Butyric acid

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Butyric acid
Skeletal structure of butyric acid
Flat structure of butyric acid
Space filling model of butyric acid
Names
Preferred IUPAC name
Butanoic acid[1]
Other names
Butyric acid[1]
1-Propanecarboxylic acid
Propanecarboxylic acid
C4:0 (Lipid numbers)
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.003.212
EC Number 203-532-3
KEGG
MeSH Butyric+acid
RTECS number ES5425000
UNII
UN number 2820
Properties
C
3
H
7
COOH
Molar mass 88.11 g·mol−1
Appearance Colorless liquid
Odor Unpleasant, similar to vomit or body odor
Density 1.135 g/cm3 (−43 °C)[2]
0.9528 g/cm3 (25 °C)[3]
Melting point −5.1 °C (22.8 °F; 268.0 K)[3]
Boiling point 163.75 °C (326.75 °F; 436.90 K)[3]
Sublimes at −35 °C
ΔsublHo = 76 kJ/mol[4]
Miscible
Solubility Slightly soluble in CCl4[5]
Miscible with ethanol, ether
log P 0.79[5]
Vapor pressure 0.112 kPa (20 °C)[6]
0.74 kPa (50 °C)
9.62 kPa (100 °C)[4]
5.35·10−4 L·atm/mol[5]
Acidity (pKa) 4.82[5]
-55.10·10−6 cm3/mol
Thermal conductivity 1.46·105 W/m·K
1.398 (20 °C)[3]
Viscosity 1.814 cP (15 °C)[7]
1.426 cP (25 °C)[5]
Structure
Monoclinic (−43 °C)[2]
C2/m[2]
a = 8.01 Å, b = 6.82 Å, c = 10.14 Å[2]
α = 90°, β = 111.45°, γ = 90°
0.93 D (20 °C)[7]
Thermochemistry
178.6 J/mol·K[4][5]
222.2 J/mol·K[7]
−533.9 kJ/mol[4]
2183.5 kJ/mol[4]
Hazards
Safety data sheet External MSDS
GHS pictograms The corrosion pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)[8]
GHS signal word Danger
H314[8]
P280, P305+351+338, P310[8]
NFPA 704
Flammability code 2: Must be moderately heated or exposed to relatively high ambient temperature before ignition can occur. Flash point between 38 and 93 °C (100 and 200 °F). E.g., diesel fuelHealth code 3: Short exposure could cause serious temporary or residual injury. E.g., chlorine gasReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogenSpecial hazards (white): no codeNFPA 704 four-colored diamond
2
3
0
Flash point 71 to 72 °C (160 to 162 °F; 344 to 345 K)[6][8]
440 °C (824 °F; 713 K)[8]
Explosive limits 2.2–13.4%[6]
Lethal dose or concentration (LD, LC):
2000 mg/kg (oral, rat)
Related compounds
Other anions
Butyrate
Propionic acid, Pentanoic acid
Related compounds
1-Butanol
Butyraldehyde
Methyl butyrate
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Butyric acid (from Ancient Greek: βούτῡρον, meaning "butter"), also known under the systematic name butanoic acid, abbreviated BTA,[6] is a carboxylic acid with the structural formula CH3CH2CH2-COOH. Salts and esters of butyric acid are known as butyrates or butanoates. Butyric acid is found in milk, especially goat, sheep and buffalo milk, butter, parmesan cheese, and as a product of anaerobic fermentation (including in the colon and as body odor). Butyric acid has an acrid taste, with a sweetish aftertaste similar to ether, and unpleasant odor and is present in rancid butter and human vomit.[9] Mammals with good scent detection abilities, such as dogs, can detect it at 10 parts per billion, whereas humans can only detect it in concentrations above 10 parts per million.

Butyric acid was first observed in 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, a 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.[10] By 1817, he published some of his findings regarding the properties of butyric acid and named it.[11] However, it was not until 1823 that he presented the properties of butyric acid in detail.[12] The name of butyric acid comes from the Latin word for butter, butyrum (or buturum), the substance in which butyric acid was first found.

