T3DB: Ketoleucine

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation XML

Record Information

Version

2.0

Creation Date

2014-08-29 06:51:13 UTC

Update Date

2018-03-21 17:46:21 UTC

Accession Number

T3D4426

Identification

Common Name

Ketoleucine

Class

Small Molecule

Description

Ketoleucine is an abnormal metabolite that arises from the incomplete breakdown of branched-chain amino acids. Ketoleucine is both a neurotoxin and a metabotoxin. A neurotoxin causes damage to nerve cells and nerve tissues. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of ketoleucine are associated with maple syrup urine disease (MSUD). MSUD is a metabolic disorder caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), leading to a buildup of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products (ketoacids) in the blood and urine. The symptoms of MSUD often show in infancy and lead to severe brain damage if untreated. MSUD may also present later depending on the severity of the disease. If left untreated in older individuals, during times of metabolic crisis, symptoms of the condition include uncharacteristically inappropriate, extreme, or erratic behaviour and moods, hallucinations, anorexia, weight loss, anemia, diarrhea, vomiting, dehydration, lethargy, oscillating hypertonia and hypotonia, ataxia, seizures, hypoglycemia, ketoacidosis, opisthotonus, pancreatitis, rapid neurological decline, and coma. In maple syrup urine disease, the brain concentration of branched-chain ketoacids can increase 10- to 20-fold. This leads to a depletion of glutamate and a consequent reduction in the concentration of brain glutamine, aspartate, alanine, and other amino acids. The result is a compromise of energy metabolism because of a failure of the malate-aspartate shuttle and a diminished rate of protein synthesis (PMID: 15930465).

Compound Type

Animal Toxin
Food Toxin
Metabolite
Natural Compound
Organic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
2-Keto-4-Methylvalerate
2-Keto-4-Methylvaleric acid
2-Ketoisocaproate
2-Ketoisocaproic acid
2-Oxo-4-methylpentanoate
2-Oxo-4-methylpentanoic acid
2-Oxo-4-methylvalerate
2-Oxo-4-methylvaleric acid
2-Oxoisocaproate
2-Oxoisocaproic acid
2-Oxoleucine
4-Methyl-2-oxo-Valerate
4-Methyl-2-oxo-Valeric acid
4-Methyl-2-oxopentanoate
4-Methyl-2-oxopentanoic acid
a-Ketoisocaproate
a-Ketoisocaproic acid
a-Ketoisocapronate
a-Ketoisocapronic acid
a-Oxoisocaproate
a-Oxoisocaproic acid
alpha-Keto-isocaproate
alpha-Keto-isocaproic acid
alpha-Ketoisocaproate
alpha-Ketoisocaproic acid
alpha-Ketoisocapronate
alpha-Ketoisocapronic acid
alpha-Oxoisocaproate
alpha-Oxoisocaproic acid
Ketoisocaproate
Ketoisocaproic acid
Methyloxovalerate
Methyloxovaleric acid
Oxoisocaproate
Oxoisocaproic acid

Chemical Formula

C₆H₁₀O₃

Average Molecular Mass

130.142 g/mol

Monoisotopic Mass

130.063 g/mol

CAS Registry Number

816-66-0

IUPAC Name

4-methyl-2-oxopentanoic acid

Traditional Name

ketoisocaproate

SMILES

CC(C)CC(=O)C(O)=O

InChI Identifier

InChI=1S/C6H10O3/c1-4(2)3-5(7)6(8)9/h4H,3H2,1-2H3,(H,8,9)

InChI Key

InChIKey=BKAJNAXTPSGJCU-UHFFFAOYSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as short-chain keto acids and derivatives. These are keto acids with an alkyl chain the contains less than 6 carbon atoms.

Kingdom

Organic compounds

Super Class

Organic acids and derivatives

Class

Keto acids and derivatives

Sub Class

Short-chain keto acids and derivatives

Direct Parent

Short-chain keto acids and derivatives

Alternative Parents

Substituents

Branched fatty acid
Methyl-branched fatty acid
Short-chain keto acid
Alpha-keto acid
Fatty acyl
Alpha-hydroxy ketone
Ketone
Carboxylic acid derivative
Carboxylic acid
Monocarboxylic acid or derivatives
Carbonyl group
Hydrocarbon derivative
Organic oxygen compound
Organooxygen compound
Organic oxide
Aliphatic acyclic compound

Molecular Framework

Aliphatic acyclic compounds

External Descriptors

2-oxo monocarboxylic acid (CHEBI:48430 )

Biological Properties

Status

Detected and Not Quantified

Origin

Endogenous

Cellular Locations

Cytoplasm
Extracellular
Membrane
Mitochondria

Biofluid Locations

Not Available

Tissue Locations

Muscle
Neuron
Prostate

Pathways

Name	SMPDB Link	KEGG Link
Valine, Leucine and Isoleucine Degradation	SMP00032	map00280
Maple Syrup Urine Disease	SMP00199	Not Available

