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{{Infobox_gene}}
{{PBB_Controls
'''Aspartate aminotransferase, mitochondrial''' is an [[enzyme]] that in humans is encoded by the ''GOT2'' [[gene]]. Glutamic-oxaloacetic transaminase is a [[pyridoxal phosphate]]-dependent enzyme which exists in [[cytoplasmic]] and [[mitochondria|inner-membrane mitochondrial]] forms, GOT1 and GOT2, respectively. GOT plays a role in [[amino acid metabolism]] and the [[urea]] and [[tricarboxylic acid]] cycles. Also, GOT2 is a major participant in the malate-aspartate shuttle, which is a passage from the [[cytosol]] to the [[mitochondria]]. The two enzymes are [[homodimeric]] and show close homology.<ref name="entrez">{{cite web | title = Entrez Gene: GOT2 glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2806| accessdate = }}</ref> GOT2 has been seen to have a role in [[cell proliferation]], especially in terms of [[tumor]] growth.
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Structure ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =  
| Name = Glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)
| HGNCid = 4433
| Symbol = GOT2
| AltSymbols =; FLJ40994
| OMIM = 138150
| ECnumber = 
| Homologene = 1572
| MGIid = 95792
| GeneAtlas_image1 = PBB_GE_GOT2_200708_at_tn.png
| Function = {{GNF_GO|id=GO:0004069 |text = aspartate transaminase activity}}
| Component = {{GNF_GO|id=GO:0005739 |text = mitochondrion}}
| Process = {{GNF_GO|id=GO:0006520 |text = amino acid metabolic process}} {{GNF_GO|id=GO:0006533 |text = aspartate catabolic process}} {{GNF_GO|id=GO:0009058 |text = biosynthetic process}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2806
    | Hs_Ensembl = ENSG00000125166
    | Hs_RefseqProtein = NP_002071
    | Hs_RefseqmRNA = NM_002080
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 16
    | Hs_GenLoc_start = 57298538
    | Hs_GenLoc_end = 57325747
    | Hs_Uniprot = P00505
    | Mm_EntrezGene = 14719
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = NM_010325
    | Mm_RefseqProtein = NP_034455
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end = 
    | Mm_Uniprot = 
  }}
}}
'''Glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)''', also known as '''GOT2''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: GOT2 glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2806| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
GOT2 is a dimer containing two identical [[Protein subunit|subunit]]s that hold overlapping subunit regions. The top and sides of the enzyme are made up of [[Alpha helices|helices]], while the bottom is formed by strands of [[beta sheets]] and extended hairpin loops. The subunit itself can be categorized into four different parts: a large domain, which binds pyridoxal-P, a small domain, an NH2-terminal arm, and a bridge across two domains, which is formed by residues 48-75 and 301-358.<ref name="pmid6930651">{{cite journal | vauthors = Ford GC, Eichele G, Jansonius JN | title = Three-dimensional structure of a pyridoxal-phosphate-dependent enzyme, mitochondrial aspartate aminotransferase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 77 | issue = 5 | pages = 2559–63 | date = May 1980 | pmid = 6930651 | doi=10.1073/pnas.77.5.2559 | pmc=349441}}</ref> Virtually ubiquitous in [[eukaryotic cells]], GOT2 [[nucleic acid]] and [[protein sequences]] are highly conserved, and its 5’regulatory regions in [[genomic DNA]] resemble those of typical house-keeping genes in that, e.g.,they lack a [[TATA box]].<ref name="pmid9537447">{{cite journal | vauthors = Zhou SL, Gordon RE, Bradbury M, Stump D, Kiang CL, Berk PD | title = Ethanol up-regulates fatty acid uptake and plasma membrane expression and export of mitochondrial aspartate aminotransferase in HepG2 cells | journal = Hepatology | volume = 27 | issue = 4 | pages = 1064–74 | date = Apr 1998 | pmid = 9537447 | doi = 10.1002/hep.510270423 }}</ref> The ''GOT2'' gene is also located on 16q21 and has an [[exon]] count of 10.<ref name="entrez"/>
{{PBB_Summary
| section_title =  
| summary_text = Glutamic-oxaloacetic transaminase is a pyridoxal phosphate-dependent enzyme which exists in cytoplasmic and inner-membrane mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the urea and tricarboxylic acid cycles. The two enzymes are homodimeric and show close homology.<ref name="entrez">{{cite web | title = Entrez Gene: GOT2 glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2806| accessdate = }}</ref>
}}


