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{{expand section|transporter proteins<ref name="β-D-hydroxybutyric acid IUPHAR" /> that move it across lipid membranes|date=February 2018|small=no}} |
{{expand section|transporter proteins<ref name="β-D-hydroxybutyric acid IUPHAR" /> that move it across lipid membranes|date=February 2018|small=no}} |
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<small>D</small>-β-Hydroxybutyric acid, along with [[butyric acid]], are the two primary [[endogenous]] [[agonist]]s of [[hydroxycarboxylic acid receptor 2]] (HCA<sub>2</sub>), a {{nowrap|[[Gi alpha subunit|G<sub>i/o</sub>-coupled]]}} [[GPCR]].<ref name="IUPHAR's comprehensive 2011 review on HCARs" |
<small>D</small>-β-Hydroxybutyric acid, along with [[butyric acid]], are the two primary [[endogenous]] [[agonist]]s of [[hydroxycarboxylic acid receptor 2]] (HCA<sub>2</sub>), a {{nowrap|[[Gi alpha subunit|G<sub>i/o</sub>-coupled]]}} [[GPCR]].<ref name="IUPHAR's comprehensive 2011 review on HCARs"/><ref name="IUPHAR-DB HCAR family page"/><ref name="β-D-hydroxybutyric acid IUPHAR">{{cite web|title=β-D-hydroxybutyric acid: Biological activity|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=1593|website=IUPHAR/BPS Guide to Pharmacology|publisher=International Union of Basic and Clinical Pharmacology|accessdate=5 February 2018|quote=}}</ref> |
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β-Hydroxybutyric acid is able to cross the [[blood-brain-barrier]] into the [[central nervous system]].<ref name="pmid27253067">{{cite journal |vauthors=Sleiman SF, Henry J, Al-Haddad R, El Hayek L, Abou Haidar E, Stringer T, Ulja D, Karuppagounder SS, Holson EB, Ratan RR, Ninan I, Chao MV |title=Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate |journal=eLife |volume=5 |issue= |pages= |year=2016 |pmid=27253067 |pmc=4915811 |doi=10.7554/eLife.15092 |url=}}</ref> Levels of β-hydroxybutyric acid increase in the [[liver]], [[heart]], [[muscle]], [[brain]], and other tissues with [[exercise]], [[calorie restriction]], [[fasting]], and [[ketogenic diet]]s.<ref name="pmid27253067" /> The compound has been found to act as a [[histone deacetylase inhibitor|histone deacetylase (HDAC) inhibitor]].<ref name="pmid27253067" /> Through inhibition of the HDAC class I [[isoenzyme]]s [[HDAC2]] and [[HDAC3]], β-hydroxybutyric acid has been found to increase [[brain-derived neurotrophic factor]] (BDNF) levels and [[TrkB]] [[cell signaling|signaling]] in the [[hippocampus]].<ref name="pmid27253067" /> Moreover, a rodent study found that prolonged exercise increases plasma β-hydroxybutyrate concentrations, which induces [[promoter (genetics)|promoters]] of the BDNF gene in the hippocampus.<ref name="pmid27253067" /> These findings may have clinical relevance in the treatment of [[depression (mood)|depression]], [[anxiety]], and [[cognitive impairment]].<ref name="pmid27253067" /> |
β-Hydroxybutyric acid is able to cross the [[blood-brain-barrier]] into the [[central nervous system]].<ref name="pmid27253067">{{cite journal |vauthors=Sleiman SF, Henry J, Al-Haddad R, El Hayek L, Abou Haidar E, Stringer T, Ulja D, Karuppagounder SS, Holson EB, Ratan RR, Ninan I, Chao MV |title=Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate |journal=eLife |volume=5 |issue= |pages= |year=2016 |pmid=27253067 |pmc=4915811 |doi=10.7554/eLife.15092 |url=}}</ref> Levels of β-hydroxybutyric acid increase in the [[liver]], [[heart]], [[muscle]], [[brain]], and other tissues with [[exercise]], [[calorie restriction]], [[fasting]], and [[ketogenic diet]]s.<ref name="pmid27253067" /> The compound has been found to act as a [[histone deacetylase inhibitor|histone deacetylase (HDAC) inhibitor]].<ref name="pmid27253067" /> Through inhibition of the HDAC class I [[isoenzyme]]s [[HDAC2]] and [[HDAC3]], β-hydroxybutyric acid has been found to increase [[brain-derived neurotrophic factor]] (BDNF) levels and [[TrkB]] [[cell signaling|signaling]] in the [[hippocampus]].<ref name="pmid27253067" /> Moreover, a rodent study found that prolonged exercise increases plasma β-hydroxybutyrate concentrations, which induces [[promoter (genetics)|promoters]] of the BDNF gene in the hippocampus.<ref name="pmid27253067" /> These findings may have clinical relevance in the treatment of [[depression (mood)|depression]], [[anxiety]], and [[cognitive impairment]].<ref name="pmid27253067" /> |
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Names | |
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IUPAC name
3-Hydroxybutanoic acid | |
Identifiers | |
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3D model (JSmol) |
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3DMet | |
773861 | |
ChEBI | |
ChEMBL | |
ChemSpider |
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ECHA InfoCard | 100.005.546 ![]() |
KEGG | |
MeSH | beta-Hydroxybutyrate |
PubChem CID |
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CompTox Dashboard (EPA) |
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Properties | |
C4H8O3 | |
Molar mass | 104.105 g·mol−1 |
Appearance | white solid |
Melting point | 44-46 |
