Aspartate aminotransferase, mitochondrial is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that in humans is encoded by the ''GOT2''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. Glutamic-oxaloacetic transaminase is a

pyridoxal phosphate Pyridoxal phosphate (PLP, pyridoxal 5'-phosphate, P5P), the active form of vitamin B6, is a coenzyme in a variety of enzymatic reactions. The International Union of Biochemistry and Molecular Biology has catalogued more than 140 PLP-dependen ...

-dependent enzyme which exists in

cytoplasmic The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell and ...

and inner-membrane mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

and Kreb's cycle. Also, GOT2 is a major participant in the malate-aspartate shuttle, which is a passage from the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

to the

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

. The two enzymes are

homodimeric In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ' ...

and show close homology. GOT2 has been seen to have a role in

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...

, especially in terms of

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

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 A helix (; ) is a shape like a cylindrical coil spring or the thread of a machine screw. It is a type of smoothness (mathematics), smooth space curve with tangent lines at a constant angle to a fixed axis. Helices are important in biology, as ...

, while the bottom is formed by strands of

beta sheets The beta sheet (β-sheet, also β-pleated sheet) is a common motif of the regular protein secondary structure. Beta sheets consist of beta strands (β-strands) connected laterally by at least two or three backbone hydrogen bonds, forming a gene ...

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. Virtually ubiquitous in

eukaryotic cells The eukaryotes ( ) constitute the domain of Eukaryota or Eukarya, organisms whose cells have a membrane-bound nucleus. All animals, plants, fungi, seaweeds, and many unicellular organisms are eukaryotes. They constitute a major group of li ...

, GOT2

nucleic acid Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a pentose, 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nuclei ...

and

protein sequences Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthes ...

are highly conserved, and its 5’regulatory regions in

genomic DNA Genomic deoxyribonucleic acid (abbreviated as gDNA) is chromosomal DNA, in contrast to extra-chromosomal DNAs like plasmids. Most organisms have the same genomic DNA in every cell; however, only certain genes are active in each cell to allow for c ...

resemble those of typical house-keeping genes in that, e.g., they lack a

TATA box In molecular biology, the TATA box (also called the Goldberg–Hogness box) is a sequence of DNA found in the core promoter region of genes in archaea and eukaryotes. The bacterial homolog of the TATA box is called the Pribnow box which has a ...

. The ''GOT2'' gene is also located on 16q21 and has an

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...

count of 10.

Function

In order to produce the energy needed for everyday activities, our body needs to go through the process of

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...

, which breaks down

glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...

into

pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic ...

. In this pathway, one very important part is the reduction of

NAD+ Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...

NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...

and then the rapid

oxidation Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

of NADH back into NAD+. The oxidation phase mainly occurs in the mitochondria as part of the

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules which transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

, 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 Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...

into

aspartate Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protein ...

transamination Transamination is a chemical reaction that transfers an amino group to a ketoacid to form new amino acids.This pathway is responsible for the deamination of most amino acids. This is one of the major degradation pathways which convert essential a ...

. This aspartate as well as alpha-ketoglutarate return into the cytosol, which is then converted back to oxaloacetate and glutamate, respectively. Another function of GOT2 is that it is believed to transaminate

kynurenine -Kynurenine is a metabolite of the amino acid -tryptophan used in the production of niacin. Kynurenine is synthesized by the enzyme tryptophan dioxygenase, which is made primarily but not exclusively in the liver, and indoleamine 2,3-dioxygena ...

into

kynurenic acid Kynurenic acid (KYNA or KYN) is a product of the normal metabolism of amino acid -tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an ...

(KYNA) in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

. The KYNA made by the GOT2 is thought to be an important factor in brain

pathology Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...

. It is suggested that KYNA synthesized by GOT2 could constitute a common, and mechanistically relevant, feature of the

neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

caused by mitochondrial poisons, such as rotenone,

malonate The conjugate acids are in :Carboxylic acids. {{Commons category, Carboxylate ions, Carboxylate anions Carbon compounds Anions ...

, 1-methyl-4-phenylpyridinium, and 3-nitropropionic acid.

Clinical Significance

In nearly all cancer cells, glycolysis has been seen to be highly elevated to meet their increased energy,

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

, and

redox Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is t ...

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 chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply ''acetates''. Deacetylation is the opposite react ...

in PANC-1 cells and that GOT2 3K acetylation plays a critical role in coordinating glucose and

glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of proteins. Its side chain is similar to that of glutamic acid, except the carboxylic acid group is replaced by an amide. It is classified as a charge-neutral ...

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. Mutations in this gene have been associated with an early onset infantile

encephalopathy Encephalopathy (; ) means any disorder or disease of the brain, especially chronic degenerative conditions. In modern usage, encephalopathy does not refer to a single disease, but rather to a syndrome of overall brain dysfunction; this syndrome ...

.van Karnebeek CDM, Ramos RJ, Wen XY, Tarailo-Graovac M, Gleeson JG, Skrypnyk C, Brand-Arzamendi K, Karbassi F, Issa MY, van der Lee R, Drögemöller BI, Koster J, Rousseau J, Campeau PM, Wang Y, Cao F, Li M, Ruiter J, Ciapaite J, Kluijtmans LAJ, Willemsen MAAP, Jans JJ, Ross CJ, Wintjes LT, Rodenburg RJ, Huigen MCDG, Jia Z, Waterham HR, Wasserman WW9, Wanders RJA, Verhoeven-Duif NM, Zaki MS, Wevers RA (2019) Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy. Am J Hum Genet

Structure

Function

Clinical Significance

Interactions

Interactive pathway map

References

Further reading