==References==
== Function ==
{{reflist|2}}
 
==Further reading==
In order to produce the energy needed for everyday activities, our body needs to go through the process of [[glycolysis]], which breaks down [[glucose]] into [[pyruvate]]. In this pathway, one very important part is the [[Redox reaction|reduction]] of [[NAD+]] to [[NADH]] and then the rapid [[oxidation]] of NADH back into NAD+. The oxidation phase mainly occurs in the mitochondria as part of the [[electron transport chain]], but the transfer of NADH into the mitochondria from the cytosol is impossible, due to the [[Semipermeable membrane|impermeability]] of the inner mitochondrial membrane to NADH. Therefore, the [[malate-aspartate shuttle]] is needed to transfer reducing equivalents across the mitochondrial membrane for energy production. GOT2 and another enzyme, [[malate dehydrogenase|MDH]], are essential for the functioning of the shuttle. GOT2 converts [[oxaloacetate]] into [[aspartate]] by [[transamination]]. This aspartate as well as [[alpha-ketoglutarate]] return into the cytosol, which is then converted back to oxaloacetate and glutamate, respectively.<ref name="pmid25755250">{{cite journal | vauthors = Yang H, Zhou L, Shi Q, Zhao Y, Lin H, Zhang M, Zhao S, Yang Y, Ling ZQ, Guan KL, Xiong Y, Ye D | title = SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth | journal = The EMBO Journal | volume = 34 | issue = 8 | pages = 1110–25 | date = Apr 2015 | pmid = 25755250 | doi = 10.15252/embj.201591041 | pmc=4406655}}</ref>
{{refbegin | 2}}
 
{{PBB_Further_reading
Another function of GOT2 is that it is believed to transaminate [[kynurenine]] into [[kynurenic acid]] (KYNA) in the [[brain]]. The KYNA made by the GOT2 is thought to be an important factor in brain [[pathology]]. It is suggested that KYNA synthesized by GOT2 could constitute a common, and mechanistically relevant, feature of the [[neurotoxicity]] caused by mitochondrial poisons, such as otenone, [[malonate]], [[1-methyl-4-phenylpyridinium]], and [[3-nitropropionic acid]].<ref name="pmid17442055">{{cite journal | vauthors = Guidetti P, Amori L, Sapko MT, Okuno E, Schwarcz R | title = Mitochondrial aspartate aminotransferase: a third kynurenate-producing enzyme in the mammalian brain | journal = Journal of Neurochemistry | volume = 102 | issue = 1 | pages = 103–11 | date = Jul 2007 | pmid = 17442055 | doi = 10.1111/j.1471-4159.2007.04556.x }}</ref>
| citations =
 
*{{cite journal  | author=Doonan S, Barra D, Bossa F |title=Structural and genetic relationships between cytosolic and mitochondrial isoenzymes. |journal=Int. J. Biochem. |volume=16 |issue= 12 |pages= 1193-9 |year= 1985 |pmid= 6397370 |doi= }}
==Clinical Significance==
*{{cite journal  | author=Furuya E, Yoshida Y, Tagawa K |title=Interaction of mitochondrial aspartate aminotransferase with negatively charged lecithin liposomes. |journal=J. Biochem. |volume=85 |issue= 5 |pages= 1157-63 |year= 1979 |pmid= 376500 |doi= }}
In nearly all cancer cells, glycolysis has been seen to be highly elevated to meet their increased energy, [[biosynthesis]], and [[redox]] needs. Therefore, the malate-aspartate shuttle promotes the net transfer of cytosolic NADH into mitochondria to ensure a high rate of glycolysis in diverse cancer cell lines. In a study completed in 2008, inhibiting the malate-aspartate shuttle was found to impair the glycolysis process and essentially decreased [[adenocarcinoma|breast adenocarcinoma]] cell proliferation. Furthermore, knocking down GOT2 and GOT1 has also been reported to inhibit cell proliferation and colony formation in [[pancreatic cancer|pancreatic cancer cell]] lines, suggesting that the GOT enzyme is essential for maintaining a high rate of glycolysis to support rapid tumor cell growth. Also, both glucose and glutamine increase GOT2 3K [[acetylation]] in [[PANC-1]] cells and that GOT2 3K acetylation plays a critical role in coordinating glucose and [[glutamine]] uptake to provide energy and support cell proliferation and tumor growth. This implies that inhibiting GOT2 3K acetylation may merit exploration as a [[therapeutic agent]] especially for pancreatic cancer.<ref name="pmid25755250"/>
*{{cite journal  | author=Craig IW, Tolley E, Bobrow M, van Heyningen V |title=Assignment of a gene necessary for the expression of mitochondrial glutamic-oxaloacetic transaminase in human-mouse hybrid cells. |journal=Cytogenet. Cell Genet. |volume=22 |issue= 1-6 |pages= 190-4 |year= 1979 |pmid= 752471 |doi=  }}
 
