Α-Ketoisocaproic acid: Difference between revisions
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'''α-Ketoisocaproic acid''' ('''α-KIC''') and its [[conjugate base]], '''α-ketoisocaproate''', are [[metabolic intermediate]]s in the [[Leucine metabolism|metabolic pathway for {{smallcaps all|L}}-leucine]].<ref name="ISSN position stand 2013" /> [[Leucine]] is a [[non-essential amino acid]], and its degradation is critical for many biological duties.<ref>https://pubchem.ncbi.nlm.nih.gov/compound/Leucine</ref> 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 acid]]s [[alanine]] and [[Glutamate (neurotransmitter)|glutamate]] as well. In the [[liver]], α-KIC can be converted to a vast number of compounds depending on the [[enzyme]]s and [[Cofactor (biochemistry)|cofactors]] present, including [[cholesterol]], [[acetyl-CoA]], [[isovaleryl-CoA]], and other biological molecules. Isovaleryl-CoA is the main compound synthesized from ɑ-KIC.<ref name="Wilson1">Wilson |
'''α-Ketoisocaproic acid''' ('''α-KIC''') and its [[conjugate base]], '''α-ketoisocaproate''', are [[metabolic intermediate]]s in the [[Leucine metabolism|metabolic pathway for {{smallcaps all|L}}-leucine]].<ref name="ISSN position stand 2013" /> [[Leucine]] is a [[non-essential amino acid]], and its degradation is critical for many biological duties.<ref>https://pubchem.ncbi.nlm.nih.gov/compound/Leucine</ref> 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 acid]]s [[alanine]] and [[Glutamate (neurotransmitter)|glutamate]] as well. In the [[liver]], α-KIC can be converted to a vast number of compounds depending on the [[enzyme]]s and [[Cofactor (biochemistry)|cofactors]] present, including [[cholesterol]], [[acetyl-CoA]], [[isovaleryl-CoA]], and other biological molecules. Isovaleryl-CoA is the main compound synthesized from ɑ-KIC.<ref name="Wilson1">{{cite journal |last1=Wilson |first1=Jacob M. |last2=Fitschen |first2=Peter J. |last3=Campbell |first3=Bill |last4=Wilson |first4=Gabriel J. |last5=Zanchi |first5=Nelo |last6=Taylor |first6=Lem |last7=Wilborn |first7=Colin |last8=Kalman |first8=Douglas S. |last9=Stout |first9=Jeffrey R. |last10=Hoffman |first10=Jay R. |last11=Ziegenfuss |first11=Tim N. |last12=Lopez |first12=Hector L. |last13=Kreider |first13=Richard B. |last14=Smith-Ryan |first14=Abbie E. |last15=Antonio |first15=Jose |title=International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB) |journal=Journal of the International Society of Sports Nutrition |date=2 February 2013 |volume=10 |issue=1 |pages=6 |doi=10.1186/1550-2783-10-6 |pmid=23374455 |pmc=3568064 }}</ref><ref name="Zanchi1">{{cite journal |last1=Zanchi |first1=Nelo Eidy |last2=Gerlinger-Romero |first2=Frederico |last3=Guimarães-Ferreira |first3=Lucas |last4=de Siqueira Filho |first4=Mário Alves |last5=Felitti |first5=Vitor |last6=Lira |first6=Fabio Santos |last7=Seelaender |first7=Marília |last8=Lancha |first8=Antonio Herbert |title=HMB supplementation: clinical and athletic performance-related effects and mechanisms of action |journal=Amino Acids |date=April 2011 |volume=40 |issue=4 |pages=1015–1025 |doi=10.1007/s00726-010-0678-0 |pmid=20607321 }}</ref><ref name="Kohlmeier1">Kohlmeier M (May 2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388. {{ISBN|978-0-12-387784-0}}. Retrieved 6 June 2016.</ref> α-KIC is a key [[metabolite]] present in the [[urine]] of people with [[Maple syrup urine disease]], along with other [[branched-chain amino acid]]s.<ref name=NBK1319>{{cite book |first1=Kevin A |last1=Strauss |first2=Erik G |last2=Puffenberger |first3=Vincent J |last3=Carson |chapter=Maple Syrup Urine Disease |title=GeneReviews |chapterurl=https://www.ncbi.nlm.nih.gov/books/NBK1319/ }}</ref> 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]]<nowiki/>supplements present as well.<ref name="Stevens1">{{cite journal |doi=10.1016/B978-0-12-396454-0.00044-8 }}</ref> α-KIC has also been observed to reduce [[skeletal muscle]] damage after eccentrically biased [[Resistance exercise|resistance exercises]] in people who do not usually perform those exercises.<ref name="Van1">{{cite journal |last1=Someren |first1=Ken A. van |last2=Edwards |first2=Adam J. |last3=Howatson |first3=Glyn |title=Supplementation with β-Hydroxy- β-Methylbutyrate (HMB) and α-Ketoisocaproic Acid (KIC) Reduces Signs and Symptoms of Exercise-Induced Muscle Damage in Man |journal=International Journal of Sport Nutrition and Exercise Metabolism |date=1 August 2005 |volume=15 |issue=4 |pages=413–424 |doi=10.1123/ijsnem.15.4.413 |pmid=16286672 }}</ref> |
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==Biological Activity== |
==Biological Activity== |
||
===Supplements=== |
