Alpha-Ketoisocaproic acid
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α-Ketoisocaproic acid (α-KIC) and its
conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...
, α-ketoisocaproate, are
metabolic intermediate Metabolic intermediates are molecules that are the precursors or metabolites of biologically significant molecules. Although these intermediates are of relatively minor direct importance to cellular function, they can play important roles in the a ...
s in the metabolic pathway for -leucine. Leucine is an essential amino acid, and its degradation is critical for many biological duties. α-KIC is produced in one of the first steps of the pathway by
branched-chain amino acid aminotransferase Branched-chain amino acid aminotransferase (BCAT), also known as branched-chain amino acid transaminase, is an aminotransferase enzyme which acts upon branched-chain amino acids (BCAAs). It is encoded by the ''BCAT2'' gene in humans. The BCAT enz ...
by transferring the
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
on L-leucine onto
alpha ketoglutarate Alpha (uppercase , lowercase ; grc, ἄλφα, ''álpha'', or ell, άλφα, álfa) is the first letter of the Greek alphabet. In the system of Greek numerals, it has a value of one. Alpha is derived from the Phoenician letter aleph , whic ...
, and replacing that amine with a
ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
. The degradation of L-leucine in the
muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
to this compound allows for the production of the amino acids alanine and
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
as well. In the liver, α-KIC can be converted to a vast number of compounds depending on the enzymes and
cofactors Cofactor may also refer to: * Cofactor (biochemistry), a substance that needs to be present in addition to an enzyme for a certain reaction to be catalysed * A domain parameter in elliptic curve cryptography, defined as the ratio between the order ...
present, including cholesterol,
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...
,
isovaleryl-CoA Isovaleryl-coenzyme A, also known as isovaleryl-CoA, is an intermediate in the metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main fun ...
, and other biological molecules. Isovaleryl-CoA is the main compound synthesized from ɑ-KIC. α-KIC is a key
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
present in the urine of people with
Maple syrup urine disease Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder affecting branched-chain amino acids. It is one type of organic acidemia. The condition gets its name from the distinctive sweet odor of affected infants' urine and ear ...
, along with other branched-chain amino acids. Derivatives of α-KIC have been studied in humans for their ability to improve physical performance during
anaerobic exercise Anaerobic exercise is a type of exercise that breaks down glucose in the body without using oxygen; ''anaerobic'' means "without oxygen". In practical terms, this means that anaerobic exercise is more intense, but shorter in duration than aerobi ...
as a supplemental bridge between short-term and long-term exercise supplements. These studies show that α-KIC does not achieve this goal without other ergogenicsupplements present as well. α-KIC has also been observed to reduce
skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
damage after eccentrically biased resistance exercises in people who do not usually perform those exercises.


Biological Activity


Supplements

α-KIC has been studied as a nutritional supplement to aid in the performance of strenuous physical activity. Studies have shown that taking ɑ-KIC and its derivatives before acute physical activity led to an increase in muscle work by 10%, as well as a decrease in muscle
fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
during the early phase of the physical activity. When taken with other supplements over a two-week period, such as
beta-hydroxy beta-methylbutyrate β-Hydroxy β-methylbutyric acid (HMB), otherwise known as its conjugate base, , is a naturally produced substance in humans that is used as a dietary supplement and as an ingredient in certain medical foods that are intended to promote wou ...
(HMB), participants reported delayed onset of
muscle soreness Muscle soreness may refer to: * Acute muscle soreness (AMS), which appears during or immediately after exercise and lasts up to 24 hours. * Delayed onset muscle soreness Delayed onset muscle soreness (DOMS) is the pain and stiffness felt in musc ...
, as well as other positive effects such as increased muscle girth. It is important to note that studies have also suggested that ɑ-KIC taken alone did not have any significant positive impacts on physical performance, so it should be taken in conjunction with other ergogenic substances. ɑ-KIC is not available as a supplement on its own, but its aminated form HMB is available in calcium salt capsules or powder.


Applications

The biochemical implications of α-KIC are largely connected to other biochemical pathways.
Protein Synthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside Cell (biology), cells, homeostasis, balancing the loss of cellular proteins (via Proteolysis, degradation or Protein targeting, export) through the product ...
, skeletal muscle
regeneration Regeneration may refer to: Science and technology * Regeneration (biology), the ability to recreate lost or damaged cells, tissues, organs and limbs * Regeneration (ecology), the ability of ecosystems to regenerate biomass, using photosynthesis ...
, and skeletal muscle
proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
have all been noted to change when ɑ-KIC is taken. There is not much research into the specific mechanisms taking part in these processes, but there is a noticeable correlation between ɑ-KIC ingestion and increased skeletal muscle protein synthesis, regeneration, and proteolysis.


Toxicity

Multiple studies have demonstrated that there have been no adverse effects on humans nor animals that ingested α-KIC or HMB. In patients with
maple syrup urine disease Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder affecting branched-chain amino acids. It is one type of organic acidemia. The condition gets its name from the distinctive sweet odor of affected infants' urine and ear ...
, who are unable to metabolize the branched chain alpha keto acids, α-KIC is believed to be one of the key mediators of neurotoxicity.


Medical Use

Branched-chain alpha-keto acids such as α-KIC are found in high concentrations in the urine of people who suffer from Maple Syrup Urine Disease. This is disease is caused by a partial
branched-chain alpha-keto acid dehydrogenase The branched-chain α-ketoacid dehydrogenase complex (BCKDC or BCKDH complex) is a multi-subunit complex of enzymes that is found on the mitochondrial inner membrane. This enzyme complex catalyzes the oxidative decarboxylation of branched, short-ch ...
deficiency, which leads to a buildup of branched-chain alpha-keto acids, including α-KIC and HMB. These keto-acids build up in the liver, and since limited isovaleryl-CoA can be produced, these keto-acids must be excreted in the urine as α-KIC, HMB, and many other similar keto acids. Flare-ups in people who have this condition are caused due to poor diet. Symptoms of Maple Syrup Urine Disease include sweet smelling urine, irritability, lethargy, and in serious cases
edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...
of the brain,
apnea Apnea, BrE: apnoea, is the temporal cessation of breathing. During apnea, there is no movement of the muscles of inhalation, and the volume of the lungs initially remains unchanged. Depending on how blocked the airways are ( patency), there ...
,
coma A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to respond normally to painful stimuli, light, or sound, lacks a normal wake-sleep cycle and does not initiate voluntary actions. Coma patients exhi ...
, or respiratory failure. Treatment includes lowering leucine intake and a specialized diet to make up for the lack of leucine ingestion.


Leucine metabolism


References

{{DEFAULTSORT:Ketoisocaproic acid, alpha- Alpha-keto acids