*{{cite journal  | author=Pol S, Bousquet-Lemercier B, Pavé-Preux M, ''et al.'' |title=Chromosomal localization of human aspartate aminotransferase genes by in situ hybridization. |journal=Hum. Genet. |volume=83 |issue= 2 |pages= 159-64 |year= 1989 |pmid= 2777255 |doi= }}
== Interactions ==
*{{cite journal  | author=Fahien LA, Kmiotek EH, MacDonald MJ, ''et al.'' |title=Regulation of malate dehydrogenase activity by glutamate, citrate, alpha-ketoglutarate, and multienzyme interaction. |journal=J. Biol. Chem. |volume=263 |issue= 22 |pages= 10687-97 |year= 1988 |pmid= 2899080 |doi= }}
 
*{{cite journal | author=Pol S, Bousquet-Lemercier B, Pave-Preux M, ''et al.'' |title=Nucleotide sequence and tissue distribution of the human mitochondrial aspartate aminotransferase mRNA. |journal=Biochem. Biophys. Res. Commun. |volume=157 |issue= 3 |pages= 1309-15 |year= 1989 |pmid= 3207426 |doi=  }}
GOT2 has been seen to interact with:
*{{cite journal | author=Fahien LA, Kmiotek EH, Woldegiorgis G, ''et al.'' |title=Regulation of aminotransferase-glutamate dehydrogenase interactions by carbamyl phosphate synthase-I, Mg2+ plus leucine versus citrate and malate. |journal=J. Biol. Chem. |volume=260 |issue= 10 |pages= 6069-79 |year= 1985 |pmid= 3997814 |doi= }}
* [[oxaloacetate]]
*{{cite journal | author=Martini F, Angelaccio S, Barra D, ''et al.'' |title=The primary structure of mitochondrial aspartate aminotransferase from human heart. |journal=Biochim. Biophys. Acta |volume=832 |issue= 1 |pages= 46-51 |year= 1985 |pmid= 4052435 |doi= }}
* [[kynurenine]]
*{{cite journal | author=Davidson RG, Cortner JA, Rattazzi MC, ''et al.'' |title=Genetic polymorphisms of human mitochondrial glutamic oxaloacetic transaminase. |journal=Science |volume=169 |issue= 943 |pages= 391-2 |year= 1970 |pmid= 5450376 |doi=  }}
* [[aspartate]]
*{{cite journal | author=Ford GC, Eichele G, Jansonius JN |title=Three-dimensional structure of a pyridoxal-phosphate-dependent enzyme, mitochondrial aspartate aminotransferase. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=77 |issue= 5 |pages= 2559-63 |year= 1980 |pmid= 6930651 |doi= }}
* [[alpha-ketoglutarate]]
*{{cite journal | author=Jeremiah SJ, Povey S, Burley MW, ''et al.'' |title=Mapping studies on human mitochondrial glutamate oxaloacetate transaminase. |journal=Ann. Hum. Genet. |volume=46 |issue= Pt 2 |pages= 145-52 |year= 1982 |pmid= 7114792 |doi=  }}
 
*{{cite journal | author=Tolley E, van Heyningen V, Brown R, ''et al.'' |title=Assignment to chromosome 16 of a gene necessary for the expression of human mitochondrial glutamate oxaloacetate transaminase (aspartate aminotransferase) (E.C. 2.6.1.1.). |journal=Biochem. Genet. |volume=18 |issue= 9-10 |pages= 947-54 |year= 1981 |pmid= 7225087 |doi= }}
== Interactive pathway map ==
*{{cite journal | author=Lain B, Iriarte A, Mattingly JR, ''et al.'' |title=Structural features of the precursor to mitochondrial aspartate aminotransferase responsible for binding to hsp70. |journal=J. Biol. Chem. |volume=270 |issue= 42 |pages= 24732-9 |year= 1995 |pmid= 7559589 |doi= }}
{{GlycolysisGluconeogenesis_WP534|highlight=GOT2}}
*{{cite journal | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171-4 |year= 1994 |pmid= 8125298 |doi= }}
 
