinemia type II). Case report and literature review | journal = Ophthalmic Genet. | volume = 16 | issue = 1 | pages = 21–6 |date=March 1995 | pmid = 7648039 | doi = 10.3109/13816819509057850}}</ref>  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.<ref name="pmid16318910">{{cite journal | vauthors = Minami-Hori M, Ishida-Yamamoto A, Katoh N, Takahashi H, Iizuka H | title = Richner-Hanhart syndrome: report of a case with a novel mutation of tyrosine aminotransferase | journal = J. Dermatol. Sci. | volume = 41 | issue = 1 | pages = 82–4 |date=January 2006 | pmid = 16318910 | doi = 10.1016/j.jdermsci.2005.10.007 }}</ref>  Twelve different TAT gene mutations have been reported.<ref name="pmid16318910"/>

==References==
{{Reflist}}

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==
* {{MeshName|Tyrosine+aminotransferase}}
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P17735 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Tyrosine aminotransferase

{{Amino acid metabolism enzymes}}
{{Nitrogenous transferases}}
{{Enzymes}}
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[[Category:EC 2.6.1]]