GOT2 is adimer containing two identicalsubunits that hold overlapping subunit regions. The top and sides of the enzyme are made up ofhelices, while the bottom is formed by strands ofbeta 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, anNH2-terminal arm, and a bridge across two domains, which is formed by residues 48-75 and 301-358.[6] Virtually ubiquitous ineukaryotic cells, GOT2nucleic acid andprotein sequences are highly conserved, and its 5’regulatory regions ingenomic DNA resemble those of typical house-keeping genes in that, e.g., they lack aTATA box.[7] TheGOT2 gene is also located on 16q21 and has anexon count of 10.[5]
In order to produce the energy needed for everyday activities, our body needs to go through the process ofglycolysis, which breaks downglucose intopyruvate. In this pathway, one very important part is thereduction ofNAD+ toNADH and then the rapidoxidation of NADH back into NAD+. The oxidation phase mainly occurs in the mitochondria as part of theelectron transport chain, but the transfer of NADH into the mitochondria from the cytosol is impossible, due to theimpermeability of the inner mitochondrial membrane to NADH. Therefore, themalate-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 convertsoxaloacetate intoaspartate bytransamination. This aspartate as well asalpha-ketoglutarate return into the cytosol, which is then converted back to oxaloacetate and glutamate, respectively.[8]
Another function of GOT2 is that it is believed to transaminatekynurenine intokynurenic acid (KYNA) in thebrain. The KYNA made by the GOT2 is thought to be an important factor in brainpathology. It is suggested that KYNA synthesized by GOT2 could constitute a common, and mechanistically relevant, feature of theneurotoxicity caused by mitochondrial poisons, such as rotenone,malonate,1-methyl-4-phenylpyridinium, and3-nitropropionic acid.[9]
In nearly all cancer cells, glycolysis has been seen to be highly elevated to meet their increased energy,biosynthesis, andredox 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 decreasedbreast adenocarcinoma cell proliferation. Furthermore, knocking down GOT2 and GOT1 has also been reported to inhibit cell proliferation and colony formation inpancreatic 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 3Kacetylation inPANC-1 cells and that GOT2 3K acetylation plays a critical role in coordinating glucose andglutamine uptake to provide energy and support cell proliferation and tumor growth. This implies that inhibiting GOT2 3K acetylation may merit exploration as atherapeutic agent especially for pancreatic cancer.[8]
Mutations in this gene have been associated with an early onset infantileencephalopathy.[10]
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