Β-Hydroxybutyric acid

Biosynthesis

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: :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 of D-β-(D-β-hydroxybutyryloxy)-butyrate into D-β-hydroxybutyrate, 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 and skeletal muscle when blood glucose is low. 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.

Biological activity

D-β-Hydroxybutyric acid, along with butyric acid, are the two primary endogenous agonists of hydroxycarboxylic acid receptor 2 (HCA2), a Gi/o-coupled GPCR.

β-Hydroxybutyrate is primarily carried via two classes of transporters: monocarboxylate transporters (MCTs) and sodium-coupled monocarboxylate transporters (SMCTs). MCTs enable keton bodies like β-hydroxybutyrate to enter extrahepatic tissues, like the brain, muscle and kidneys, while SMCTs (which co-transport sodium) are found in the kidneys, intestines, and certain neurones. Evidence suggests that MCT1 deficiency can lead to recurrent ketoacidosis.

β-Hydroxybutyric acid is able to cross the blood-brain-barrier into the central nervous system. Levels of β-hydroxybutyric acid increase in the liver, heart, muscle, brain, and other tissues with exercise, calorie restriction, fasting, and ketogenic diets. The compound has been found to act as a histone deacetylase (HDAC) inhibitor. 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. 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, and cognitive impairment.

In epilepsy 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.

Laboratory and industrial chemistry

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.

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

The concentration of β-hydroxybutyrate in blood 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.

Notes

References

References

1. "Hydroxycarboxylic acid receptors". International Union of Basic and Clinical Pharmacology.
2. (1 November 2017). "Butanoate metabolism - Reference pathway". Kanehisa Laboratories.
3. (October 30, 2015). "Beta-Hydroxybutyrate". WebMD LLC..
4. (October 1967). "Brain metabolism during fasting". The Journal of Clinical Investigation.
5. (January 2023). "Ketone monoester ingestion increases postexercise serum erythropoietin concentrations in healthy men". American Journal of Physiology. Endocrinology and Metabolism.
6. (2006-08-01). "Fuel metabolism in starvation". Annual Review of Nutrition.
7. (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.
8. (27 January 2016). "Valine, leucine and isoleucine degradation - Reference pathway". Kanehisa Laboratories.
9. "β-D-hydroxybutyric acid: Biological activity". International Union of Basic and Clinical Pharmacology.
10. Felmlee, Melanie A.. (2020). "Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease". Pharmacological Reviews.
11. Roth, K. S.. (1982). "Transport of beta-hydroxy-beta-methyl-glutarate and beta-hydroxbutyrate by renal brushborder membrane vesicles". Pediatric Research.
12. Carneiro, L.. (2015). "Monocarboxylate transporters: new players in body weight regulation". Obesity Reviews: An Official Journal of the International Association for the Study of Obesity.
13. van Hasselt, Peter M.. (2014-11-13). "Monocarboxylate transporter 1 deficiency and ketone utilization". The New England Journal of Medicine.
14. (June 2016). "Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate". eLife.
15. (December 2000). "The ketogenic diet: seizure control correlates better with serum beta-hydroxybutyrate than with urine ketones". Journal of Child Neurology.
16. (1988). "Nuclear magnetic resonance studies on unusual bacterial copolyesters of 3-hydroxybutyrate and 4-hydroxybutyrate". Macromolecules.
17. (April 1993). "Direct Degradation of the Biopolymer Poly[(''R'')-3-Hydroxybutrric Acid to (''R'')-3-Hydroxybutanoic Acid and Its Methyl Ester". Organic Syntheses.