Alpha-Ketogluterate

Alpha-ketoglutarate (AKG) is one of the active QoL Enhancer ™ ingredients in the proprietary Molecular Action Blend ™ of Ypera ®.

Introduction

Alpha-ketoglutarate (AKG) is a naturally occurring, nitrogen-free portion of the amino acids glutamine and glutamic acid. AKG is an essential biologic compound and is a crucial intermediate in the citric acid cycle. The citric acid cycle, also known as the tricarboxylic acid cycle, or the Krebs cycle, is a series of chemical reactions of central importance in all living cells that utilize oxygen as part of cellular respiration. AKG is an essential substrate of one of the main metabolic enzymatic complexes (alpha- dehydrogenase, HIFalpha, alpha-keto-oxygenase, GOT, etc.). In the citric cycle, the high reductive potential of AKG results in the formation of NADH+ from NAD+ and two electrons, which starts the initial reduction oxygen forming intracellular ATP.

AKG is also essential for the detoxification of NH4+ on glutamate (detoxification of ammonia and amines within the urea cycle). It can combine with ammonia resulting in glutamate and then glutamine. Through transaminase and glutamate dehydrogenase it can modulate the excess of nitrogen producing urea. In addition it is also involved as co-substratein important oxidative reactions. Furthermore, AKG regulates through glutamate production of non-essential amino acids.

AKG is also essential for the detoxification of NH4+ on glutamate (detoxification of ammonia and amines within the urea cycle). It can combine with ammonia resulting in glutamate and then glutamine. Through transaminase and glutamate dehydrogenase, it can modulate the excess of nitrogen producing urea. Besides, it is also involved as co-substrate in important oxidative reactions.

TheFurthermore, AKG regulates through glutamate production of non-essential amino acids. The pathological metabolism of cancer cells is also characterized by an increased formation of nitrogen bases from the de-amination of nucleotides, ethanolamine (sphingolipids) and amino acids.

Nitrogen released by these processes is removed by AKG and balances the body’s nitrogen load and prevents nitrogen overload. AKG is one of the most crucial nitrogen transporters in metabolic pathways. The amino groups of amino acid are adhered to it by transamination and carried to the liver, where the urea cycle takes place.

The AKG is transaminated, along with glutamine to form the excitatory neurotransmitter glutamate and in a further step arginine. AKG has a high redox potential which is at least eight times higher than that of vitamin C and is, therefore, a vital intra- and extracellular antioxidant.

AKG reacts non-enzymatically with the intracellular H2O2 forming succinate, which itself is a necessary intermediate in the citric cycle. H2O2 is reduced to succinate, CO2, and water. AKG also reacts with peroxynitrite (mainly produced by macrophages) forming succinate and nitrite, which itself can be recycled to NO*.

Specification

Nomenclature

International non-proprietary name: α-Ketoglutaric acid

Chemical name: 2-oxo-glutaric acid

CAS Registry number: 328-50-7

Structure

Structural formula

Molecular formula: C5H6O5

Molecular mass: 146.07

General Properties

Appearance: White or weakly yellowish crystals or crystalline powder

Solubility: > 100 g/100 ml water (20 °C)

Melting point 112 – 116 °C

Safety

At present, there is no report about the possible toxicological effect of AKG in humans or animals. Furthermore, no daily dose has been determined by the FDA, EMEA, or other competent authorities for approval of drugs for human use.

In a work of Blomqvist, patients undergoing surgery were given 0.28 g/kg b.w., corresponding to about 20 kg / 70 kg, to evaluate the effect of the substance in decreasing the protein catabolism in muscle cells.

Coudray conducted experiments on the wound healing properties of the combination ornithine- AKG, where patients suffering severe burns were enterally administered with 20g/d. This concentration was considered to be “safe and well-tolerated.” In animal experiments, the amount of AKG administered ranged from mg to g/kg b.w. However, nothing is mentioned about adverse effects.

Metabolism and Pharmacokinetic

Outside the citrate cycle, there are three more main metabolic pathways involving AKG.

AKG can be used to produce 2,5-dioxopentanoate as intermediate used in the ascorbate and aldarate metabolism. AKG can be reversibly metabolized to L-glutamate and the further to glutamine.

Dabek observed that the molecule was rapidly eliminated in pigs. AKG was enterally administered through the portal vein with a half-life of less than 5 minutes. The explanation of such a short lifetime is associated with the liver metabolism.

Aussel investigated the mechanism by which AKG enters the cell. They evidenced the lack of any active, passive, or co-transport process and suggested a mechanism defined as an “unmediated diffusion process,” on which pH can play an important role.

In 1979, Schaur noticed that rats bearing the Yoshida and Walker carcinoma show an increase in the daily AKG excretion in urine. The same observation was also made by Kronberger(35), who found the event in context with a previous four year- survey including200 patients, where an increased AKG excretion was found too.