*{{cite journal | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149-56 |year= 1997 |pmid= 9373149 |doi= }}
== References ==
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
{{reflist|33em}}
*{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
 
*{{cite journal | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
== Further reading ==
*{{cite journal | author=Rual JF, Venkatesan K, Hao T, ''et al.'' |title=Towards a proteome-scale map of the human protein-protein interaction network. |journal=Nature |volume=437 |issue= 7062 |pages= 1173-8 |year= 2005 |pmid= 16189514 |doi= 10.1038/nature04209 }}
{{refbegin|33em}}
}}
* {{cite journal | vauthors = Doonan S, Barra D, Bossa F | title = Structural and genetic relationships between cytosolic and mitochondrial isoenzymes | journal = The International Journal of Biochemistry | volume = 16 | issue = 12 | pages = 1193–9 | year = 1985 | pmid = 6397370 | doi = 10.1016/0020-711X(84)90216-7 }}
* {{cite journal | vauthors = Furuya E, Yoshida Y, Tagawa K | title = Interaction of mitochondrial aspartate aminotransferase with negatively charged lecithin liposomes | journal = Journal of Biochemistry | volume = 85 | issue = 5 | pages = 1157–63 | date = May 1979 | pmid = 376500 | doi =  }}
* {{cite journal | vauthors = Craig IW, Tolley E, Bobrow M, van Heyningen V | title = Assignment of a gene necessary for the expression of mitochondrial glutamic-oxaloacetic transaminase in human-mouse hybrid cells | journal = Cytogenetics and Cell Genetics | volume = 22 | issue = 1–6 | pages = 190–4 | year = 1979 | pmid = 752471 | doi = 10.1159/000130933 }}
* {{cite journal | vauthors = Pol S, Bousquet-Lemercier B, Pavé-Preux M, Bulle F, Passage E, Hanoune J, Mattei MG, Barouki R | title = Chromosomal localization of human aspartate aminotransferase genes by in situ hybridization | journal = Human Genetics | volume = 83 | issue = 2 | pages = 159–64 | date = Sep 1989 | pmid = 2777255 | doi = 10.1007/BF00286710 }}
* {{cite journal | vauthors = Fahien LA, Kmiotek EH, MacDonald MJ, Fibich B, Mandic M | title = Regulation of malate dehydrogenase activity by glutamate, citrate, alpha-ketoglutarate, and multienzyme interaction | journal = The Journal of Biological Chemistry | volume = 263 | issue = 22 | pages = 10687–97 | date = Aug 1988 | pmid = 2899080 | doi =  }}
* {{cite journal | vauthors = Pol S, Bousquet-Lemercier B, Pave-Preux M, Pawlak A, Nalpas B, Berthelot P, Hanoune J, Barouki R | title = Nucleotide sequence and tissue distribution of the human mitochondrial aspartate aminotransferase mRNA | journal = Biochemical and Biophysical Research Communications | volume = 157 | issue = 3 | pages = 1309–15 | date = Dec 1988 | pmid = 3207426 | doi = 10.1016/S0006-291X(88)81017-9 }}
* {{cite journal | vauthors = Fahien LA, Kmiotek EH, Woldegiorgis G, Evenson M, Shrago E, Marshall M | title = Regulation of aminotransferase-glutamate dehydrogenase interactions by carbamyl phosphate synthase-I, Mg2+ plus leucine versus citrate and malate | journal = The Journal of Biological Chemistry | volume = 260 | issue = 10 | pages = 6069–79 | date = May 1985 | pmid = 3997814 | doi =  }}
* {{cite journal | vauthors = Martini F, Angelaccio S, Barra D, Pascarella S, Maras B, Doonan S, Bossa F | title = The primary structure of mitochondrial aspartate aminotransferase from human heart | journal = Biochimica et Biophysica Acta | volume = 832 | issue = 1 | pages = 46–51 | date = Nov 1985 | pmid = 4052435 | doi = 10.1016/0167-4838(85)90172-4 }}
* {{cite journal | vauthors = Davidson RG, Cortner JA, Rattazzi MC, Ruddle FH, Lubs HA | title = Genetic polymorphisms of human mitochondrial glutamic oxaloacetic transaminase | journal = Science | volume = 169 | issue = 3943 | pages = 391–2 | date = Jul 1970 | pmid = 5450376 | doi = 10.1126/science.169.3943.391 }}
* {{cite journal | vauthors = Ford GC, Eichele G, Jansonius JN | title = Three-dimensional structure of a pyridoxal-phosphate-dependent enzyme, mitochondrial aspartate aminotransferase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 77 | issue = 5 | pages = 2559–63 | date = May 1980 | pmid = 6930651 | pmc = 349441 | doi = 10.1073/pnas.77.5.2559 }}
* {{cite journal | vauthors = Jeremiah SJ, Povey S, Burley MW, Kielty C, Lee M, Spowart G, Corney G, Cook PJ | title = Mapping studies on human mitochondrial glutamate oxaloacetate transaminase | journal = Annals of Human Genetics | volume = 46 | issue = Pt 2 | pages = 145–52 | date = May 1982 | pmid = 7114792 | doi = 10.1111/j.1469-1809.1982.tb00705.x }}
* {{cite journal | vauthors = Tolley E, van Heyningen V, Brown R, Bobrow M, Craig IW | title = Assignment to chromosome 16 of a gene necessary for the expression of human mitochondrial glutamate oxaloacetate transaminase (aspartate aminotransferase) (E.C. 2.6.1.1.) | journal = Biochemical Genetics | volume = 18 | issue = 9–10 | pages = 947–54 | date = Oct 1980 | pmid = 7225087 | doi = 10.1007/BF00500127 }}
* {{cite journal | vauthors = Lain B, Iriarte A, Mattingly JR, Moreno JI, Martinez-Carrion M | title = Structural features of the precursor to mitochondrial aspartate aminotransferase responsible for binding to hsp70 | journal = The Journal of Biological Chemistry | volume = 270 | issue = 42 | pages = 24732–9 | date = Oct 1995 | pmid = 7559589 | doi = 10.1074/jbc.270.42.24732 }}
* {{cite journal | vauthors = Maruyama K, Sugano S | title = Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides | journal = Gene | volume = 138 | issue = 1–2 | pages = 171–4 | date = Jan 1994 | pmid = 8125298 | doi = 10.1016/0378-1119(94)90802-8 }}
* {{cite journal | vauthors = Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S | title = Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library | journal = Gene | volume = 200 | issue = 1–2 | pages = 149–56 | date = Oct 1997 | pmid = 9373149 | doi = 10.1016/S0378-1119(97)00411-3 }}
{{refend}}
{{refend}}


