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Butyric acid (; from , meaning "butter"), also known under the systematic name butanoic acid, is a straight-chain alkyl carboxylic acid with the chemical formula . It is an oily, colorless liquid with an unpleasant odor. Isobutyric acid (2-methylpropanoic acid) is an isomer. Carboxylate salt and of butyric acid are known as butyrates or butanoates. The acid does not occur widely in nature, but its esters are widespread. It is a common industrial chemical and an important component in the mammalian gut.
In humans, butyric acid is one of two primary endogenous agonists of human hydroxycarboxylic acid receptor 2 (), a G protein-coupled receptor.
Butyric acid is present as its octyl ester in parsnip ( Pastinaca sativa) and in the seed of the Ginkgo biloba.
It can be separated from aqueous solutions by saturation with salts such as calcium chloride. The calcium salt, , is less soluble in hot water than in cold.
The pathway starts with the glycolysis cleavage of glucose to two of pyruvate, as happens in most organisms. Pyruvate is oxidation into acetyl coenzyme A catalyzed by . Two molecules of carbon dioxide () and two molecules of hydrogen () are formed as waste products. Subsequently, is produced in the last step of the fermentation. Three molecules of ATP are produced for each glucose molecule, a relatively high yield. The balanced equation for this fermentation is
Other pathways to butyrate include succinate reduction and crotonate disproportionation.
| acetyl-CoA-acetyl transferase |
| β-hydroxybutyryl-CoA dehydrogenase |
| crotonase |
| butyryl CoA dehydrogenase |
| phosphobutyrylase |
| butyrate kinase |
Several species form acetone and n-Butanol in an alternative pathway, which starts as butyrate fermentation. Some of these species are:
These bacteria begin with butyrate fermentation, as described above, but, when the pH drops below 5, they switch into butanol and acetone production to prevent further lowering of the pH. Two molecules of butanol are formed for each molecule of acetone.
The change in the pathway occurs after acetoacetyl CoA formation. This intermediate then takes two possible pathways:
For commercial purposes Clostridium species are used preferably for butyric acid or butanol production. The most common species used for probiotics is the Clostridium butyricum.
Fructans are another source of prebiotic soluble dietary fibers which can be digested to produce butyrate. They are often found in the soluble fibers of foods which are high in Low-sulfur diet, such as the allium and cruciferous vegetables. Sources of fructans include wheat (although some wheat strains such as spelt contain lower amounts), rye, barley, onion, garlic, Jerusalem and globe artichoke, asparagus, beetroot, chicory, Dandelion, leek, radicchio, the white part of spring onion, broccoli, brussels sprouts, cabbage, fennel, and prebiotics, such as fructooligosaccharides (FOS), oligofructose, and inulin.
Low-molecular-weight esters of butyric acid, such as methyl butyrate, have mostly pleasant aromas or tastes. As a consequence, they are used as food and perfume additives. It is an approved food flavoring in the EU FLAVIS database (number 08.005).
Due to its powerful odor, it has also been used as a fishing bait additive. Freezer Baits , nutrabaits.net Many of the commercially available flavors used in Common carp ( Cyprinus carpio) baits use butyric acid as their ester base. It is not clear whether fish are attracted by the butyric acid itself or the substances added to it. Butyric acid was one of the few organic acids shown to be palatable for both tench and bitterling.
The substance has been used as a stink bomb by the Sea Shepherd Conservation Society to disrupt Japanese whaling crews. Japanese Whalers Injured by Acid-Firing Activists , newser.com, 10 February 2010 The Dutch branch of Extinction Rebellion has used it as a chemical agent in a clothing store; several people who became unwell were treated on site by an ambulance crew.
Like other short-chain fatty acids (SCFAs), butyrate is an agonist at the free fatty acid receptors FFAR2 and FFAR3, which function as nutrient sensors that facilitate the homeostatic control of energy balance; however, among the group of SCFAs, only butyrate is an agonist of HCA2. It is also an HDAC inhibitor (specifically, HDAC1, HDAC2, HDAC3, and HDAC8), a drug that inhibits the function of histone deacetylase enzymes, thereby favoring an acetylated state of in cells.
As a short-chain fatty acid, butyrate is metabolized by Mitochondrion as an energy (i.e., adenosine triphosphate or ATP) source through fatty acid metabolism. In particular, it is an important energy source for cells lining the mammalian colon (colonocytes). Without butyrates, colon cells undergo autophagy (i.e., self-digestion) and die.
