α-ketoglutaric acid

Structural formula
General
Surname	α-ketoglutaric acid
other names	2-oxoglutaric acid 2-oxopentanedioic acid KETOGLUTARIC ACID ( INCI )
Molecular formula	C 5 H 6 O 5
Brief description	white, almost odorless solid
External identifiers / databases
CAS number 328-50-7 EC number 206-330-3 ECHA InfoCard 100.005.756 PubChem 51 ChemSpider 50 DrugBank DB02926 Wikidata Q306140
properties
Molar mass	146.10 g mol −1
Physical state	firmly
Melting point	112-116 ° C
boiling point	Decomposition from 160 ° C
solubility	moderate in water (100 g l −1 at 20 ° C)
safety instructions
GHS labeling of hazardous substances danger H and P phrases H: 318 P: 280-305 + 351 + 338-310
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

α-ketoglutaric acid (2-oxoglutaric acid, 2-Oxopentandisäure) is from n -pentane dissipating dicarboxylic acid , the additional carbonyl group at the α - C - atom bears. It forms colorless, almost odorless crystals. Their salts are called α-ketoglutarates . They occur as intermediate products of metabolism , e.g. B. in the citric acid cycle or in important steps of nitrogen metabolism in appearance. α-Ketoglutaric acid (AKG) is a naturally occurring, nitrogen-free fraction of the amino acids glutamine and glutamic acid . α-Ketoglutaric acid (AKG), more precisely its anion α-ketoglutarate in the aqueous environment within a cell , is an intermediate product in the energy metabolism during ATP production in the cells via the citric acid cycle. It is a stronger radical scavenger (RONS) than vitamin C in the equivalent dose and acts as a nitrogen regulator in the metabolism. The pathological metabolism of cancer cells is also characterized by an increased formation of nitrogen bases. The nitrogen compounds released by the cancer cells are removed with α-ketoglutaric acid (AKG), thus balancing out the nitrogen load on the body and preventing nitrogen overload in body tissue and fluids.

Biosynthesis of α-ketoglutaric acid

The enzyme glutamate dehydrogenase (GDH, also GLD) catalyzes the reaction of L-glutamate , water and NAD (P) + to ammonium , α-ketoglutarate and NAD (P) H . The reverse reaction to L-glutamate is also catalyzed by this enzyme . Thus, α-ketoglutarate is part of nitrogen metabolism and of central importance for the fixation (assimilation) or release (dissimilation) of ammonium. In humans, there are two genes (GLUD1 and GLUD2), the two isoforms of GDH encode, with GLUD2 particularly in the retina , the testes and the brain expressed will. Mutations in GLUD1 can lead to hyperinsulinism-hyperammonaemia syndrome . While the GDHs of higher eukaryotes can use both cofactors ( NADH and NADPH ), the GDHs of prokaryotes and lower eukaryotes are dependent on a certain coenzyme . NADPH-dependent GDHs are usually anabolic enzymes and catalyze the assimilation of ammonium, while NADH- dependent GDHs contribute to catabolism and mostly dissimilate ammonium.

Properties and use

α-Ketoglutaric acid in surgery

α-Ketoglutaric acid leads to faster optimization of operations by increasing the ATP synthesis and metabolic support of the oxygen supply in the heart and skeletal muscles (protein synthesis) and other related improvements in physical performance. The supplementation with α-ketoglutaric acid optimizes the course of the operation by the preventive reduction of oxidative stress and the limitation of an oxidative increase during the operation, as well as the reduction of the formation of reactive species formed from free radicals (RONS) in excess. Furthermore, α-ketoglutaric acid is able to increase the healing rate in many diseases due to the increased ATP synthesis and activity of the mitochondrial enzyme (energy production).