{{protein-stub}}
{{Transaminases}}
{{WikiDoc Sources}}
 
[[Category:Mitochondrial proteins]]

Latest revision as of 09:17, 10 January 2019

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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Location (UCSC)n/an/a
PubMed searchn/an/a
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View/Edit Human

Aspartate aminotransferase, mitochondrial is an enzyme that in humans is encoded by the GOT2 gene. Glutamic-oxaloacetic transaminase is a pyridoxal phosphate-dependent enzyme which exists in cytoplasmic and inner-membrane mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the urea and tricarboxylic acid cycles. Also, GOT2 is a major participant in the malate-aspartate shuttle, which is a passage from the cytosol to the mitochondria. The two enzymes are homodimeric and show close homology.[1] GOT2 has been seen to have a role in cell proliferation, especially in terms of tumor growth.

Structure

GOT2 is a dimer containing two identical subunits that hold overlapping subunit regions. The top and sides of the enzyme are made up of helices, while the bottom is formed by strands of beta sheets and extended hairpin loops. The subunit itself can be categorized into four different parts: a large domain, which binds pyridoxal-P, a small domain, an NH2-terminal arm, and a bridge across two domains, which is formed by residues 48-75 and 301-358.[2] Virtually ubiquitous in eukaryotic cells, GOT2 nucleic acid and protein sequences are highly conserved, and its 5’regulatory regions in genomic DNA resemble those of typical house-keeping genes in that, e.g.,they lack a TATA box.[3] The GOT2 gene is also located on 16q21 and has an exon count of 10.[1]