In humans, the butyrate precursor tributyrin, which is naturally present in butter, is metabolized by triacylglycerol lipase into dibutyrin and butyrate through the reaction:
Decreased butyrate levels lead to a damaged or dysfunctional intestinal epithelial barrier. Butyrate reduction has also been associated with Clostridioides difficile proliferation. Conversely, a high-fiber diet results in higher butyric acid concentration and inhibition of C. difficile growth.
In the gut microbiomes found in the class Mammalia, omnivores and herbivores have butyrate-producing bacterial communities dominated by the butyryl-CoA:acetate CoA-transferase pathway, whereas carnivores have butyrate-producing bacterial communities dominated by the butyrate kinase pathway.
The odor of butyric acid, which emanates from the sebaceous follicles of all mammals, works on ticks as a signal.
Pharmacology
+ Human enzyme and GPCR binding
! Inhibited enzyme !! IC50 () !! Entry note Lower bound Lower bound Lower bound Lower bound Lower bound Full agonist Full agonist Agonist
Pharmacodynamics
Butyric acid (pKa 4.82) is fully Ionization at physiological pH, so its anion is the material that is mainly relevant in biological systems.
It is one of two primary endogenous agonists of human hydroxycarboxylic acid receptor 2 (, also known as GPR109A), a G protein-coupled receptor (GPCR),
Pharmacokinetics
Butyrate that is produced in the colon through microbial fermentation of dietary fiber is primarily absorbed and metabolized by colonocytes and the liver for the generation of ATP during energy metabolism; however, some butyrate is absorbed in the distal colon, which is not connected to the portal vein, thereby allowing for the systemic distribution of butyrate to multiple organ systems through the circulatory system. Butyrate that has reached systemic circulation can readily cross the blood–brain barrier via monocarboxylate transporters (i.e., certain members of the SLC16A group of transporters). Other transporters that mediate the passage of butyrate across lipid membranes include SLC5A8 (SMCT1), SLC27A1 (FATP1), and SLC27A4 (FATP4).
Metabolism
Butyric acid is metabolized by various human (ACSM1, ACSM2B, ASCM3, ACSM4, ACSM5, and ACSM6), also known as butyrate–CoA ligase. The metabolite produced by this reaction is butyryl–CoA, and is produced as follows:
Biochemistry
Butyrate has numerous effects on energy homeostasis in humans. These effects occur through its metabolism by mitochondria to generate during fatty acid metabolism or through one or more of its histone-modifying enzyme targets (i.e., the class I histone deacetylases) and G-protein coupled receptor targets (i.e., FFAR2, FFAR3, and ).
Mammalian gut
Butyrate is essential to host immune homeostasis. Although the role and importance of butyrate in the gut is not fully understood, many researchers argue that a depletion of butyrate-producing bacteria in patients with several vasculitic conditions is essential to the pathogenesis of these disorders. A depletion of butyrate in the gut is typically caused by an absence or depletion of butyrate-producing-bacteria (BPB). This depletion in BPB leads to microbial dysbiosis. This is characterized by an overall low biodiversity and a depletion of key butyrate-producing members. Butyrate is an essential microbial metabolite with a vital role as a modulator of proper immune function in the host. It has been shown that children lacking in BPB are more susceptible to allergic disease and type 1 diabetes. Butyrate is also reduced in a diet low in dietary fiber, which can induce inflammation and have other adverse affects insofar as these short-chain fatty acids activate PPAR-γ.
Immunomodulation
Butyrate's effects on the immune system are mediated through the inhibition of class I histone deacetylases and activation of its G-protein coupled receptor targets: (GPR109A), FFAR2 (GPR43), and FFAR3 (GPR41).
Colonocytes
Responsible for about 70% of energy from the colonocytes, butyric acid is a critical SCFA in colon homeostasis. Short-chain fatty acids, which include butyric acid, are produced by beneficial Gut flora that feed on, or ferment prebiotics, supporting colonocytes by increasing energy conversion.
Butyrate salts and esters
The butanoate ion, , is the conjugate base of butyric acid. It is the form found in biological systems at physiological pH. A butyric (or butanoic) compound is a carboxylate salt or ester of butyric acid.
Examples
Salts
Esters
See also
Notes
External links
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