Applications

Not Available

Biological Roles

Chemical Roles

Not Available

Physical Properties

State

Liquid

Appearance

Not Available

Experimental Properties

Property	Value
Melting Point	8 - 10°C
Boiling Point	Not Available
Solubility	32 mg/mL
LogP	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	6.76 g/L	ALOGPS
logP	0.82	ALOGPS
logP	1.5	ChemAxon
logS	-1.3	ALOGPS
pKa (Strongest Acidic)	3.53	ChemAxon
pKa (Strongest Basic)	-9.7	ChemAxon
Physiological Charge	-1	ChemAxon
Hydrogen Acceptor Count	3	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	54.37 Å²	ChemAxon
Rotatable Bond Count	3	ChemAxon
Refractivity	31.77 m³·mol⁻¹	ChemAxon
Polarizability	13 Å³	ChemAxon
Number of Rings	0	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
GC-MS	GC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (3 TMS)	splash10-000i-9400000000-49d055f04bfe1877ac5b	2014-06-16	View Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (3 TMS)	splash10-029j-8930000000-c6c54bf6ee2995a2195b	2014-06-16	View Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Pegasus III TOF-MS system, Leco; GC 6890, Agilent Technologies) (Non-derivatized)	splash10-0002-1910000000-0ba38257e25873312809	2014-06-16	View Spectrum
GC-MS	GC-MS Spectrum - GC-MS (2 TMS)	splash10-0a5c-4930000000-61247369a805fa2a77a7	2014-06-16	View Spectrum
GC-MS	GC-MS Spectrum - GC-MS (1 MEOX; 1 TMS)	splash10-000i-9510000000-8bfc5a54e29f65edf361	2014-06-16	View Spectrum
GC-MS	GC-MS Spectrum - GC-MS (1 MEOX; 1 TMS)	splash10-00lj-9620000000-aa8409ceb2359d903f38	2014-06-16	View Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Non-derivatized)	splash10-000i-9400000000-49d055f04bfe1877ac5b	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Non-derivatized)	splash10-029j-8930000000-c6c54bf6ee2995a2195b	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Non-derivatized)	splash10-0002-1910000000-0ba38257e25873312809	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-MS (Non-derivatized)	splash10-0a5c-4930000000-61247369a805fa2a77a7	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-MS (Non-derivatized)	splash10-000i-9510000000-8bfc5a54e29f65edf361	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-MS (Non-derivatized)	splash10-00lj-9620000000-aa8409ceb2359d903f38	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Non-derivatized)	splash10-00ks-7930000000-4e9cfd715fa884d30e7f	2017-09-12	View Spectrum
GC-MS	GC-MS Spectrum - GC-EI-TOF (Non-derivatized)	splash10-000i-9500000000-709ebcb57f006703c269	2017-09-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0006-9000000000-e410bce23706f826f8dd	2016-09-22	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positive	splash10-0006-9400000000-c4f06cea1e27a2b24660	2017-10-06	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_2) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TBDMS_1_1) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TBDMS_1_2) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)	splash10-0006-9000000000-bed7ac074a60210971e3	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)	splash10-014i-9200000000-2fa08d2b4df406cf63ea	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)	splash10-014j-9000000000-045be8e8dca3f93d45ba	2012-07-24	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 10V, Negative	splash10-004i-0900000000-237fa8ad6bfb929be31e	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 20V, Negative	splash10-004r-9700000000-8d38d24fce78b1ff13e6	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 30V, Negative	splash10-0a59-9000000000-759cfc0817917283d1a5	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 40V, Negative	splash10-0a4l-9000000000-2a068ada71fbe0a5a988	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ (API3000, Applied Biosystems) 50V, Negative	splash10-0a4l-9000000000-58e61e31f3c96d84d799	2012-08-31	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-004i-0900000000-237fa8ad6bfb929be31e	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-004r-9700000000-8d38d24fce78b1ff13e6	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0a59-9000000000-759cfc0817917283d1a5	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0a4l-9000000000-2a068ada71fbe0a5a988	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-QQ , negative	splash10-0a4l-9000000000-58e61e31f3c96d84d799	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-ITFT , negative	splash10-004i-0900000000-556a0d1cf568609752d1	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - LC-ESI-IT , negative	splash10-004r-5900000000-20f6923c8ed45e9fa088	2017-09-14	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 35V, Negative	splash10-004i-0900000000-b66d521478c92e2d77d0	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 10V, Negative	splash10-004i-0900000000-9c3a698d9f28af574ef6	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 40V, Negative	splash10-03di-9000000000-47ced70de4860e900283	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 20V, Negative	splash10-03xr-7900000000-0461a5a56e36a03fe522	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-08gr-7900000000-31021fda89eb6535185f	2015-05-27	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-0btm-9200000000-3bf5df4b557ef87267f4	2015-05-27	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0a4i-9000000000-37839bf70647d24b94a4	2015-05-27	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-004i-4900000000-796467909d1d4c087a07	2015-05-27	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-01ri-9400000000-0abcd021721f32c10e42	2015-05-27	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-015l-9000000000-5c33a47dfeb09a182983	2015-05-27	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 500 MHz, H₂O, experimental)	Not Available	2012-12-04	View Spectrum
1D NMR	¹H NMR Spectrum (1D, D₂O, experimental)	Not Available	2016-10-22	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, D₂O, experimental)	Not Available	2016-10-22	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 100 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 100 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 1000 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 1000 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 200 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 200 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 300 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 300 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 400 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 400 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 500 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 500 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 600 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 600 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 700 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 700 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 800 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 800 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 900 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
1D NMR	¹³C NMR Spectrum (1D, 900 MHz, D₂O, predicted)	Not Available	2021-09-24	View Spectrum
2D NMR	[¹H, ¹³C]-HSQC NMR Spectrum (2D, 600 MHz, H₂O, experimental)	Not Available	2012-12-05	View Spectrum