Physiological importance

α-Ketoglutaric acid in the citric acid cycle

In the citric acid cycle, 1.5 - 2 kg of α-ketoglutaric acid are formed daily and immediately further converted into succinyl-CoA , which is also part of the citric acid cycle. The citric acid cycle, which is located in the mitochondrial matrix, is primarily used for the oxidative breakdown of acetyl-CoA , which is produced when carbohydrates are broken down from pyruvate , when fatty acids are broken down through β-oxidation and finally when some amino acids are broken down. Acetyl-CoA is broken down into CO ₂ and reduction equivalents ( NADH , FADH ) in a cyclical process, the citric acid cycle . The reoxidation of these reduction equivalents in the respiratory chain provides considerable amounts of energy in the form of ATP . The citric acid cycle is closely related to the carbohydrate, fat and amino acid metabolism and provides starting products for gluconeogenesis , fatty acid biosynthesis , heme biosynthesis and the synthesis of non-essential amino acids. The regulation of the citric acid cycle takes place via the cellular energy demand. If this is increased, the enzyme complex is activated . In the balance, 2 moles of CO ₂ , 3 moles of NADH / H + and 1 mole of reduced ubiquinol are produced per mole of acetyl residue in the citrate cycle . By oxidative phosphorylation , the cell gains 12 moles of ATP from these reduced coenzymes .

α-ketoglutaric acid in sport

α-Ketoglutaric acid plays an important role, especially in sport. "Supplementation with α-ketoglutaric acid is safe from a health point of view in its current form and dosage adapted to body weight". However, this also leads to increased resilience and an additional improvement in the training effects of physical activity. Furthermore, the supplementation with α-ketoglutaric acid accelerates the urea synthesis during physical training and provokes a reduced urea production.

Pharmacokinetics and metabolism

Outside of the citric acid cycle, there are three other important metabolic pathways in which α-ketoglutaric acid is involved. α-Ketoglutaric acid can be used to produce 2,5-dioxopentanoate as an intermediate product for the ascorbate and aldarate metabolism. It can be reversibly metabolized to L-glutamate and further to glutamine .

The α-ketoglutarate malate carrier (OGC) (also mitochondrial 2-oxoglutarate malate carrier protein, gene: SLC25A11) is the protein that enables the exchange of α-ketoglutarate and malate through the inner cell membrane of mitochondria . It is one of two transport proteins in the malate-aspartate shuttle and is therefore essential for the energy metabolism in eukaryotes .

The catalyzed membrane transport is:

α-ketoglutarate (outside) + malate (inside) ⇔ α-ketoglutarate (inside) + malate (outside)

So it is an antiport . Instead of malate, anions of other dicarboxylic acids and glutathione can also be transported.

The molecule has been reported to be rapidly eliminated in pigs. α-Ketoglutaric acid was administered enterally via the portal vein with a half-life of less than 5 minutes. The explanation for such a short lifespan is linked to liver metabolism. In 1979 it was observed that rats with Yoshida and Walker carcinoma show an increase in the daily urinary α-ketoglutaric acid excretion. The same observation was made in connection with an earlier 4-year study among 200 patients in which increased α-ketoglutaric acid excretion was also found. Subsequent experiments showed similar results in dogs in the catabolic state after an infusion solution at a maximum concentration of 20 µmol / kg / min was administered. They found that the concentration of α-ketoglutaric acid was the highest in skeletal muscles, followed by the kidney, liver and intestines.

function

mechanism

α-Ketoglutaric acid plays an important role in human cells . It can combine with ammonia to form glutamate and then to glutamine . Through transaminase and glutamate dehydrogenase , it can modulate the excess of nitrogen-producing urea and is also involved as a co-substrate in important oxidative reactions. In this way, α-ketoglutaric acid in combination with ornithine can be used as an anti-catabolic supplement for patients who are undergoing surgical operation or severe burns or other injuries, in particular due to a "gentle effect" on the glutamine pool. Velvizhi found that α-ketoglutaric acid can exert a chemopreventive effect during hepatocarcinogenesis through a positive modulation of transaminase activities and the oxidative-antioxidant imbalance. Two enzymes are of fundamental importance within the citric acid cycle : succinate dehydrogenase (SDH) and fumarate hydratase (FH). The deficiency of these two enzymes induces pseudohypoxia by activating the hypoxia-inducible factor (HIF by stabilizing the HIF1α factor by succinate or fumarate ). HIF1α is a transcription factor that upregulates genes such as those involved in angiogenesis and glycolysis . It also plays a central role in regulating the cellular use of oxygen and is an essential regulator of angiogenesis in ischemic solid tumor disorders and ischemic diseases. MacKenzie showed that an increased intracellular concentration of α-ketoglutaric acid can contrast this mechanism and also suggests that the use of ester derivatives leads to an improvement in membrane permeability . More than 90% of the glycolytic pyruvate is diverted to lactate formation. Most of the remaining pyruvic carbons enter a shortened citrate cycle from which the citrate is preferentially extruded into the cytosol , where it feeds an already deregulated sterol synthesis. Glutamine is a main substrate for the tumorous citric acid cycle: it is preferably converted to glutamate by intra-mitochondrial glutaminase . Glutamate is mostly transaminated to α-ketoglutaric acid, which enters the citric acid cycle. This means that the administration of α-ketoglutaric acid can help regulate mitochondrial metabolism, particularly the citric acid cycle pathways. α-Ketoglutaric acid is also an important component in activating HIF-1α proline hydroxylases (PHD), a key enzyme that inhibits HIF1α, which is responsible for activating HIF. HIF is the hypoxia-inducible factor that is not activated in a state of normoxia. The introduction of α-ketoglutaric acid restores normal PHD activity and the level of HIF1α and opens up new therapeutic options in connection with TCA cycle dysfunction. Perera showed the effectiveness of alpha-keto acids such as α-ketoglutaric acid in relation to their possible use as therapeutic agents in the disease process under oxidative stress .

