In organic chemistry, keto acids, also known as oxo acids or oxoacids, are organic compounds characterized by the presence of both a carboxylic acid group (−COOH) and a ketone group (>C=O). In many instances, the keto group is hydrated. These compounds play crucial roles in various metabolic pathways.
Types of Keto Acids
Keto acids are classified based on the position of the ketone group relative to the carboxylic acid group:
- Alpha-keto acids (α-keto acids or 2-oxoacids): The keto group is adjacent to the carboxylic acid. They often arise from the oxidative deamination of amino acids and are precursors to the same. An example is α-ketoglutaric acid, a 5-carbon ketoacid derived from glutamic acid.
- Beta-keto acids (β-keto acids or 3-oxoacids): The ketone group is located at the second carbon from the carboxylic acid. Acetoacetic acid is an example. They generally form through the Claisen condensation.
- Gamma-keto acids (γ-keto acids or 4-oxoacids): The ketone group is at the third carbon from the carboxylic acid.
Formation and Occurrence
Keto acids appear in a wide variety of anabolic pathways in metabolism. When ingested sugars and carbohydrate levels are low, stored fats and proteins are the primary source of energy production. Glucogenic amino acids from proteins and/or Glycerol from Triglycerides are converted to glucose.
Alpha-keto acids often arise by oxidative deamination of amino acids, and reciprocally, they are precursors to the same. Beta-keto acids generally form by the Claisen condensation.
Alpha-Ketoglutaric Acid: A Detailed Look
α-Ketoglutaric acid (α-KG) is an organic compound with the formula HO2CCO(CH2)2CO2H. It is a white, nontoxic solid and a common dicarboxylic acid. In biological systems, it exists in water as its conjugate base, α-ketoglutarate. It is also classified as a 2-ketocarboxylic acid, with β-ketoglutaric acid being an isomer.
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Role in the Citric Acid Cycle
α-Ketoglutarate is an intermediate in the citric acid cycle, a crucial pathway that supplies energy to cells. In this cycle, isocitrate dehydrogenase 3 converts isocitrate to α-ketoglutarate, which is then converted to succinyl-CoA by the oxoglutarate dehydrogenase complex of enzymes.
Metabolic Pathways
Aside from the citric acid cycle, α-ketoglutarate is produced by glutaminolysis, where glutaminase removes the amino group from glutamine to form glutamate, which is then converted to α-ketoglutarate by glutamate dehydrogenase, alanine transaminase, or aspartate transaminase. It also participates in various pyridoxal phosphate-dependent transamination reactions.
In these pathways, α-ketoglutarate contributes to the production of amino acids such as glutamine, proline, arginine, and lysine, and helps regulate cellular carbon and nitrogen levels, preventing the accumulation of toxic elements in cells and tissues. It also prevents the accumulation of the neurotoxin ammonia by transferring the −NH2 group from an amino acid to α-ketoglutarate, forming the α-keto acid of the original amino acid and glutamate. The cellular glutamate then enters the circulation and is taken up by the liver, where it delivers its acquired −NH2 group to the urea cycle.
Antioxidant Properties
α-Ketoglutarate acts as a non-enzymatic antioxidant agent, reacting with hydrogen peroxide (H2O2) to form succinate, carbon dioxide (CO2), and water (H2O), thereby reducing H2O2 levels.
Role in Neurotransmission
A study on GABAergic neurons in the neocortex of rat brains reported that the cytosolic form of aspartate transaminase metabolizes α-ketoglutarate to glutamate, which is then metabolized by glutamic acid decarboxylase to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
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Interaction with OXGR1 Receptor
OXGR1 (also known as GPR99) is a G protein-coupled receptor on the surface membrane of cells. Studies suggest that α-ketoglutarate binds to and stimulates OXGR1. A study in mice found that OXGR1 colocalizes with pendrin in the β-intercalated cells and non-α non-β intercalated cells lining the tubules of their kidney's collecting duct system (CDS). α-Ketoglutarate stimulated the rate of Cl− for HCO3− exchange in CDS tubules isolated from control mice but not in CDS tubules isolated from Oxgr1 gene knockout mice.
Effects of Resistance Exercise
Studies have found that resistance exercise increases muscle production and serum levels of α-ketoglutarate, which suppresses diet-induced obesity by stimulating OXGR1 on adrenal gland chromaffin cells to release epinephrine. Middle-aged mice supplemented with α-ketoglutarate in their drinking water showed improved glucose tolerance and reduced obesity. Rats fed α-ketoglutarate-rich water experienced decreased fat tissue masses and increased whole-body insulin sensitivity.