Function

In order to produce the energy needed for everyday activities, our body needs to go through the process of glycolysis, which breaks down glucose into pyruvate. In this pathway, one very important part is the reduction of NAD+ to NADH and then the rapid oxidation of NADH back into NAD+. The oxidation phase mainly occurs in the mitochondria as part of the electron transport chain, but the transfer of NADH into the mitochondria from the cytosol is impossible, due to the impermeability of the inner mitochondrial membrane to NADH. Therefore, the malate-aspartate shuttle is needed to transfer reducing equivalents across the mitochondrial membrane for energy production. GOT2 and another enzyme, MDH, are essential for the functioning of the shuttle. GOT2 converts oxaloacetate into aspartate by transamination. This aspartate as well as alpha-ketoglutarate return into the cytosol, which is then converted back to oxaloacetate and glutamate, respectively.[4]

Another function of GOT2 is that it is believed to transaminate kynurenine into kynurenic acid (KYNA) in the brain. The KYNA made by the GOT2 is thought to be an important factor in brain pathology. It is suggested that KYNA synthesized by GOT2 could constitute a common, and mechanistically relevant, feature of the neurotoxicity caused by mitochondrial poisons, such as otenone, malonate, 1-methyl-4-phenylpyridinium, and 3-nitropropionic acid.[5]

Clinical Significance

In nearly all cancer cells, glycolysis has been seen to be highly elevated to meet their increased energy, biosynthesis, and redox needs. Therefore, the malate-aspartate shuttle promotes the net transfer of cytosolic NADH into mitochondria to ensure a high rate of glycolysis in diverse cancer cell lines. In a study completed in 2008, inhibiting the malate-aspartate shuttle was found to impair the glycolysis process and essentially decreased breast adenocarcinoma cell proliferation. Furthermore, knocking down GOT2 and GOT1 has also been reported to inhibit cell proliferation and colony formation in pancreatic cancer cell lines, suggesting that the GOT enzyme is essential for maintaining a high rate of glycolysis to support rapid tumor cell growth. Also, both glucose and glutamine increase GOT2 3K acetylation in PANC-1 cells and that GOT2 3K acetylation plays a critical role in coordinating glucose and glutamine uptake to provide energy and support cell proliferation and tumor growth. This implies that inhibiting GOT2 3K acetylation may merit exploration as a therapeutic agent especially for pancreatic cancer.[4]

Interactions

GOT2 has been seen to interact with:

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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<imagemap> Image:WP534.png
|{{{bSize}}}px|alt=Glycolysis and Gluconeogenesis edit]]
Glycolysis and Gluconeogenesis edit
  1. ↑ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".

References

  1. ↑ 1.0 1.1 "Entrez Gene: GOT2 glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2)".
  2. ↑ Ford GC, Eichele G, Jansonius JN (May 1980). "Three-dimensional structure of a pyridoxal-phosphate-dependent enzyme, mitochondrial aspartate aminotransferase". Proceedings of the National Academy of Sciences of the United States of America. 77 (5): 2559–63. doi:10.1073/pnas.77.5.2559. PMC 349441. PMID 6930651.
  3. ↑ Zhou SL, Gordon RE, Bradbury M, Stump D, Kiang CL, Berk PD (Apr 1998). "Ethanol up-regulates fatty acid uptake and plasma membrane expression and export of mitochondrial aspartate aminotransferase in HepG2 cells". Hepatology. 27 (4): 1064–74. doi:10.1002/hep.510270423. PMID 9537447.
  4. ↑ 4.0 4.1 Yang H, Zhou L, Shi Q, Zhao Y, Lin H, Zhang M, Zhao S, Yang Y, Ling ZQ, Guan KL, Xiong Y, Ye D (Apr 2015). "SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth". The EMBO Journal. 34 (8): 1110–25. doi:10.15252/embj.201591041. PMC 4406655. PMID 25755250.
  5. ↑ Guidetti P, Amori L, Sapko MT, Okuno E, Schwarcz R (Jul 2007). "Mitochondrial aspartate aminotransferase: a third kynurenate-producing enzyme in the mammalian brain". Journal of Neurochemistry. 102 (1): 103–11. doi:10.1111/j.1471-4159.2007.04556.x. PMID 17442055.

