β-Hydroxybutyric acid
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| Names | |
|---|---|
| Preferred IUPAC name
3-Hydroxybutanoic acid | |
| Identifiers | |
3D model (JSmol)
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| 3DMet | |
| 773861 | |
| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| ECHA InfoCard | 100.005.546 |
| KEGG | |
| MeSH | beta-Hydroxybutyrate |
PubChemCID
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| UNII | |
CompTox Dashboard(EPA)
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| Properties | |
| C4H8O3 | |
| Molar mass | 104.105g·mol−1 |
| Appearance | white solid |
| Melting point | 44-46 |
| Related compounds | |
Otheranions
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hydroxybutyrate |
Relatedcarboxylic acids
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propionic acid lactic acid 3-hydroxypropanoic acid malonic acid hydroxypentanoic acid butyric acid β-methylbutyric acid β-hydroxy β-methylbutyric acid |
Related compounds
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erythrose threose 1,2-butanediol 1,3-butanediol 2,3-butanediol 1,4-butanediol |
Except where otherwise noted, data are given for materials in theirstandard state(at 25 °C [77 °F], 100 kPa).
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β-Hydroxybutyric acid,also known as3-hydroxybutyric acidorBHB,is an organic compound and abeta hydroxy acidwith thechemical formulaCH3CH(OH)CH2CO2H; itsconjugate baseisβ-hydroxybutyrate,also known as3-hydroxybutyrate.β-Hydroxybutyric acid is achiralcompound with twoenantiomers:D-β-hydroxybutyric acid andL-β-hydroxybutyric acid. Its oxidized and polymeric derivatives occur widely in nature. In humans,D-β-hydroxybutyric acid is one of two primaryendogenousagonistsofhydroxycarboxylic acid receptor 2(HCA2), aGi/o-coupledG protein-coupled receptor(GPCR).[1][2]
Biosynthesis
[edit]In humans,D-β-hydroxybutyratecan be synthesized in thelivervia themetabolism of fatty acids(e.g.,butyrate),β-hydroxyβ-methylbutyrate,andketogenic amino acidsthrough a series of reactions that metabolize these compounds intoacetoacetate,which is the firstketone bodythat is produced in thefastingstate. The biosynthesis ofD-β-hydroxybutyratefrom acetoacetate is catalyzed by theβ-hydroxybutyrate dehydrogenaseenzyme.
Butyrate can also be metabolized intoD-β-hydroxybutyratevia a secondmetabolic pathwaythat does not involve acetoacetate as a metabolic intermediate. This metabolic pathway is as follows:[3]
- butyrate→butyryl-CoA→crotonyl-CoA→β-hydroxybutyryl-CoA→poly-β-hydroxybutyrate→D-β-(D-β-hydroxybutyryloxy)-butyrate→D-β-hydroxybutyrate
The last reaction in this metabolic pathway, which involves the conversion ofD-β-(D-β-hydroxybutyryloxy)-butyrateintoD-β-hydroxybutyrate,is catalyzed by thehydroxybutyrate-dimer hydrolaseenzyme.[3]
The concentration of β-hydroxybutyrate in human blood plasma, as with otherketone bodies,increases throughketosis.[4]This elevated β-hydroxybutyrate level is naturally expected, as β-hydroxybutyrate is formed from acetoacetate. The compound can be used as an energy source by the brain and skeletal muscle whenblood glucoseis low.[5][6][7][8]Diabeticpatients can have their ketone levels tested via urine or blood to indicatediabetic ketoacidosis.Inalcoholic ketoacidosis,this ketone body is produced in greatest concentration. Ketogenesis occurs ifoxaloacetatein the liver cells is depleted, a circumstance created by reduced carbohydrate intake (through diet or starvation); prolonged, excessivealcoholconsumption; and/or insulin deficiency. Because oxaloacetate is crucial for entry ofacetyl-CoAinto the TCA cycle, the rapid production of acetyl-CoA from fatty acid oxidation in the absence of ample oxaloacetate overwhelms the decreased capacity of the TCA cycle, and the resultant excess of acetyl-CoA is shunted towards ketone body production.[citation needed]