Other Actions
α-Ketoglutarate has been reported to increase lifespan and delay the development of old age-related diseases in roundworms and mice. A study reported that the median and range of the biological age of females before treatment was 62.15 (range, 46.4 to 73) years and fell to 55.55 (range 33.4 to 63.7) years after an average of 7 months treatment. These values for men were 61.85 (range 41.9 to 79.7) years before and 53.3 (33 to 74.9) years after treatment.
Role as a Cofactor
α-Ketoglutarate is a cofactor that activates the histone-lysine demethylase protein superfamily, specifically the Fe2+/α-ketoglutarate-dependent dioxygenases. These enzymes remove methyl groups from lysine residues on histones, altering gene expression. It is also required by the TET enzymes (ten-eleven translocation methylcytosine dioxygenase family of enzymes) to remove methyl groups from the 5-methylcytosines of DNA sites that regulate the expression of nearby genes.
α-Ketoacid Dehydrogenase Complex (KDHc)
The α-ketoacid dehydrogenase complex (KDHc) is a class of mitochondrial enzymes composed of four members: pyruvate dehydrogenase (PDHc), α-ketoglutarate dehydrogenase (KGDHc), branched-chain keto acid dehydrogenase (BCKDHc), and 2-oxoadipate dehydrogenase (OADHc). These enzyme complexes occupy critical metabolic intersections that connect monosaccharide, amino acid, and fatty acid metabolism to Krebs cycle flux and oxidative phosphorylation (OxPhos). This feature also imbues KDHc enzymes with the heightened capacity to serve as platforms for propagation of intracellular and intercellular signaling.
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Signaling Roles of KDHc Enzymes
KDHc enzymes serve as a source and sink for mitochondrial hydrogen peroxide (mtH2O2), a vital second messenger used to trigger oxidative eustress pathways. Deactivation of KDHc enzymes through reversible oxidation by mtH2O2 and other electrophiles modulates the availability of several Krebs cycle intermediates and related metabolites, which serve as powerful intracellular and intercellular messengers. The KDHc enzymes also play important roles in the modulation of mitochondrial metabolism and epigenetic programming in the nucleus through the provision of various acyl-CoAs, which are used to acylate proteinaceous lysine residues.
KDHc Enzyme Components and Function
The KDHc enzymes are composed of the same basic subunits: E1 (α-ketoacid decarboxylase; KDC), E2 (dihydrolipoyl acyltransferase; DLAT), and E3 (dihydrolipoamide dehydrogenase; DLDH). However, they differ in terms of the number of copies and orientation of the three subunits that are used to form the multimer complexes.
A variety of co-factors and prosthetic groups are utilized by KDHc to catalyze the multistep conversion of the α-keto acid to acyl-CoA and NADH. These cofactors and prosthetic groups are thiamine pyrophosphate (TPP), lipoic acid, CoASH, and NAD+. The conversion of α-keto acid to acyl-CoA and NADH is initiated by the decarboxylase activity of the E1 subunit.
Individual KDHc Enzymes
- Pyruvate Dehydrogenase Complex (PDHc): Connects glycolysis to the Krebs cycle by converting pyruvate formed by monosaccharide metabolism into acetyl-CoA. The amino acids Ala, Gly, Cys, Ser, and Thr also form pyruvate through transamination reactions, making PDH an important point for the intake of certain amino acids into the Krebs cycle. PDHc is heavily regulated by a kinase (PDHK) and phosphatase (PDP).
- α-Ketoglutarate Dehydrogenase Complex (KGDHc): Catalyzes the oxidative degradation of α-ketoglutarate to succinyl-CoA. KGDHc is vital for amino acid metabolism because it is required for glutamate biosynthesis, the main source and sink for amines in cells.
- Branched Chain Keto Acid Dehydrogenase Complex (BCKDHc): Required for the degradation of branched chain amino acids (BCAA) leucine (Leu), isoleucine (Ile), and valine (Val). BCAA metabolism begins when branched chain amino acid transferase (BCAT) transaminates α-ketoglutarate to form the corresponding branched-chain keto acids (BCKA), ketoleucine, ketoisoleucine, and ketovaline. These BCAAs are then oxidized by BCKDHc generating acetyl-, propionyl-, and/or succinyl-CoA.
- 2-Oxoadipate Dehydrogenase Complex (OADHc): Required for the mitochondrial degradation of lysine and converts 2-oxoadipate to glutaryl-CoA and NADH. Impaired OADH is also linked to insulin resistance, cardiovascular disease risks, and Charcot-Marie-Tooth neuropathy.
Beta-Ketoglutaric Acid
β-Ketoglutaric acid has been detected in the saliva of individuals chewing betel quid, a complex mixture derived from betel nuts mixed with various other materials. Chronic chewing betel quid is associated with the development of certain cancers, particularly those in the oral cavity. The study showed that β-ketoglutaric acid bound to the cancer-promoting protein TET-2 thereby inhibiting α-ketoglutarate's binding to this protein.