Butyric acid

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Butyric acid (Template:IPAc-en; from Template:Langx, meaning "butter"), also known under the systematic name butanoic acid, is a straight-chain alkyl carboxylic acid with the chemical formula Template:Chem2. It is an oily, colorless liquid with an unpleasant odor. Isobutyric acid (2-methylpropanoic acid) is an isomer. Salts and esters 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<ref name=Ullmann>Template:Ullmann</ref> and an important component in the mammalian gut.

History

Butyric acid was first observed in an impure form in 1814 by the French chemist Michel Eugène Chevreul. By 1818, he had purified it sufficiently to characterize it. However, Chevreul did not publish his early research on butyric acid; instead, he deposited his findings in manuscript form with the secretary of the Academy of Sciences in Paris, France. Henri Braconnot, another French chemist, was also researching the composition of butter and was publishing his findings and this led to disputes about priority. As early as 1815, Chevreul claimed that he had found the substance responsible for the smell of butter.<ref>Chevreul (1815) "Lettre de M. Chevreul à MM. les rédacteurs des Annales de chimie" (Letter from Mr. Chevreul to the editors of the Annals of Chemistry), Annales de chimie, 94 : 73–79; in a footnote spanning pp. 75–76, he mentions that he had found a substance that is responsible for the smell of butter.</ref> By 1817, he published some of his findings regarding the properties of butyric acid and named it.<ref>Chevreul (1817) "Extrait d'une lettre de M. Chevreul à MM. les Rédacteurs du Journal de Pharmacie" (Extract of a letter from Mr. Chevreul to the editors of the Journal of Pharmacy), Journal de Pharmacie et des sciences accessoires, 3 : 79–81. On p. 81, he named butyric acid: "Ce principe, que j'ai appelé depuis acid butérique, … " (This principle [i.e., constituent], which I have since named "butyric acid", … )</ref> However, it was not until 1823 that he presented the properties of butyric acid in detail.<ref>E. Chevreul, Recherches chimiques sur les corps gras d'origine animale [Chemical researches on fatty substances of animal origin] (Paris, France: F.G. Levrault, 1823), pages 115–133.</ref> The name butyric acid comes from Template:Wikt-lang, meaning "butter", the substance in which it was first found. The Latin name butyrum (or buturum) is similar.

Occurrence

Triglycerides of butyric acid make up 3–4% of butter. When butter goes rancid, butyric acid is liberated from the glyceride by hydrolysis.<ref>Template:Cite journal</ref> It is one of the fatty acid subgroup called short-chain fatty acids. Butyric acid is a typical carboxylic acid that reacts with bases and affects many metals.<ref name="inchem1">ICSC 1334 – Butyric acid. Inchem.org (23 November 1998). Retrieved on 2020-10-27.</ref> It is found in animal fat and plant oils, bovine milk, breast milk, butter, parmesan cheese, body odor, and vomit as a product of anaerobic fermentation (including in the colon).<ref name="morrison">Template:Cite journal</ref> It has a taste somewhat like butter and an unpleasant odor. Mammals with good scent detection abilities, such as dogs, can detect it at 10 parts per billion, whereas humans can detect it only in concentrations above 10 parts per million. In food manufacturing, it is used as a flavoring agent.<ref>Template:Cite web</ref>

In humans, butyric acid is one of two primary endogenous agonists of human hydroxycarboxylic acid receptor 2 (Template:Chem2), a Template:Nowrap G protein-coupled receptor.<ref name="IUPHAR's comprehensive 2011 review on HCARs">Template:Cite journal</ref><ref name="IUPHAR-DB HCAR family page">Template:Cite web</ref>

Butyric acid is present as its octyl ester in parsnip (Pastinaca sativa)<ref>Template:Cite journal </ref> and in the seed of the ginkgo tree.<ref>Template:Cite book</ref>

Production

Industrial

In industry, butyric acid is produced by hydroformylation from propene and syngas, forming butyraldehyde, which is oxidised to the final product.<ref name=Ullmann/>

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It can be separated from aqueous solutions by saturation with salts such as calcium chloride. The calcium salt, Template:Chem2, is less soluble in hot water than in cold.

Microbial biosynthesis

File:ButyrateBisyn.svg
One pathway for butyrate biosynthesis. Relevant enzymes: acetoacetyl-CoA thiolase, NAD- and NADP-dependent 3-hydroxybutyryl-CoA dehydrogenase, 3-hydroxybutyryl-CoA dehydratase, and NAD-dependent butyryl-CoA dehydrogenase.