Roth conducted experiments on dogs undergoing catabolic state., after the administration of an infusion solution with a maximal concentration of 20 μmol/kg/min., They found that the concentration of AKG was the highest in skeletal muscles, followed by kidney, liver, and guts.

In a study of Jeppsson, eleven patients received intravenous infusion of 30 g AKG/h after a coronary operation, to evaluate the renal effects of the substance.

Mode of Action

AKG plays an essential role in human cells. It can combine with ammonia to form glutamate and then glutamine. Through transaminase and glutamate dehydrogenase, it can modulate the excess of nitrogen producing urea, and it is also involved as co-substrate in important oxidative reactions.

Using these pathways, AKG can be used in combination with ornithine as an anti-catabolic supplement for patients undergoing surgical operations or suffering severe burns or other injuries, particularly by a “sparing effect” on the glutamine pool.

Velvizhi found that AKG can exert a chemopreventive effect during hepatocarcinogenesis through a positive modulation of the transaminase activities and the oxidative/anti-oxidative imbalance.

Within the Krebs cycle, two enzymes are fundamental: succinate dehydrogenase (SDH) and fumarate hydratase (FH). The lack of these two enzymes induces pseudohypoxia via activation of hypoxia-inducible factor (HIFthrough stabilization of 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 pivotal role in the regulation of cellular utilization of oxygen and is an essential regulator of angiogenesis in solid tumor and ischemic disorders”. MacKenzie (43) demonstrated that an elevated intracellular concentration of AKG could contrast this mechanism and also suggests the use of ester derivatives to enhance the membrane permeability.

As stated by Baggetto, “…more than 90% of the glycolytic pyruvate is deviated to lactate formation. Most of the remaining pyruvic carbons enter a truncated Krebs cycle from which citrate is preferentially extruded to the cytosol where it feeds an already deregulated sterol synthesis. Glutamine is a major substrate for the tumoral Krebs cycle: it is preferentially transformed to glutamate through intra-mitochondrial glutaminase. Glutamate is mostly transaminated to alpha-ketoglutarate that enters the Krebs cycle…”. This means that the administration of AKG can help in regulating mitochondrial metabolism, particularly the citrate cycle pathways.

AKG is also a vital component to activate HIF-1α proline hydroxylases (PHD), a key enzyme for the inhibition of HIF1α which is responsible for HIF activation. HIF is the hypoxia-inducible factor that in the state of normoxia is not activated. The introduction of AKG restores regular PHD activity and HIF1α levels, indicating new therapy possibilities associated with TCA cycle dysfunction.

Perera demonstrated the efficacy of alpha-keto acids such as AKG in terms of their potential use as therapeutic agents in the disease process involving oxidative stress.

Mode of Action – Intracellular

Energy generation (Krebs cycle) – intracellular

In aerobic organisms, the citric acid cycle is a part of a metabolic pathway involved in the chemical conversion of carbohydrates, fats, and proteins into carbon dioxide and water to generate a form of usable energy. It is the second of three metabolic pathways that are involved in fuel molecule catabolism and ATP production.

The other two are glycolysis and oxidative phosphorylation, which produce energy and occur in most body cells. In this enzymatically regulated reaction (oxidative decarboxylation), the 5-carbon AKG is converted into succinyl-CoA (an intermediate of the hemoglobin synthesis) and in a further step to succinate and GTP. All these steps are regulated by the central metabolic enzymatic system in the whole body.

Additionally, building the formal substance, iso-citrate, can also be initiated in an enzymatic step starting from AKG.

So AKG as a nonessential alpha-keto-acid has no side effects in healthy cells because of its unique biological properties.

Mode of Action – Intra and Extracellular (Antioxidant)

In In many oxygenases, alpha-ketoglutarate supports the reaction by being oxidized together with the primary substrate. One of the alpha-ketoglutarate-dependent oxygenases is an O2 sensor that informs the organism on the oxygen level in its environment.

  • It is included in the ATP production of cellular energy via the NADH+H+ pathway during the citric acid cycle.
  • The main area of the production of superoxide, the primary reactive oxygen species (ROS), is considered to be the respiratory chain in the mitochondria. It also has been described that the damaged key Krebs cycle enzyme, e.g., AKG- dehydrogenase (AKGDH), is also able to produce ROS. As damaged, described, as converted AKGDH is a target of ROS, it is proposed that converted AKGD is a critical factor in a vicious cycle by which oxidative stress is induced and promoted in nerve terminals.
  • It plays essential functions in oxidation reactions involving molecular oxygen e.g.in many oxygenases (e.g., AKHDG) in preventing their damage or dysfunction (O2sensor).
  • Isocitrate dehydrogenases (IDH) catalyzes the reversible conversion of isocitrate to alpha-ketoglutarate (AKG)
  • AKG with its redox potential (at least eight times higher than vitamin C) is a critical intra- but also extracellular antioxidant. Interestingly, AKG reacts with the intracellular H2O2 non- enzymatically forming succinate, which itself is a necessary intermediate in the citric cycle.