Further reading

  • Doonan S, Barra D, Bossa F (1985). "Structural and genetic relationships between cytosolic and mitochondrial isoenzymes". The International Journal of Biochemistry. 16 (12): 1193–9. doi:10.1016/0020-711X(84)90216-7. PMID 6397370.
  • Furuya E, Yoshida Y, Tagawa K (May 1979). "Interaction of mitochondrial aspartate aminotransferase with negatively charged lecithin liposomes". Journal of Biochemistry. 85 (5): 1157–63. PMID 376500.
  • Craig IW, Tolley E, Bobrow M, van Heyningen V (1979). "Assignment of a gene necessary for the expression of mitochondrial glutamic-oxaloacetic transaminase in human-mouse hybrid cells". Cytogenetics and Cell Genetics. 22 (1–6): 190–4. doi:10.1159/000130933. PMID 752471.
  • Pol S, Bousquet-Lemercier B, Pavé-Preux M, Bulle F, Passage E, Hanoune J, Mattei MG, Barouki R (Sep 1989). "Chromosomal localization of human aspartate aminotransferase genes by in situ hybridization". Human Genetics. 83 (2): 159–64. doi:10.1007/BF00286710. PMID 2777255.
  • Fahien LA, Kmiotek EH, MacDonald MJ, Fibich B, Mandic M (Aug 1988). "Regulation of malate dehydrogenase activity by glutamate, citrate, alpha-ketoglutarate, and multienzyme interaction". The Journal of Biological Chemistry. 263 (22): 10687–97. PMID 2899080.
  • Pol S, Bousquet-Lemercier B, Pave-Preux M, Pawlak A, Nalpas B, Berthelot P, Hanoune J, Barouki R (Dec 1988). "Nucleotide sequence and tissue distribution of the human mitochondrial aspartate aminotransferase mRNA". Biochemical and Biophysical Research Communications. 157 (3): 1309–15. doi:10.1016/S0006-291X(88)81017-9. PMID 3207426.
  • Fahien LA, Kmiotek EH, Woldegiorgis G, Evenson M, Shrago E, Marshall M (May 1985). "Regulation of aminotransferase-glutamate dehydrogenase interactions by carbamyl phosphate synthase-I, Mg2+ plus leucine versus citrate and malate". The Journal of Biological Chemistry. 260 (10): 6069–79. PMID 3997814.
  • Martini F, Angelaccio S, Barra D, Pascarella S, Maras B, Doonan S, Bossa F (Nov 1985). "The primary structure of mitochondrial aspartate aminotransferase from human heart". Biochimica et Biophysica Acta. 832 (1): 46–51. doi:10.1016/0167-4838(85)90172-4. PMID 4052435.
  • Davidson RG, Cortner JA, Rattazzi MC, Ruddle FH, Lubs HA (Jul 1970). "Genetic polymorphisms of human mitochondrial glutamic oxaloacetic transaminase". Science. 169 (3943): 391–2. doi:10.1126/science.169.3943.391. PMID 5450376.
  • Ford GC, Eichele G, Jansonius JN (May 1980). "Three-dimensional structure of a pyridoxal-phosphate-dependent enzyme, mitochondrial aspartate aminotransferase". Proceedings of the National Academy of Sciences of the United States of America. 77 (5): 2559–63. doi:10.1073/pnas.77.5.2559. PMC 349441. PMID 6930651.
  • Jeremiah SJ, Povey S, Burley MW, Kielty C, Lee M, Spowart G, Corney G, Cook PJ (May 1982). "Mapping studies on human mitochondrial glutamate oxaloacetate transaminase". Annals of Human Genetics. 46 (Pt 2): 145–52. doi:10.1111/j.1469-1809.1982.tb00705.x. PMID 7114792.
  • Tolley E, van Heyningen V, Brown R, Bobrow M, Craig IW (Oct 1980). "Assignment to chromosome 16 of a gene necessary for the expression of human mitochondrial glutamate oxaloacetate transaminase (aspartate aminotransferase) (E.C. 2.6.1.1.)". Biochemical Genetics. 18 (9–10): 947–54. doi:10.1007/BF00500127. PMID 7225087.
  • Lain B, Iriarte A, Mattingly JR, Moreno JI, Martinez-Carrion M (Oct 1995). "Structural features of the precursor to mitochondrial aspartate aminotransferase responsible for binding to hsp70". The Journal of Biological Chemistry. 270 (42): 24732–9. doi:10.1074/jbc.270.42.24732. PMID 7559589.
  • Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
  • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
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