===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.<ref name="Stevens1"/> When taken with other supplements over a two week period, such as [[Beta-Hydroxy beta-methylbutyric acid|beta-hydroxy beta-methylbutyrate]] (HMB), participants reported delayed onset of [[muscle soreness]], as well as other positive effects such as increased muscle girth.<ref name="Van1"/> 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.<ref>Yarrow |
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.<ref name="Stevens1"/> When taken with other supplements over a two week period, such as [[Beta-Hydroxy beta-methylbutyric acid|beta-hydroxy beta-methylbutyrate]] (HMB), participants reported delayed onset of [[muscle soreness]], as well as other positive effects such as increased muscle girth.<ref name="Van1"/> 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.<ref>{{cite journal |last1=Yarrow |first1=Joshua F |last2=Parr |first2=Jeffrey J |last3=White |first3=Lesley J |last4=Borsa |first4=Paul A |last5=Stevens |first5=Bruce R |title=The effects of short-term alpha-ketoisocaproic acid supplementation on exercise performance: a randomized controlled trial |journal=Journal of the International Society of Sports Nutrition |date=December 2007 |volume=4 |issue=1 |pages=2 |doi=10.1186/1550-2783-4-2 }}</ref> ɑ-KIC is not available as a supplement on its own, but its aminated form HMB is available in calcium salt capsules or powder.<ref name="Wilson1"/> |
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===Applications=== |
===Applications=== |
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==Toxicity== |
==Toxicity== |
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Multiple studies have demonstrated that there have been no adverse effects on humans nor animals that ingested α-KIC or HMB.<ref>Nissen S |
Multiple studies have demonstrated that there have been no adverse effects on humans nor animals that ingested α-KIC or HMB.<ref>{{cite journal |last1=Nissen |first1=S. |last2=Sharp |first2=R. L. |last3=Panton |first3=L. |last4=Vukovich |first4=M. |last5=Trappe |first5=S. |last6=Fuller |first6=J. C. |title=β-Hydroxy-β-Methylbutyrate (HMB) Supplementation in Humans Is Safe and May Decrease Cardiovascular Risk Factors |journal=The Journal of Nutrition |date=1 August 2000 |volume=130 |issue=8 |pages=1937–1945 |doi=10.1093/jn/130.8.1937 |pmid=10917905 }}</ref><ref>{{cite journal |last1=Baxter |first1=J.H. |last2=Carlos |first2=J.L. |last3=Thurmond |first3=J. |last4=Rehani |first4=R.N. |last5=Bultman |first5=J. |last6=Frost |first6=D. |title=Dietary toxicity of calcium β-hydroxy-β-methyl butyrate (CaHMB) |journal=Food and Chemical Toxicology |date=December 2005 |volume=43 |issue=12 |pages=1731–1741 |doi=10.1016/j.fct.2005.05.016 }}</ref> |
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==Medical Use== |
==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 complex|branched-chain alpha-keto acid dehydrogenase]] deficiency, which leads to a buildup of branched-chain alpha-keto acids, including α-KIC and HMB.<ref name="Strauss1">Strauss |
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 complex|branched-chain alpha-keto acid dehydrogenase]] deficiency, which leads to a buildup of branched-chain alpha-keto acids, including α-KIC and HMB.<ref name="Strauss1">{{cite journal |last1=Strauss |first1=Kevin A. |last2=Wardley |first2=Bridget |last3=Robinson |first3=Donna |last4=Hendrickson |first4=Christine |last5=Rider |first5=Nicholas L. |last6=Puffenberger |first6=Erik G. |last7=Shelmer |first7=Diana |last8=Moser |first8=Ann B. |last9=Morton |first9=D. Holmes |title=Classical maple syrup urine disease and brain development: Principles of management and formula design |journal=Molecular Genetics and Metabolism |date=April 2010 |volume=99 |issue=4 |pages=333–345 |doi=10.1016/j.ymgme.2009.12.007 }}</ref> These keto-acids build up in the [[liver]],<ref name="Wilson1"/><ref name="Zanchi1"/><ref name="Kohlmeier1"/> and since limited isovaleryl-CoA can be produced, these keto-acids must be [[excrete]]<nowiki/>d in the urine as α-KIC, HMB, and many other similar [[keto acid]]s. Flare-ups in people who have this condition are caused due to poor diet.<ref name=NBK1319/> 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]].<ref name="Strauss1"/><ref name=NBK1319/> Treatment includes lowering leucine intake and a specialized diet to make up for the lack of leucine ingestion.<ref name=NBK1319/> |
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==Leucine metabolism== |
==Leucine metabolism== |
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Revision as of 18:01, 8 December 2020
| |
| Names | |
|---|---|
| IUPAC name
4-Methyl-2-oxopentanoic acid
| |
| Systematic IUPAC name
4-Methyl-2-oxopentanoic acid[1] | |
| Other names
4-Methyl-2-oxovaleric acid
| |
| Identifiers | |
3D model (JSmol)
|
|
| 3DMet | |
| 1701823 | |
| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| DrugBank | |
| ECHA InfoCard | 100.011.304 |
| EC Number |
|
| KEGG | |
| MeSH | Alpha-ketoisocaproic+acid |
PubChem CID
|