Butyrate is produced by several fermentation processes performed by obligate anaerobic bacteria.<ref>Template:Cite journal </ref> This fermentation pathway was discovered by Louis Pasteur in 1861. Examples of butyrate-producing species of bacteria:

The pathway starts with the glycolytic cleavage of glucose to two molecules of pyruvate, as happens in most organisms. Pyruvate is oxidized into acetyl coenzyme A catalyzed by pyruvate:ferredoxin oxidoreductase. Two molecules of carbon dioxide (Template:Chem2) and two molecules of hydrogen (Template:Chem2) are formed as waste products. Subsequently, Template:Abbr 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

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Other pathways to butyrate include succinate reduction and crotonate disproportionation.

Action Responsible enzyme
Acetyl coenzyme A converts into acetoacetyl coenzyme A acetyl-CoA-acetyl transferase
Acetoacetyl coenzyme A converts into β-hydroxybutyryl CoA β-hydroxybutyryl-CoA dehydrogenase
β-hydroxybutyryl CoA converts into crotonyl CoA crotonase
Crotonyl CoA converts into butyryl CoA (Template:Chem2) butyryl CoA dehydrogenase
A phosphate group replaces CoA to form butyryl phosphate phosphobutyrylase
The phosphate group joins ADP to form ATP and butyrate 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:

  • acetoacetyl CoA → acetoacetate → acetone
  • acetoacetyl CoA → butyryl CoA → butyraldehyde → butanol

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.<ref>Template:Cite journal</ref>

Fermentable fiber sources

Highly-fermentable fiber residues, such as those from resistant starch, oat bran, pectin, and guar are transformed by colonic bacteria into short-chain fatty acids (SCFA) including butyrate, producing more SCFA than less fermentable fibers such as celluloses.<ref name=morrison/><ref name="lupton">Template:Cite journal</ref> One study found that resistant starch consistently produces more butyrate than other types of dietary fiber.<ref>Template:Cite journal</ref> The production of SCFA from fibers in ruminant animals such as cattle is responsible for the butyrate content of milk and butter.<ref>Template:Cite journal</ref>

Fructans are another source of prebiotic soluble dietary fibers which can be digested to produce butyrate.<ref name="pmc4923077">Template:Cite journal</ref> They are often found in the soluble fibers of foods which are high in sulfur, such as the allium and cruciferous vegetables. Sources of fructans include wheat (although some wheat strains such as spelt contain lower amounts),<ref>Template:Cite web</ref> rye, barley, onion, garlic, Jerusalem and globe artichoke, asparagus, beetroot, chicory, dandelion leaves, leek, radicchio, the white part of spring onion, broccoli, brussels sprouts, cabbage, fennel, and prebiotics, such as fructooligosaccharides (FOS), oligofructose, and inulin.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Chemical reactions

Butyric acid reacts as a typical carboxylic acid: it can form amide, ester, anhydride, and chloride derivatives.<ref>Template:Cite book</ref> The latter, butyryl chloride, is commonly used as the intermediate to obtain the others.

Uses

Butyric acid is used in the preparation of various butyrate esters. It is used to produce cellulose acetate butyrate (CAB), which is used in a wide variety of tools, paints, and coatings, and is more resistant to degradation than cellulose acetate.<ref>Template:Cite bookTemplate:ISBN?Template:Page needed</ref> CAB can degrade with exposure to heat and moisture, releasing butyric acid.<ref>Template:Cite news</ref>

Low-molecular-weight esters of butyric acid, such as methyl butyrate, have mostly pleasant aromas or tastes.<ref name=Ullmann/> 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.<ref>Freezer Baits Template:Webarchive, nutrabaits.net</ref> Many of the commercially available flavors used in 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.<ref>Template:Cite journal</ref>

The substance has been used as a stink bomb by the Sea Shepherd Conservation Society to disrupt Japanese whaling crews.<ref>Japanese Whalers Injured by Acid-Firing Activists Template:Webarchive, newser.com, 10 February 2010</ref> 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.<ref>Template:Cite web</ref>

Pharmacology

Human enzyme and GPCR binding<ref name="IUPHAR">Template:Cite web</ref><ref name="BindingDB">Template:Cite web</ref>
Inhibited enzyme IC50 (Template:Abbr) Entry note
HDAC1 16,000
HDAC2 12,000
HDAC3 9,000
HDAC4 2,000,000 Lower bound
HDAC5 2,000,000 Lower bound
HDAC6 2,000,000 Lower bound
HDAC7 2,000,000 Lower bound
HDAC8 15,000
HDAC9 2,000,000 Lower bound
CA1 511,000
CA2 1,032,000
GPCR target pEC50 Entry note
FFAR2 2.9–4.6 Full agonist
FFAR3 3.8–4.9 Full agonist
[[Hydroxycarboxylic acid receptor 2|Template:Chem2]] 2.8 Agonist