Toxicity Profile

Route of Exposure

Not Available

Mechanism of Toxicity

Ketoleucine is a metabolite that accumulates in Maple Syrup Urine Disease (MSUD) and shown to compromise brain energy metabolism by blocking the respiratory chain.

Metabolism

Not Available

Toxicity Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

This is an endogenously produced metabolite found in the human body. It is used in metabolic reactions, catabolic reactions or waste generation.

Minimum Risk Level

Not Available

Health Effects

Chronically high levels of keto-leucine are associated with Maple Syrup Urine Disease.

Symptoms

Not Available

Treatment

Not Available

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

DB03229

HMDB ID

HMDB00695

PubChem Compound ID

ChEMBL ID

CHEMBL445647

ChemSpider ID

KEGG ID

C00233

UniProt ID

Not Available

OMIM ID

ChEBI ID

48430

BioCyc ID

2K-4CH3-PENTANOATE

CTD ID

Not Available

Stitch ID

Not Available

PDB ID

COI

ACToR ID

Not Available

Wikipedia Link

Not Available

References

Synthesis Reference

Not Available

MSDS

Link

General References

Sgaravatti AM, Rosa RB, Schuck PF, Ribeiro CA, Wannmacher CM, Wyse AT, Dutra-Filho CS, Wajner M: Inhibition of brain energy metabolism by the alpha-keto acids accumulating in maple syrup urine disease. Biochim Biophys Acta. 2003 Nov 20;1639(3):232-8. [14636955 ]
Martin PM, Gopal E, Ananth S, Zhuang L, Itagaki S, Prasad BM, Smith SB, Prasad PD, Ganapathy V: Identity of SMCT1 (SLC5A8) as a neuron-specific Na+-coupled transporter for active uptake of L-lactate and ketone bodies in the brain. J Neurochem. 2006 Jul;98(1):279-88. [16805814 ]
Chow LS, Albright RC, Bigelow ML, Toffolo G, Cobelli C, Nair KS: Mechanism of insulin's anabolic effect on muscle: measurements of muscle protein synthesis and breakdown using aminoacyl-tRNA and other surrogate measures. Am J Physiol Endocrinol Metab. 2006 Oct;291(4):E729-36. Epub 2006 May 16. [16705065 ]
Wang Y, Holmes E, Nicholson JK, Cloarec O, Chollet J, Tanner M, Singer BH, Utzinger J: Metabonomic investigations in mice infected with Schistosoma mansoni: an approach for biomarker identification. Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12676-81. Epub 2004 Aug 16. [15314235 ]
Mitch WE, Walser M, Sapir DG: Nitrogen sparing induced by leucine compared with that induced by its keto analogue, alpha-ketoisocaproate, in fasting obese man. J Clin Invest. 1981 Feb;67(2):553-62. [7462428 ]
Yudkoff M, Daikhin Y, Nissim I, Horyn O, Luhovyy B, Lazarow A, Nissim I: Brain amino acid requirements and toxicity: the example of leucine. J Nutr. 2005 Jun;135(6 Suppl):1531S-8S. [15930465 ]
Schadewaldt P, Hammen HW, Ott AC, Wendel U: Renal clearance of branched-chain L-amino and 2-oxo acids in maple syrup urine disease. J Inherit Metab Dis. 1999 Aug;22(6):706-22. [10472531 ]
Hachey DL, Patterson BW, Reeds PJ, Elsas LJ: Isotopic determination of organic keto acid pentafluorobenzyl esters in biological fluids by negative chemical ionization gas chromatography/mass spectrometry. Anal Chem. 1991 May 1;63(9):919-23. [1858984 ]
Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J, Laxman B, Mehra R, Lonigro RJ, Li Y, Nyati MK, Ahsan A, Kalyana-Sundaram S, Han B, Cao X, Byun J, Omenn GS, Ghosh D, Pennathur S, Alexander DC, Berger A, Shuster JR, Wei JT, Varambally S, Beecher C, Chinnaiyan AM: Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature. 2009 Feb 12;457(7231):910-4. doi: 10.1038/nature07762. [19212411 ]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Ketoleucine (T3D4426)

Structure for T3D4426: Ketoleucine