|
| UNII | |
| UN number | 3265 |
CompTox Dashboard (EPA)
|
|
| |
| |
| Properties | |
| 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 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
| |
α-Ketoisocaproic acid (α-KIC) and its conjugate base, α-ketoisocaproate, are metabolic intermediates in the metabolic pathway for L-leucine.[2] Leucine is a non-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.[4][5][6] α-KIC is a key metabolite present in the urine of people with Maple syrup urine disease, along with other branched-chain amino acids.[7] 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.[8] 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.[9]
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.[8] 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.[9] 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.[10] ɑ-KIC is not available as a supplement on its own, but its aminated form HMB is available in calcium salt capsules or powder.[4]
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.[4]
Toxicity
Multiple studies have demonstrated that there have been no adverse effects on humans nor animals that ingested α-KIC or HMB.[11][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,[4][5][6] 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.[7] 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][7] Treatment includes lowering leucine intake and a specialized diet to make up for the lack of leucine ingestion.[7]
Leucine metabolism
 |
References
- ^ CID 70 from PubChem
- ^ a b c Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". Journal of the International Society of Sports Nutrition. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455.
- ^ https://pubchem.ncbi.nlm.nih.gov/compound/Leucine
- ^ a b c d 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 (2 February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". Journal of the International Society of Sports Nutrition. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ a b Zanchi, Nelo Eidy; Gerlinger-Romero, Frederico; Guimarães-Ferreira, Lucas; de Siqueira Filho, Mário Alves; Felitti, Vitor; Lira, Fabio Santos; Seelaender, Marília; Lancha, Antonio Herbert (April 2011). "HMB supplementation: clinical and athletic performance-related effects and mechanisms of action". Amino Acids. 40 (4): 1015–1025. doi:10.1007/s00726-010-0678-0. PMID 20607321.
- ^ a b Kohlmeier M (May 2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388. ISBN 978-0-12-387784-0. Retrieved 6 June 2016.
- ^ a b c d Strauss, Kevin A; Puffenberger, Erik G; Carson, Vincent J. "Maple Syrup Urine Disease". GeneReviews.
{{cite book}}: External link in|chapterurl=|chapterurl=ignored (|chapter-url=suggested) (help) - ^ a b . doi:10.1016/B978-0-12-396454-0.00044-8.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ a b Someren, Ken A. van; Edwards, Adam J.; Howatson, Glyn (1 August 2005). "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. 15 (4): 413–424. doi:10.1123/ijsnem.15.4.413. PMID 16286672.
- ^ Yarrow, Joshua F; Parr, Jeffrey J; White, Lesley J; Borsa, Paul A; Stevens, Bruce R (December 2007). "The effects of short-term alpha-ketoisocaproic acid supplementation on exercise performance: a randomized controlled trial". Journal of the International Society of Sports Nutrition. 4 (1): 2. doi:10.1186/1550-2783-4-2.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Nissen, S.; Sharp, R. L.; Panton, L.; Vukovich, M.; Trappe, S.; Fuller, J. C. (1 August 2000). "β-Hydroxy-β-Methylbutyrate (HMB) Supplementation in Humans Is Safe and May Decrease Cardiovascular Risk Factors". The Journal of Nutrition. 130 (8): 1937–1945. doi:10.1093/jn/130.8.1937. PMID 10917905.
- ^ Baxter, J.H.; Carlos, J.L.; Thurmond, J.; Rehani, R.N.; Bultman, J.; Frost, D. (December 2005). "Dietary toxicity of calcium β-hydroxy-β-methyl butyrate (CaHMB)". Food and Chemical Toxicology. 43 (12): 1731–1741. doi:10.1016/j.fct.2005.05.016.
- ^ a b Strauss, Kevin A.; Wardley, Bridget; Robinson, Donna; Hendrickson, Christine; Rider, Nicholas L.; Puffenberger, Erik G.; Shelmer, Diana; Moser, Ann B.; Morton, D. Holmes (April 2010). "Classical maple syrup urine disease and brain development: Principles of management and formula design". Molecular Genetics and Metabolism. 99 (4): 333–345. doi:10.1016/j.ymgme.2009.12.007.
- ^ a b Kohlmeier M (May 2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388. ISBN 978-0-12-387784-0. Retrieved 6 June 2016.
Energy fuel: Eventually, most Leu is broken down, providing about 6.0kcal/g. About 60% of ingested Leu is oxidized within a few hours ... Ketogenesis: A significant proportion (40% of an ingested dose) is converted into acetyl-CoA and thereby contributes to the synthesis of ketones, steroids, fatty acids, and other compounds
Figure 8.57: Metabolism of L-leucine
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