AKG removes nitrogen released by the catabolism of amino acids, thereby it balances the body’s nitrogen chemistry and prevents nitrogen overload in body tissues and fluids.

As a result of excessive protein ingestion or poor amino acid metabolism, excess nitrogen and ammonia can accumulate in cell tissue.

AKG is one of the most critical nitrogen transporters in metabolic pathways. The amino groups of amino acids are adhered to it by transamination and carried to the liver where the urea cycle takes place. AKG is transaminated, along with glutamine, to form the excitatory neurotransmitter, glutamate.

  • It is a crucial nitrogen transporter in metabolic pathways. It balances the body’s nitrogen chemistry and prevents a nitrogen overload
  • It forms the excitatory neurotransmitter glutamate. This is an enzymatically controlled detoxification of ammonia from the tissue.

The main area of production 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 are not investigated yet. Recently it has been described that a key Krebs cycle enzyme, AKG dehydrogenase (AKGDH), is also able to produce ROS after oxidative modification (= converted AKGDH). As turned AKGDH is not only a generator but also a target of ROS, it is proposed that converted AKGD is a critical factor in a vicious cycle by which oxidative stress is induced and promoted in nerve terminals.

AKG is suggested to prevent oxidative modification of AKGDH in the inner membrane of mitochondria:

  • Included in the production of cellular energy via the chemical transfer of energy during the citric acid cycle
  • Formation of carnitine, necessary for proper metabolism of fats and
  • In formation of a biologically active coenzyme form of vitamin B3

Also, AKG has been identified as the most likely physiological anion involved in renal proximal tubule basolateral membrane dicarboxylate/organic anion exchange.

Therefore:

  • AKG plays a vital role in anabolic/anticatabolic actions on protein metabolism. In detail, AKG reduces Peroxides (RONS) more effectively than 5-HMF
  • ONOO- (peroxynitrite: one of the most dangerous oxidative, delaminating and nitrating substances of purines and pyrimidines) is reduced
  • Both peroxides are generated in the inner mitochondrial membrane (dysfunction in complex III)
  • AKG is a capable detoxification substance of ammonia controlled mainly enzymatically forming either urea metabolic substances like glutamine/glutamate and arginine.

In the kidney, AKG regulates the biochemical exchange of negative charged toxic compounds in the basal membrane of the glomerulus apparatus.

Comparison of AKG vs. Vitamins

  • Antioxidants like Vitamin C and E react with all free radicals i.e., also in situ “essential” radicals (immune defense) which leads to many dysfunctions.
  • AKG eliminates predominately highly Reactive Oxygen and Nitrogen Species (RONS) (e.g., peroxides) but not the “Essential” one!
  • In their function to remove free radicals antioxidants turn to highly potential substances (e.g., Vitamin C Radical) which also result in uncontrolled dysfunctions (e.g., NOS dysfunction)
  • AKG, in its function as an antioxidant, turns to a harmless substance (succinate) without any oxidative potential. Succinate itself is used in many essential physiological processes in vivo. e.g., the central nervous system

AKG in Surgery

In a research of Blomqvist, patients undergoing surgery were given 0.28 g/kg b.w., corresponding to about 20 kg / 70 kg, to evaluate the effect of the substance in decreasing the protein catabolism in muscle cells.

Coudray conducted experiments on the wound healing properties of the combination ornithine- AKG, where patients suffering severe burns were enterally administered with 20 g/d. This concentration was considered to be “safe and well-tolerated.”

After Coudray AKG affected the whole-body energy expenditure and in contrary to observations with glutamine or glutamate, AKG was retained in the body independently from the method of administration.

AKG enhances renal blood flow after coronary artery surgery (and increases myocardial oxidative capacity.

AKG as a precursor for glutamine synthesis in skeletal muscle is crucial for the degree of muscle protein catabolism and may improve recovery after trauma.

AKG as Part of Ypera ®

Alpha-Ketoglutarate (AKG) is one of the active QoL Enhancer ™ ingredients in the proprietary Molecular Action Blend ™ of Ypera ®.

Also see: Ypera ®

as Part of Ypera ®

Alpha-Ketoglutarate (AKG) is one of the active QoL Enhancer ™ ingredients in the proprietary Molecular Action Blend ™ of Ypera ®.