Butyric acid is a pharmacologically active compound which functions as an agonist of hydroxycarboxylic acid receptor 2 (HCA2) and the free fatty acid receptors FFAR2 and FFAR3.[13][14] It also acts as a histone deacetylase inhibitor which is selective for class I histone deacetylase enzymes (i.e., HDAC1, HDAC2, HDAC3, and HDAC8).[13][14]

Chemistry[edit]

Butyric acid is a fatty acid occurring in the form of esters in animal fats. The triglyceride of butyric acid makes up 3–4% of butter. When butter goes rancid, butyric acid is liberated from the glyceride by hydrolysis, leading to the unpleasant odor. It is an important member of the fatty acid subgroup called short-chain fatty acids. Butyric acid is a medium-strong acid that reacts with bases and strong oxidants, and attacks many metals.[15]

The acid is an oily, colorless liquid that is easily soluble in water, ethanol, and ether, and can be separated from an aqueous phase by saturation with salts such as calcium chloride. It is oxidized to carbon dioxide and acetic acid using potassium dichromate and sulfuric acid, while alkaline potassium permanganate oxidizes it to carbon dioxide. The calcium salt, Ca(C4H7O2)2·H2O, is less soluble in hot water than in cold.

Butyric acid has a structural isomer called isobutyric acid (2-methylpropanoic acid).

Safety[edit]

Personal protective equipment such as rubber or PVC gloves, protective eye goggles, and chemical-resistant clothing and shoes are used to minimize risks when handling butyric acid.

Inhalation of butyric acid may result in soreness of throat, coughing, a burning sensation, and laboured breathing. Ingestion of the acid may result in abdominal pain, shock, and collapse. Physical exposure to the acid may result in pain, blistering and skin burns, while exposure to the eyes may result in pain, severe deep burns and loss of vision.[15]

Production[edit]

It is industrially prepared by the fermentation of sugar or starch, brought about by the addition of putrefying cheese, with calcium carbonate added to neutralize the acids formed in the process. The butyric fermentation of starch is aided by the direct addition of Bacillus subtilis. Salts and esters of the acid are called butyrates or butanoates.[citation needed]

Butyric acid or fermentation butyric acid is also found as a hexyl ester hexyl butyrate in the oil of Heracleum giganteum (a type of hogweed)[citation needed] and as the octyl ester octyl butyrate in parsnip (Pastinaca sativa)[citation needed] and in the fruit of the ginko tree.[16] It has also been noticed in skin flora and perspiration.[citation needed]

Uses[edit]

Butyric acid is used in the preparation of various butyrate esters. 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 also used as an animal feed supplement due to the ability to reduce pathogenic bacterial colonization.[17] 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.[18] Many of the commercially available flavors used in carp (Cyprinus carpio) baits use butyric acid as their ester base; however, it is not clear whether fish are attracted by the butyric acid itself or the substances added to it. Butyric acid was, however, one of the few organic acids shown to be palatable for both tench and bitterling.[19]

The substance has also been used as a stink bomb by Sea Shepherd Conservation Society to disrupt Japanese whaling crews,[20] as well as by anti-abortion protesters to disrupt abortion clinics.[21]

Butyric acid, along with acetic acid, can be reacted with cellulose to produce the organic ester cellulose acetate butyrate (CAB), which is used in a wide variety of tools, parts, and coatings and is more resistant to degradation than cellulose acetate.[22] However, CAB can degrade with exposure to heat and moisture, releasing butyric acid.[23] This process is sometimes observed in the unpleasant, vomit-like odor of aging screwdrivers and other hand tools.[24][unreliable source]

Biochemistry[edit]

Microbial biosynthesis[edit]

Butyrate is produced as end-product of a fermentation process solely performed by obligate anaerobic bacteria. Fermented Kombucha "tea" includes butyric acid as a result of the fermentation. 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 then oxidized into acetyl coenzyme A using a unique mechanism that involves an enzyme system called pyruvate:ferredoxin oxidoreductase. Two molecules of carbon dioxide (CO2) and two molecules of elemental hydrogen (H2) are formed as waste products from the cell. Then,