Pharmacodynamics

Butyric acid (pKa 4.82) is fully ionized 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 (Template:Chem2, also known as GPR109A), a Template:Nowrap G protein-coupled receptor (GPCR),<ref name="IUPHAR's comprehensive 2011 review on HCARs" /><ref name="IUPHAR-DB HCAR family page" />

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.<ref name="Review – General summary as of April 2015" /><ref name="Butyrate pharmacodynamics and neuroepigenetic effects 2016 review">Template:Cite journal</ref> It is also an HDAC inhibitor (specifically, HDAC1, HDAC2, HDAC3, and HDAC8),<ref name="IUPHAR" /><ref name="BindingDB" /> a drug that inhibits the function of histone deacetylase enzymes, thereby favoring an acetylated state of histones in cells.<ref name="Butyrate pharmacodynamics and neuroepigenetic effects 2016 review" />

Pharmacokinetics

Butyrate that is produced in the colon through microbial fermentation of dietary fiber is primarily absorbed and metabolized by colonocytes and the liver<ref group="note">Most of the butyrate that is absorbed into blood plasma from the colon enters the circulatory system via the portal vein; most of the butyrate that enters the circulatory system by this route is taken up by the liver.<ref name="Butyrate pharmacodynamics and neuroepigenetic effects 2016 review" /></ref> 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.<ref name="Butyrate pharmacodynamics and neuroepigenetic effects 2016 review" /><ref>Template:Cite journal</ref> 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).<ref name="SCFA MCT-mediated BBB passage – 2005 review">Template:Cite journal</ref><ref name="SCFA MCT-mediated BBB passage – 2014 review">Template:Cite journal</ref> Other transporters that mediate the passage of butyrate across lipid membranes include SLC5A8 (SMCT1), SLC27A1 (FATP1), and SLC27A4 (FATP4).<ref name="IUPHAR" /><ref name="SCFA MCT-mediated BBB passage – 2014 review" />

Metabolism Template:Anchor

Butyric acid is metabolized by various human XM-ligases (ACSM1, ACSM2B, ASCM3, ACSM4, ACSM5, and ACSM6), also known as butyrate–CoA ligase.<ref name="HMDB">Template:Cite web</ref><ref name="Butyrate metabolism">Template:Cite web</ref> The metabolite produced by this reaction is butyryl–CoA, and is produced as follows:<ref name="HMDB" />

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As a short-chain fatty acid, butyrate is metabolized by mitochondria as an energy (i.e., adenosine triphosphate or ATP) source through fatty acid metabolism.<ref name="Butyrate pharmacodynamics and neuroepigenetic effects 2016 review" /> In particular, it is an important energy source for cells lining the mammalian colon (colonocytes).<ref name=pmc4923077/> Without butyrates, colon cells undergo autophagy (i.e., self-digestion) and die.<ref>Template:Cite journal</ref>

In humans, the butyrate precursor tributyrin, which is naturally present in butter, is metabolized by triacylglycerol lipase into dibutyrin and butyrate through the reaction:<ref name="BRENDA tributyrin">Template:Cite web</ref>

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Biochemistry

Butyrate has numerous effects on energy homeostasis in humans. These effects occur through its metabolism by mitochondria to generate Template:Abbr 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 [[Hydroxycarboxylic acid receptor 2|Template:Chem2]]).<ref name="Review – General summary as of April 2015">Template:Cite journal</ref><ref name="Review for diabetes">Template:Cite journal</ref>

Mammalian gut

Butyrate is essential to host immune homeostasis.<ref name="Review – General summary as of April 2015" /> 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<ref>Template:Cite journal</ref> and type 1 diabetes.<ref>Template:Cite journal</ref> 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.<ref name="pmid32623619">Template:Cite journal</ref>

Decreased butyrate levels lead to a damaged or dysfunctional intestinal epithelial barrier.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

The odor of butyric acid, which emanates from the sebaceous follicles of all mammals, works on ticks as a signal.

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: [[Hydroxycarboxylic acid receptor 2|Template:Chem2]] (GPR109A), FFAR2 (GPR43), and FFAR3 (GPR41).<ref name="REVIEW butyrate human LL-37">Template:Cite journal</ref>

Colonocytes

Responsible for about 70% of energy from the colonocytes, butyric acid is a critical SCFA in colon homeostasis.<ref>Template:Cite journal</ref> Short-chain fatty acids, which include butyric acid, are produced by beneficial colonic bacteria that feed on, or ferment prebiotics, supporting colonocytes by increasing energy conversion.<ref name="lupton"/>

Butyrate salts and esters

The butanoate ion, Template:Chem2, 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

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Notes

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References

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