Also see: Ypera ®

  • Is known as glutamine and glutamic acid; exists naturally in the body’s cells as a complete nitrogen-free part of the amino acids
  • Is a crucial biological intermediate in ATP production to generate energy in the cells (citric acid cycle)
  • Is a stronger free radical (RONS) scavenger than vitamin C
  • Has an essential function in the oxidation reactions with molecular oxygen (for example, AKDHG) for the reduction of tissue damage or dysfunction (O2 sensor)
  • Acts as a nitrogen regulator in the metabolism and prevents an escalated nitrogen level (NH4+)
  • Generates the stimulating neurotransmitter glutamate and leads to an enzymatically controlled detoxification of ammonia from the tissues (for example, the central nervous system)

quicker optimization of urgent and vital operations through

  • Increase in ATP synthesis
  • Metabolic support of the oxygen supply in the cardiac and skeletal musculature (protein synthesis)

and other associated improvements to the body’s performance.

Optimizes the course of surgery due to

  • The preventative reduction of oxidative stress and the restriction of an oxidative rise
  • During the operation the decline of oxidative injuries and their associated effects such as ischemia and reperfusion
  • A decrease in the generation of free radicals and their toxic products (RONS)

Reduces the occurrence of complications after surgery through

  • The restriction of ischemia and reperfusion

Optimization and an increase in the rate of the healing process through

  • Increased ATP synthesis
  • Improvement in the ratio of aerobic and anaerobic metabolism and, therefore, an increased anaerobic threshold (training optimization)
  • Enhanced activity of the mitochondria enzyme (energy production)
  • Better performance and better utilization of oxygen
  • Metabolic support of the oxygen supply in the cardiac and skeletal musculature (protein synthesis)
  • Better performance and better use of oxygen
  • Metabolic support of the oxygen supply in the cardiac and skeletal musculature (protein synthesis)

The synergistic effects of AKG in the proprietary  Molecular Action Blend ™ of Ypera ®

  • Increases ATP production and improves the general state of health, as well as physical performance associated with accelerated recovery and rehabilitation.
  • Impedes and discourages harmful changes in the body, which appear as a result of oxidative stress reactions.
  • Enhances oxygen utilization and muscle protein synthesis during the rehabilitation period.

Integrated Overview and Conclusions

AKG is a naturally occurring nitrogen-free portion of the amino acids glutamine and glutamic acid and a key intermediate in the citric acid cycle. It is naturally occurring in human metabolism and can, therefore, be considered to be nontoxic. AKG is also essential for the detoxification of ammonia and amines within the urea cycle by the transport of glutamate. In tumor cells, anaerobic metabolism is often observed accompanied by downregulation of different enzymes of the citric acid cycle after oxidative damage, one of that is alpha-ketoglutarate dehydrogenase. AKG was shown to exert antioxidant effects which may be of benefit for patients. AKG was shown to be well absorbed by the gastrointestinal tract, and it was shown to be evenly distributed throughout the body. AKG was completely metabolized, most probably in the liver; no unchanged AKG was excreted in test subjects.

AKG has been shown to reduce ischemic injury and to improve myocardial function in experimental and clinical heart operations. A clinical randomized, controlled study with 24 male patients undergoing coronary surgery demonstrated that AKG (28 g/L) when added to blood cardioplegia for intermittent antegrade intracoronary perfusion, reduced the appearance of the ischemic markers creatine kinase MB and troponin T in the blood. It was suggested that the attenuated ischemic injury observed with AKG was secondary to an enhanced myocardial oxidative capacity(47). Due to its effect on myocardial protection during heart surgery AKG (1 mmol/L) is included in approved cardioplegic solutions such as Custodiol.

In a randomized, controlled study, the role of AKG in renal function after cardiac surgical procedures were investigated. Eleven patients received intravenous infusion of 30 g AKG at 300 g/l following coronary surgery(37). AKG significantly enhanced renal blood flow in these patients compared to patients in the control group. Even though the exact mechanism remained unclear primarily metabolic effects were suggested to convey this beneficial effect on renal function.

There are limited data on the pharmacokinetic properties of AKG in humans. Besides the citrate cycle, there are three additional main metabolic pathways involving AKG: AKG can be used to produce 2,5- dioxopentanoate as an intermediate used in the ascorbate and aldarate metabolism. Furthermore, AKG can be reversibly metabolized to L-glutamate and then further to glutamine.

Following ingestion, AKG is absorbed from the small intestine from where it is transported to the liver. In the liver, AKG is metabolized mainly to L-glutamine. AKG that is not metabolized by the liver is transported via the systemic circulation and distributed to various tissues of the body, including the brain. Under conditions of trauma or burn injury, AKG may be metabolized in immune cells, enterocytes (epithelial cells of the superficial layer of the small and large intestine tissue that can help break up molecules and transport them into the tissues) and muscle tissue to produce L-glutamine.

In clinical studies, the efficacy and safety of AKG in the treatment of burn and other trauma patients, as well as in chronically malnourished patients, post-surgery and sports were examined. Oral and intravenous daily doses up to 30 g in adults and 15 g in prepubertal children are considered safe.


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* These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.