Α-Ketoisocaproic acid explained

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 -leucine. Leucine is an essential amino acid, and its degradation is critical for many biological duties.[1] 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] [3] [4] α-KIC is a key metabolite present in the urine of people with Maple syrup urine disease, along with other branched-chain amino acids.[5] 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 ergogenicsupplements present as well.[6] 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.[7]

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.[6] 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.[7] 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.[8] 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.[9] [10]

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.[11]

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.[12] These keto-acids build up in the liver,[2] [3] [4] 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.[5] 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.[12] [5] Treatment includes lowering leucine intake and a specialized diet to make up for the lack of leucine ingestion.[5]

Leucine metabolism

Notes and References

  1. Web site: Leucine.
  2. Wilson . Jacob M. . Fitschen . Peter J. . Campbell . Bill . Wilson . Gabriel J. . Zanchi . Nelo . Taylor . Lem . Wilborn . Colin . Kalman . Douglas S. . Stout . Jeffrey R. . Hoffman . Jay R. . Ziegenfuss . Tim N. . Lopez . Hector L. . Kreider . Richard B. . Smith-Ryan . Abbie E. . Antonio . Jose . International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB) . Journal of the International Society of Sports Nutrition . 2 February 2013 . 10 . 1 . 6 . 10.1186/1550-2783-10-6 . free . 23374455 . 3568064 .
  3. Zanchi . Nelo Eidy . Gerlinger-Romero . Frederico . Guimarães-Ferreira . Lucas . de Siqueira Filho . Mário Alves . Felitti . Vitor . Lira . Fabio Santos . Seelaender . Marília . Lancha . Antonio Herbert . HMB supplementation: clinical and athletic performance-related effects and mechanisms of action . Amino Acids . April 2011 . 40 . 4 . 1015–1025 . 10.1007/s00726-010-0678-0 . 20607321 . 11120110 .
  4. Book: Kohlmeier . M . May 2015 . Leucine . Nutrient Metabolism: Structures, Functions, and Genes . 2nd . Academic Press . 385–388 . 978-0-12-387784-0 .
  5. Book: Kevin A . Strauss . Erik G . Puffenberger . Vincent J . Carson . Maple Syrup Urine Disease . GeneReviews . 1993 . University of Washington, Seattle . https://www.ncbi.nlm.nih.gov/books/NBK1319/ .
  6. Book: 10.1016/B978-0-12-396454-0.00044-8 . An Overview of Glycine-Arginine-Alpha-Ketoisocaproic Acid (GAKIC) in Sports Nutrition . Nutrition and Enhanced Sports Performance . 2013 . Stevens . Bruce R. . 433–438 . 978-0-12-396454-0 .
  7. Someren . Ken A. van . Edwards . Adam J. . Howatson . Glyn . Supplementation with β-Hydroxy- β-Methylbutyrate (HMB) and α-Ketoisocaproic Acid (KIC) Reduces Signs and Symptoms of Exercise-Induced Muscle Damage in Man . International Journal of Sport Nutrition and Exercise Metabolism . 1 August 2005 . 15 . 4 . 413–424 . 10.1123/ijsnem.15.4.413 . 16286672 .
  8. Yarrow . Joshua F . Parr . Jeffrey J . White . Lesley J . Borsa . Paul A . Stevens . Bruce R . The effects of short-term alpha-ketoisocaproic acid supplementation on exercise performance: a randomized controlled trial . Journal of the International Society of Sports Nutrition . December 2007 . 4 . 1 . 2 . 10.1186/1550-2783-4-2 . free . 17908285 . 2042499 .
  9. Nissen . S. . Sharp . R. L. . Panton . L. . Vukovich . M. . Trappe . S. . Fuller . J. C. . β-Hydroxy-β-Methylbutyrate (HMB) Supplementation in Humans Is Safe and May Decrease Cardiovascular Risk Factors . The Journal of Nutrition . 1 August 2000 . 130 . 8 . 1937–1945 . 10.1093/jn/130.8.1937 . 10917905 . free .
  10. Baxter . J.H. . Carlos . J.L. . Thurmond . J. . Rehani . R.N. . Bultman . J. . Frost . D. . Dietary toxicity of calcium β-hydroxy-β-methyl butyrate (CaHMB) . Food and Chemical Toxicology . December 2005 . 43 . 12 . 1731–1741 . 10.1016/j.fct.2005.05.016 . 16006030 .
  11. Interrupting the mechanisms of brain injury in a model of maple syrup urine disease encephalopathy. 10.1007/s10545-011-9333-5. 2012. Zinnanti. William J.. Lazovic. Jelena. Journal of Inherited Metabolic Disease. 35. 1. 71–79. 21541722. 1253267.
  12. Strauss . Kevin A. . Wardley . Bridget . Robinson . Donna . Hendrickson . Christine . Rider . Nicholas L. . Puffenberger . Erik G. . Shelmer . Diana . Moser . Ann B. . Morton . D. Holmes . Classical maple syrup urine disease and brain development: Principles of management and formula design . Molecular Genetics and Metabolism . April 2010 . 99 . 4 . 333–345 . 10.1016/j.ymgme.2009.12.007 . 20061171 . 3671925 .

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