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Biological activity
[edit]![[icon]](/translate/en.wikipedia.org?u=https%3A%2F%2Fen.wikipedia.org%2Fwiki%2FFile%3AWiki_letter_w_cropped.svg&t=hv){kind=small} | This sectionneeds expansionwith: transporter proteins[12]that move it across lipid membranes. You can help byadding to it.(February 2018) |
D-β-Hydroxybutyric acid, along withbutyric acid,are the two primaryendogenousagonistsofhydroxycarboxylic acid receptor 2(HCA2), aGi/o-coupledGPCR.[1][2][12]
β-Hydroxybutyric acid is able to cross theblood-brain-barrierinto thecentral nervous system.[13]Levels of β-hydroxybutyric acid increase in theliver,heart,muscle,brain,and other tissues withexercise,calorie restriction,fasting,andketogenic diets.[13]The compound has been found to act as ahistone deacetylase (HDAC) inhibitor.[13]Through inhibition of the HDAC class IisoenzymesHDAC2andHDAC3,β-hydroxybutyric acid has been found to increasebrain-derived neurotrophic factor(BDNF) levels andTrkBsignalingin thehippocampus.[13]Moreover, a rodent study found that prolonged exercise increases plasma β-hydroxybutyrate concentrations, which inducespromotersof the BDNF gene in the hippocampus.[13]These findings may have clinical relevance in the treatment ofdepression,anxiety,andcognitive impairment.[13]
Inepilepsypatients on the ketogenic diet, blood β-hydroxybutyrate levels correlate best with degree ofseizurecontrol. The threshold for optimalanticonvulsanteffect appears to be approximately 4 mmol/L.[14]
Laboratory and industrial chemistry
[edit]β-Hydroxybutyric acid is the precursor to polyesters, which arebiodegradable plastics.This polymer,poly(3-hydroxybutyrate),is alsonaturally producedby the bacteriaAlcaligenes eutrophus.[15]
β-Hydroxybutyrate can be extracted from poly(3-hydroxybutyrate) by acidhydrolysis.[16]
The concentration ofβ-hydroxybutyrateinblood plasmais measured through a test that usesβ-hydroxybutyrate dehydrogenase,withNAD+as an electron-accepting cofactor. The conversion ofβ-hydroxybutyrateto acetoacetate, which is catalyzed by this enzyme, reduces the NAD+toNADH,generating an electrical change; the magnitude of this change can then be used to extrapolate the amount ofβ-hydroxybutyratein the sample.
See also
[edit]Notes
[edit]- ^This reaction is catalyzed by an unknownthioesteraseenzyme.[9][10]
References
[edit]- ^abOffermanns S, Colletti SL, Lovenberg TW, Semple G, Wise A, IJzerman AP (June 2011)."International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)".Pharmacological Reviews.63(2): 269–290.doi:10.1124/pr.110.003301.PMID21454438.
- ^abOffermanns S, Colletti SL, IJzerman AP, Lovenberg TW, Semple G, Wise A, Waters MG."Hydroxycarboxylic acid receptors".IUPHAR/BPS Guide to Pharmacology.International Union of Basic and Clinical Pharmacology.Retrieved13 July2018.
- ^ab"Butanoate metabolism - Reference pathway".Kyoto Encyclopedia of Genes and Genomes.Kanehisa Laboratories. 1 November 2017.Retrieved1 February2018.
- ^Perelas A, Staros EB (October 30, 2015)."Beta-Hydroxybutyrate".Medscape.WebMD LLC.RetrievedFebruary 8,2017.
- ^Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GF (October 1967)."Brain metabolism during fasting".The Journal of Clinical Investigation.46(10): 1589–1595.doi:10.1172/JCI105650.PMC292907.PMID6061736.