Antioxidant properties

In many oxygenases , α-ketoglutaric acid supports the reaction by oxidizing it together with the main substrate. In fact, one of the alpha-ketoglutarate-dependent oxygenases is an O ₂ sensor, which informs the organism about the oxygen content in its environment. The main area of superoxide production , the primary reactive oxygen species (ROS), is believed to be the respiratory chain in the mitochondria . It has also been reported that the damaged key enzyme of the citric acid cycle , e.g. B. α-ketoglutaric acid dehydrogenase (AKGDH), can also produce ROS. The converted AKGD is a key factor that induces oxidative stress and promotes it in nerve endings. It has important functions in oxidation reactions with molecular oxygen, e.g. B. in many oxygenases (e.g. AKGDH) to prevent their damage or dysfunction (O ₂ sensor). Interestingly, α-ketoglutaric acid reacts with the intracellular H ₂ O ₂ , which non-enzymatically forms succinate , which is itself a necessary intermediate in the citric acid cycle.

Detoxification

α-Ketoglutaric acid removes the nitrogen compounds released by the breakdown of amino acids , thus balancing the body's nitrogen balance. Excessive protein intake or poor amino acid metabolism can cause excess nitrogen and ammonia to build up in cell tissue. α-Ketoglutaric acid is one of the most important nitrogen transporters in metabolic pathways. The amino groups of the amino acids are bound to them by transamination and transported to the liver, where the urea cycle takes place. α-Ketoglutaric acid is transaminated together with glutamine to form the excitatory neurotransmitter glutamate. This is an enzymatically controlled detoxification of ammonia from the tissue. The main production area of superoxide , the primary reactive oxygen species (ROS), is considered to be the respiratory chain in the mitochondria , but the exact mechanism and the physiologically relevant ROS generation within the respiratory chain has not yet been investigated. It was recently described that a key enzyme of the citric acid cycle, α-ketoglutaric acid dehydrogenase (AKGDH), can also produce ROS after oxidative modification (= converted AKGDH). Since converted AKGDH is not only a generator but also a target of ROS, it is suggested that converted AKGD is a key factor by which oxidative stress is induced and promoted in nerve endings. α-Ketoglutaric acid is recommended to prevent oxidative alteration of AKGDH in the inner membrane of the mitochondria , which are involved in the generation of cell energy through chemical energy transfer during the citric acid cycle. In addition, α-ketoglutaric acid was identified as the most likely physiological anion involved in dicarboxylate / organic anion exchange on the renal proximal basolateral membrane in the tubule.

Individual evidence

1. ↑ Entry on KETOGLUTARIC ACID in the CosIng database of the EU Commission, accessed on May 5, 2020.
2. ↑ ^{a b c} Data sheet 2-oxoglutaric acid (PDF) from Merck , accessed on May 8, 2017.
3. ↑ ^{a b c} data sheet α-Ketoglutaric acid from Sigma-Aldrich , accessed on May 8, 2017 ( PDF ).
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25. ↑ Edwards et al .: Alpha-ketoglutarate transport in rat renal brushborder and basolateral membrane vesicles, JPET, 1997; 281: 1059-64. ( Abstract ).