β-Hydroxybutyric acid, also known as 3-hydroxybutyric acid or BHB, is an organic compound and a

beta hydroxy acid A beta hydroxy acid or β-hydroxy acid (BHA) is an organic compound that contains a carboxylic acid functional group and hydroxy functional group separated by ''two'' carbon atoms. They are closely related to alpha hydroxy acids, in which the tw ...

with the

chemical formula In chemistry, a chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbol ...

CH₃CH(OH)CH₂CO₂H; its

conjugate base A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...

is β-hydroxybutyrate, also known as 3-hydroxybutyrate. β-Hydroxybutyric acid is a

chiral Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from i ...

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 agonists of

hydroxycarboxylic acid receptor 2 Hydroxycarboxylic acid receptor 2 (HCA2), also known as niacin receptor 1 (NIACR1) and GPR109A, is a protein which in humans is encoded by the ''HCAR2'' gene. HCA2, like the other hydroxycarboxylic acid receptors HCA1 and HCA3, is a Gi/o-couple ...

(HCA₂), a

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

(GPCR).

Biosynthesis

In humans, can be synthesized in the

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

via the metabolism of fatty acids (e.g.,

butyrate The conjugate acids are in :Carboxylic acids. {{Commons category, Carboxylate ions, Carboxylate anions Carbon compounds Oxyanions ...

), , and ketogenic amino acids through a series of reactions that metabolize these compounds into acetoacetate, which is the first

ketone body Ketone bodies are water-soluble molecules that contain the ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA (acetyl- ...

that is produced in the

fasting Fasting is the abstention from eating and sometimes drinking. From a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (see " Breakfast"), or to the metabolic state achieved after ...

state. The biosynthesis of from acetoacetate is catalyzed by the β-hydroxybutyrate dehydrogenase

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

. Butyrate can also be metabolized into via a second

metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...

that does not involve acetoacetate as a metabolic intermediate. This metabolic pathway is as follows: :butyrate→

butyryl-CoA Butyryl-coenzyme A (or butyryl-CoA) is the coenzyme A-containing derivative of butyric acid. It is acted upon by butyryl-CoA dehydrogenase and an intermediary compound of ABE fermentation. Butyryl-CoA is a precursor to and converted from crotonyl- ...

→ crotonyl-CoA→ β-hydroxybutyryl-CoA→ poly-β-hydroxybutyrate→()→ The last reaction in this metabolic pathway, which involves the conversion of () into , is catalyzed by the hydroxybutyrate-dimer hydrolase enzyme. The concentration of β-hydroxybutyrate in human blood plasma, as with other ketone bodies, increases through ketosis. 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 Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the blo ...

is low.

Diabetic Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...

patients can have their ketone levels tested via urine or blood to indicate

diabetic ketoacidosis Diabetic ketoacidosis (DKA) is a potentially life-threatening complication of diabetes mellitus. Signs and symptoms may include vomiting, abdominal pain, deep gasping breathing, increased urination, weakness, confusion and occasionally loss of ...

. In alcoholic ketoacidosis, this ketone body is produced in greatest concentration. Ketogenesis occurs if

oxaloacetate Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...

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.

Biological activity

D-β-Hydroxybutyric acid, along with butyric acid, are the two primary endogenous agonists of

(HCA₂), a

GPCR G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

. β-Hydroxybutyric acid is able to cross the blood-brain-barrier into the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

. Levels of β-hydroxybutyric acid increase in the

heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...

, muscle,

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...

, and other tissues with exercise,

calorie restriction Calorie restriction (caloric restriction or energy restriction) is a dietary regimen that reduces intake of energy from caloric foods & beverages without incurring malnutrition. "Reduce" can be defined relative to the subject's previous intake b ...

, and

ketogenic diet The ketogenic diet is a high- fat, adequate-protein, low-carbohydrate dietary therapy that in conventional medicine is used mainly to treat hard-to-control (refractory) epilepsy in children. The diet forces the body to burn fats rather than ca ...

s. The compound has been found to act as a histone deacetylase (HDAC) inhibitor. Through inhibition of the HDAC class I

isoenzyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...

HDAC2 Histone deacetylase 2 (HDAC2) is an enzyme that in humans is encoded by the ''HDAC2'' gene. It belongs to the histone deacetylase class of enzymes responsible for the removal of acetyl groups from lysine residues at the N-terminal region of the co ...

and HDAC3, β-hydroxybutyric acid has been found to increase

brain-derived neurotrophic factor Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canon ...

(BDNF) levels and

TrkB Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the ''NTRK2'' gene. TrkB is a recepto ...

signaling in the

hippocampus The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...

. Moreover, a rodent study found that prolonged exercise increases plasma β-hydroxybutyrate concentrations, which induces promoters of the BDNF gene in the hippocampus. These findings may have clinical relevance in the treatment of depression,

anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...

, and

cognitive impairment Cognitive deficit is an inclusive term to describe any characteristic that acts as a barrier to the cognition process. The term may describe * deficits in overall intelligence (as with intellectual disabilities), * specific and restricted defici ...

. In

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...

patients on the ketogenic diet, blood β-hydroxybutyrate levels correlate best with degree of

seizure An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...

control. The threshold for optimal anticonvulsant effect appears to be approximately 4 mmol/L.

Laboratory and industrial chemistry

β-Hydroxybutyric acid is the precursor to polyesters, which are

biodegradable plastics Biodegradable plastics are plastics that can be decomposed by the action of living organisms, usually microbes, into water, carbon dioxide, and biomass. Biodegradable plastics are commonly produced with renewable raw materials, micro-organisms, ...

. This polymer, poly(3-hydroxybutyrate), is also naturally produced by the bacteria ''

Alcaligenes eutrophus ''Cupriavidus metallidurans'' is a non-spore-forming, Gram-negative bacterium which is adapted to survive several forms of heavy metal stress. As a model and industrial system It is an ideal subject to study heavy metal disturbance of cell ...

''. β-Hydroxybutyrate can be extracted from poly(3-hydroxybutyrate) by acid

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile. Biological hydrolys ...

.Dieter Seebach, Albert K. Beck, Richard Breitschuh, and Kurt Job "Direct Degradation of the Biopolymer Poly The_concentration_of__in_blood_plasma.html" ;"title="''R'')-3-Hydroxybutrric Acid to (''R'')-3-Hydroxybutanoic Acid and Its Methyl Ester" Org. Synth. 1993, 71, 39. The concentration of in blood plasma">''R'')-3-Hydroxybutrric Acid to (''R'')-3-Hydroxybutanoic Acid and Its Methyl Ester" Org. Synth. 1993, 71, 39. The concentration of in blood plasma is measured through a test that uses β-hydroxybutyrate dehydrogenase, with Nicotinamide adenine dinucleotide, NAD⁺ as an electron-accepting cofactor. The conversion of to acetoacetate, which is catalyzed by this enzyme, reduces the NAD⁺ to

NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...

, generating an electrical change; the magnitude of this change can then be used to extrapolate the amount of in the sample.

Notes

References

{{DEFAULTSORT:Hydroxybutyric acid, beta- Antidepressants Beta hydroxy acids Biomolecules Histone deacetylase inhibitors

Biosynthesis

Biological activity

Laboratory and industrial chemistry

See also

Notes

References