alpha-Ketoisocaproic acid

α-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
Identifiers
CAS Number	816-66-0 ;
3D model (JSmol)	Interactive image; Interactive image;
3DMet	B00066;
Beilstein Reference	1701823
ChEBI	CHEBI:48430 ;
ChEMBL	ChEMBL445647 ;
ChemSpider	69 ;
DrugBank	DB03229 ;
ECHA InfoCard	100.011.304
EC Number	212-435-5;
IUPHAR/BPS	4656;
KEGG	C00233 ;
MeSH	Alpha-ketoisocaproic+acid
PubChem CID	70;
UNII	4GUJ8AH400 ;
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) Key: BKAJNAXTPSGJCU-UHFFFAOYSA-N ; 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
EU classification (DSD) (outdated)	C
R-phrases (outdated)	R34
S-phrases (outdated)	S26, S36/37/39, S45
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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	Infobox references

α-Ketoisocaproic acid (α-KIC) and its conjugate base, α-ketoisocaproate, are metabolic intermediates in the metabolic pathway for L-leucine.[2]

Leucine metabolism

Leucine metabolism in humans

L-Leucine

Branched-chain amino
acid aminotransferase

α-Ketoglutarate

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

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.[2][3][4] Of the two major pathways, L-leucine is mostly metabolized into isovaleryl-CoA, while only about 5% is metabolized into HMB.[2][3][4]

References

CID 70 from PubChem
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.
Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (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. HMB is a metabolite of the amino acid leucine (Van Koverin and Nissen 1992), an essential amino acid. The first step in HMB metabolism is the reversible transamination of leucine to [α-KIC] that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, [α-KIC] may follow one of two pathways. In the first, HMB is produced from [α-KIC] by the cytosolic enzyme KIC dioxygenase (Sabourin and Bieber 1983). The cytosolic dioxygenase has been characterized extensively and differs from the mitochondrial form in that the dioxygenase enzyme is a cytosolic enzyme, whereas the dehydrogenase enzyme is found exclusively in the mitochondrion (Sabourin and Bieber 1981, 1983). Importantly, this route of HMB formation is direct and completely dependent of liver KIC dioxygenase. Following this pathway, HMB in the cytosol is first converted to cytosolic β-hydroxy-β-methylglutaryl-CoA (HMG-CoA), which can then be directed for cholesterol synthesis (Rudney 1957) (Fig. 1). In fact, numerous biochemical studies have shown that HMB is a precursor of cholesterol (Zabin and Bloch 1951; Nissen et al. 2000).
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

[1] CID 70 from PubChem

[ISSN_position_stand_2013-2] 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.

[HMB_athletic_performance-related_effects_2011_review-3] Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (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. HMB is a metabolite of the amino acid leucine (Van Koverin and Nissen 1992), an essential amino acid. The first step in HMB metabolism is the reversible transamination of leucine to [α-KIC] that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, [α-KIC] may follow one of two pathways. In the first, HMB is produced from [α-KIC] by the cytosolic enzyme KIC dioxygenase (Sabourin and Bieber 1983). The cytosolic dioxygenase has been characterized extensively and differs from the mitochondrial form in that the dioxygenase enzyme is a cytosolic enzyme, whereas the dehydrogenase enzyme is found exclusively in the mitochondrion (Sabourin and Bieber 1981, 1983). Importantly, this route of HMB formation is direct and completely dependent of liver KIC dioxygenase. Following this pathway, HMB in the cytosol is first converted to cytosolic β-hydroxy-β-methylglutaryl-CoA (HMG-CoA), which can then be directed for cholesterol synthesis (Rudney 1957) (Fig. 1). In fact, numerous biochemical studies have shown that HMB is a precursor of cholesterol (Zabin and Bloch 1951; Nissen et al. 2000).

[Leucine_metabolism-4] 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