Α-Ketoisocaproic acid

α-Ketoisocaproic acid (α-KIC), also known as 4-methyl-2-oxovaleric acid, and its conjugate base and carboxylate, α-ketoisocaproate, are metabolic intermediates in the metabolic pathway for L-leucine.^[2] Leucine is an essential amino acid, and its degradation is critical for many biological duties.^[3] α-KIC is produced in one of the first steps of the pathway by branched-chain amino acid aminotransferase by transferring the amine on L-leucine onto alpha ketoglutarate, and replacing that amine with a ketone. The degradation of L-leucine in the muscle to this compound allows for the production of the amino acids alanine and glutamate as well. In the liver, α-KIC can be converted to a vast number of compounds depending on the enzymes and cofactors present, including cholesterol, acetyl-CoA, isovaleryl-CoA, and other biological molecules. Isovaleryl-CoA is the main compound synthesized from ɑ-KIC.^[2][4][5] α-KIC is a key metabolite present in the urine of people with Maple syrup urine disease, along with other branched-chain amino acids.^[6] Derivatives of α-KIC have been studied in humans for their ability to improve physical performance during anaerobic exercise 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 ergogenic supplements present as well.^[7] α-KIC has also been observed to reduce skeletal muscle damage after eccentrically biased resistance exercises in people who do not usually perform those exercises.^[8]

α-Ketoisocaproic acid

Skeletal formula of alpha-ketoisocaproic acid
Names
IUPAC name 4-Methyl-2-oxopentanoic acid
Systematic IUPAC name 4-Methyl-2-oxopentanoic acid[1]
Other names 4-Methyl-2-oxovaleric acid 2-Ketoisocaproic acid 2-Oxo-4-methylpentanoic acid 2-Oxo-4-methylvaleric acid 2-Oxoisocaproic acid 2-Oxoleucine Isobutylglyoxylic acid Ketoleucine α-Ketoisocapronic acid α-Oxoisocaproic acid
Identifiers
CAS Number	816-66-0 Y
3D model (JSmol)	Interactive image Interactive image
Beilstein Reference	1701823
ChEBI	CHEBI:48430 Y
ChEMBL	ChEMBL445647 Y
ChemSpider	69 Y
DrugBank	DB03229 Y
ECHA InfoCard	100.011.304
EC Number	212-435-5
IUPHAR/BPS	4656
KEGG	C00233 Y
MeSH	Alpha-ketoisocaproic+acid
PubChem CID	70
UNII	4GUJ8AH400 Y
UN number	3265
CompTox Dashboard (EPA)	DTXSID6061157
InChI InChI=1S/C6H10O3/c1-4(2)3-5(7)6(8)9/h4H,3H2,1-2H3,(H,8,9) Y Key: BKAJNAXTPSGJCU-UHFFFAOYSA-N Y InChI=1/C6H10O3/c1-4(2)3-5(7)6(8)9/h4H,3H2,1-2H3,(H,8,9) Key: BKAJNAXTPSGJCU-UHFFFAOYAG
SMILES CC(C)CC(=O)C(O)=O O=C(C(=O)O)CC(C)C
Properties
Chemical formula	C6H10O3
Molar mass	130.143 g·mol−1
Density	1.055 g cm−3 (at 20 °C)
Melting point	8 to 10 °C (46 to 50 °F; 281 to 283 K)
Boiling point	85 °C (185 °F; 358 K) at 13 mmHg
log P	0.133
Acidity (pKa)	2.651
Basicity (pKb)	11.346
Hazards
GHS labelling:
Pictograms
Signal word	Danger
Hazard statements	H314
Precautionary statements	P260, P264, P280, P301+P330+P331, P303+P361+P353, P304+P340, P305+P351+P338, P310, P321, P363, P405, P501
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Y verify (what is YN ?) Infobox references

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 during the early phase of the physical activity.^[7] When taken with other supplements over a two-week period, such as beta-hydroxy beta-methylbutyrate (HMB), participants reported delayed onset of muscle soreness, as well as other positive effects such as increased muscle girth.^[8] 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.^[9] ɑ-KIC is not available as a supplement on its own, but its decarboxylated form HMB is available in calcium salt capsules or powder.^[2]

Applications

The biochemical implications of α-KIC are largely connected to other biochemical pathways. Protein Synthesis, skeletal muscle regeneration, and skeletal muscle proteolysis 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.^[2]

Toxicity

Multiple studies have demonstrated that there have been no adverse effects on humans nor animals that ingested α-KIC or HMB.^[10][11]

In patients with maple syrup urine disease, who are unable to metabolize the branched chain alpha keto acids, α-KIC is believed to be one of the key mediators of neurotoxicity.^[12]

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 deficiency, which leads to a buildup of branched-chain alpha-keto acids, including α-KIC and HMB.^[13] These keto-acids build up in the liver,^[2][4][5] 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.^[6] Symptoms of Maple Syrup Urine Disease include sweet smelling urine, irritability, lethargy, and in serious cases edema of the brain, apnea, coma, or respiratory failure.^[13][6] Treatment includes lowering leucine intake and a specialized diet to make up for the lack of leucine ingestion.^[6]

Leucine metabolism

Leucine metabolism in humans L-Leucine Branched-chain amino acid aminotransferase α-Ketoglutarate Glutamate Glutamate Alanine Pyruvate Muscle: α-Ketoisocaproate (α-KIC) Liver: α-Ketoisocaproate (α-KIC) Branched-chain α-ketoacid dehydrogenase (mitochondria) KIC-dioxygenase (cytosol) Isovaleryl-CoA β-Hydroxy β-methylbutyrate (HMB) Excreted in urine (10–40%) HMB-CoA β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) β-Methylcrotonyl-CoA (MC-CoA) β-Methylglutaconyl-CoA (MG-CoA) CO2 CO2 O2 CO2 H2O CO2 H2O (liver) HMG-CoA lyase Enoyl-CoA hydratase Isovaleryl-CoA dehydrogenase MC-CoA carboxylase MG-CoA hydratase HMG-CoA reductase HMG-CoA  synthase β-Hydroxybutyrate dehydrogenase Mevalonate pathway Thiolase Unknown enzyme β-Hydroxybutyrate Acetoacetyl-CoA Acetyl-CoA Acetoacetate Mevalonate Cholesterol Human metabolic pathway for HMB and isovaleryl-CoA relative to L-leucine.[14][15][16] Of the two major pathways, L-leucine is mostly metabolized into isovaleryl-CoA, while only about 5% is metabolized into HMB.[14][15][16]