Related compounds | |
Other anions |
hydroxybutyrate |
Related carboxylic acids |
propionic acid lactic acid 3-hydroxypropanoic acid malonic acid hydroxypentanoic acid butyric acid β-methylbutyric acid β-hydroxy β-methylbutyric acid |
Related compounds |
erythrose threose 1,2-butanediol 1,3-butanediol 2,3-butanediol 1,4-butanediol |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). |
β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid, is an organic compound and a beta hydroxy acid with the chemical formulaCH3CH(OH)CH2CO2H; its conjugate baseisβ-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxybutyric acid is a chiral compound with two enantiomers: D-β-hydroxybutyric acid and L-β-hydroxybutyric acid. Its oxidized and polymeric derivatives occur widely in nature. In humans, D-β-hydroxybutyric acid is one of two primary endogenous agonistsofhydroxycarboxylic acid receptor 2 (HCA2), a Gi/o-coupled G protein-coupled receptor (GPCR).[1][2]
In humans, D-β-hydroxybutyrate can be synthesized in the liver via the metabolism of fatty acids (e.g., butyrate), β-hydroxy β-methylbutyrate, and ketogenic amino acids through a series of reactions that metabolize these compounds into acetoacetate, which is the first ketone body that is produced in the fasting state. The biosynthesis of D-β-hydroxybutyrate from acetoacetate is catalyzed by the β-hydroxybutyrate dehydrogenase enzyme.
Butyrate can also be metabolized into D-β-hydroxybutyrate via a second metabolic pathway that does not involve acetoacetate as a metabolic intermediate. This metabolic pathway is as follows:[3]
The last reaction in this metabolic pathway, which involves the conversion of D-β-(D-β-hydroxybutyryloxy)-butyrate into D-β-hydroxybutyrate, is catalyzed by the hydroxybutyrate-dimer hydrolase enzyme.[3]
The concentration of β-hydroxybutyrate in human blood plasma, as with other ketone bodies, increases through ketosis.[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 when blood glucose is low.[5] Diabetic patients can have their ketone levels tested via urine or blood to indicate diabetic ketoacidosis. In alcoholic ketoacidosis, this ketone body is produced in greatest concentration. Ketogenesis occurs if oxaloacetate in the liver cells is depleted, a circumstance created by reduced carbohydrate intake (through diet or starvation), prolonged, excessive alcohol consumption, and/or insulin deficiency. Because oxaloacetate is crucial for entry of acetyl-CoA into 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]
Muscle: α-Ketoisocaproate (α-KIC)
Liver: α-Ketoisocaproate (α-KIC)
Excreted
in urine (10–40%)
β-Hydroxy β-methylglutaryl-CoA
(HMG-CoA)
β-Methylcrotonyl-CoA
(MC-CoA)
β-Methylglutaconyl-CoA
(MG-CoA)
Unknown
enzyme
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This section needs expansion with: transporter proteins[9] that move it across lipid membranes. You can help by adding to it. (February 2018)
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D-β-Hydroxybutyric acid, along with butyric acid, are the two primary endogenous agonistsofhydroxycarboxylic acid receptor 2 (HCA2), a Gi/o-coupled GPCR.[1][2][9]
β-Hydroxybutyric acid is able to cross the blood-brain-barrier into the central nervous system.[10] Levels of β-hydroxybutyric acid increase in the liver, heart, muscle, brain, and other tissues with exercise, calorie restriction, fasting, and ketogenic diets.[10] The compound has been found to act as a histone deacetylase (HDAC) inhibitor.[10] Through inhibition of the HDAC class I isoenzymes HDAC2 and HDAC3, β-hydroxybutyric acid has been found to increase brain-derived neurotrophic factor (BDNF) levels and TrkB signaling in the hippocampus.[10] Moreover, a rodent study found that prolonged exercise increases plasma β-hydroxybutyrate concentrations, which induces promoters of the BDNF gene in the hippocampus.[10] These findings may have clinical relevance in the treatment of depression, anxiety, and cognitive impairment.[10]
Inepilepsy patients on the ketogenic diet, blood β-hydroxybutyrate levels correlate best with degree of seizure control. The threshold for optimal anticonvulsant effect appears to be approximately 4 mmol/L.[11]
β-Hydroxybutyric acid is the precursor to polyesters, which are biodegradable plastics. This polymer, poly(3-hydroxybutyrate), is also naturally produced by the bacteria Alcaligenes eutrophus.[12]
β-Hydroxybutyrate can be extracted from poly(3-hydroxybutyrate) by acid hydrolysis.[13]
The concentration of β-hydroxybutyrateinblood plasma is measured through a test that uses β-hydroxybutyrate dehydrogenase, with NAD+ as an electron-accepting cofactor. The conversion of β-hydroxybutyrate to acetoacetate, which is catalyzed by this enzyme, reduces the NAD+ to NADH, generating an electrical change; the magnitude of this change can then be used to extrapolate the amount of β-hydroxybutyrate in the sample.
{{cite web}}
: CS1 maint: multiple names: authors list (link)
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.
{{cite journal}}
: CS1 maint: unflagged free DOI (link)
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