- ^Evans E, Walhin JP, Hengist A, Betts JA, Dearlove DJ, Gonzalez JT (January 2023)."Ketone monoester ingestion increases postexercise serum erythropoietin concentrations in healthy men".American Journal of Physiology. Endocrinology and Metabolism.324(1): E56–E61.doi:10.1152/ajpendo.00264.2022.PMC9870573.PMID36449571.
- ^Cahill GF (2006-08-01). "Fuel metabolism in starvation".Annual Review of Nutrition.26(1): 1–22.doi:10.1146/annurev.nutr.26.061505.111258.PMID16848698.
- ^Mikkelsen KH, Seifert T, Secher NH, Grøndal T, van Hall G (February 2015)."Systemic, cerebral and skeletal muscle ketone body and energy metabolism during acute hyper-D-β-hydroxybutyratemia in post-absorptive healthy males".The Journal of Clinical Endocrinology and Metabolism.100(2): 636–643.doi:10.1210/jc.2014-2608.PMID25415176.
- ^"KEGG Reaction: R10759".Kyoto Encyclopedia of Genes and Genomes.Kanehisa Laboratories.Retrieved24 June2016.
- ^Mock DM, Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Dawson AM, Spencer HJ, Owen SN, Boysen G, Moran JH (November 2011)."Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans".primary source.The Journal of Nutrition.141(11): 1925–1930.doi:10.3945/jn.111.146126.PMC3192457.PMID21918059.
Metabolic impairment diverts methylcrotonyl CoA to 3-hydroxyisovaleryl CoA in a reaction catalyzed by enoyl-CoA hydratase (22, 23). 3-Hydroxyisovaleryl CoA accumulation can inhibit cellular respiration either directly or via effects on the ratios of acyl CoA:free CoA if further metabolism and detoxification of 3-hydroxyisovaleryl CoA does not occur (22). The transfer to carnitine by 4 carnitine acyl-CoA transferases distributed in subcellular compartments likely serves as an important reservoir for acyl moieties (39–41). 3-Hydroxyisovaleryl CoA is likely detoxified by carnitine acetyltransferase producing 3HIA-carnitine, which is transported across the inner mitochondrial membrane (and hence effectively out of the mitochondria) via carnitine-acylcarnitine translocase (39). 3HIA-carnitine is thought to be either directly deacylated by a hydrolase to 3HIA or to undergo a second CoA exchange to again form 3-hydroxyisovaleryl CoA followed by release of 3HIA and free CoA by a thioesterase.
- ^ab"Valine, leucine and isoleucine degradation - Reference pathway".Kyoto Encyclopedia of Genes and Genomes.Kanehisa Laboratories. 27 January 2016.Retrieved1 February2018.
- ^ab"β-D-hydroxybutyric acid: Biological activity".IUPHAR/BPS Guide to Pharmacology.International Union of Basic and Clinical Pharmacology.Retrieved5 February2018.
- ^abcdefSleiman SF, Henry J, Al-Haddad R, El Hayek L, Abou Haidar E, Stringer T, et al. (June 2016)."Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate".eLife.5.doi:10.7554/eLife.15092.PMC4915811.PMID27253067.
- ^Gilbert DL, Pyzik PL, Freeman JM (December 2000). "The ketogenic diet: seizure control correlates better with serum beta-hydroxybutyrate than with urine ketones".Journal of Child Neurology.15(12): 787–790.doi:10.1177/088307380001501203.PMID11198492.S2CID46659339.
- ^Doi Y, Kunioka M, Nakamura Y, Soga K (1988). "Nuclear magnetic resonance studies on unusual bacterial copolyesters of 3-hydroxybutyrate and 4-hydroxybutyrate".Macromolecules.21(9): 2722–2727.Bibcode:1988MaMol..21.2722D.doi:10.1021/ma00187a012.
- ^Seebach D, Beck AK, Breitschuh R, Job K (April 1993). "Direct Degradation of the Biopolymer Poly[(R)-3-Hydroxybutrric Acid to (R)-3-Hydroxybutanoic Acid and Its Methyl Ester ".Organic Syntheses.71:39.doi:10.15227/orgsyn.071.0039.