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 (CH3CH2CH2C=O-CoA) 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

ATP is produced, as can be seen, 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

C6H12O6 → C4H8O2 + 2 CO2 + 2 H2

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

Fermentable fiber sources[edit]

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.[25] One study found that resistant starch consistently produces more butyrate than other types of dietary fiber.[26] The production of SCFA from fibers in ruminant animals such as cattle is responsible for the butyrate content of milk and butter.[27]

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 sulfur, such as the allium and cruciferous vegetables. Sources of fructans include wheat (although some wheat strains such as spelt contain lower amounts),[28] 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.[29][30]

Metabolism [edit]

Butyric acid is metabolized by various human XM-ligases (ACSM1, ACSM2B, ASCM3, ACSM4, ACSM5, and ACSM6), also known as butyrate–CoA ligase.[9] The metabolite produced by this reaction is butyryl–CoA, and is produced as follows:[9]

Adenosine triphosphate + butyric acid + coenzyme A → adenosine monophosphate + pyrophosphate + butyryl-CoA

As a short-chain fatty acid, butyrate is used by mitochondria as an energy (i.e., adenosine triphosphate or ATP) source through fatty acid metabolism.

In humans, the butyrate prodrug tributyrin is metabolized by triacylglycerol lipase into dibutyrin and butyrate through the reaction:[32]

Tributyrin + H2O → dibutyrin + butyric acid

Research[edit]

Preliminary research on butyrate involves laboratory studies in vitro to discern its potential receptor interactions and the mechanisms of its biological activity in vivo.[33]

Human enzyme and GPCR binding[13][14]
Inhibited enzyme IC50 (nM) 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
HCA2 2.8 Agonist

Pharmacodynamics[edit]

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 may affect energy balance;[34][35][36] unlike the other SCFAs,[36] butyrate is also an agonist of hydroxycarboxylic acid receptor 2 (HCA2, aka GPR109A).[34][35][36] Butyric acid is used by mitochondria, particularly in colonocytes and by the liver, to generate adenosine triphosphate (ATP) during fatty acid metabolism.[34] Butyric acid is also an HDAC inhibitor (specifically, HDAC1, HDAC2, HDAC3, and HDAC8),[13][14] a drug that inhibits the function of histone deacetylase enzymes, thereby favoring an acetylated state of histones in cells.[34] Histone acetylation loosens the structure of chromatin by reducing the electrostatic attraction between histones and DNA.[34] In general, it is thought that transcription factors will be unable to access regions where histones are tightly associated with DNA (i.e., non-acetylated, e.g., heterochromatin).[medical citation needed] Therefore, butyric acid is thought to enhance the transcriptional activity at promoters,[34] which are typically silenced or downregulated due to histone deacetylase activity.

Pharmacokinetics[edit]

Butyrate that is produced in the colon through microbial fermentation of dietary fiber is primarily absorbed and used by colonocytes and the liver[note 1] for the generation of ATP during energy metabolism;[34] 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.[34] 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).[37][38] Other transporters that mediate the passage of butyrate across lipid membranes include SLC5A8 (SMCT1), SLC27A1 (FATP1), and SLC27A4 (FATP4).[13][38]

Potential anti-disease effects[edit]

Butyrate has numerous effects in humans on energy homeostasis and may be involved in related diseases (diabetes and obesity).[35][39] These effects may occur through its use by mitochondria to generate ATP 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 HCA2).[35]

Immunomodulation and inflammation[edit]

Butyrate's effects on the immune system may be mediated through the inhibition of class I histone deacetylases and activation of its G-protein coupled receptor targets: HCA2 (GPR109A), FFAR2 (GPR43), and FFAR3 (GPR41).[36][40] Among the short-chain fatty acids, butyrate is the most potent promoter of intestinal regulatory T cells in vitro and the only one among the group that is an HCA2 ligand.[36] It has been shown to be a critical mediator of the colonic inflammatory response. It possesses both preventive and therapeutic potential to counteract inflammation-mediated ulcerative colitis and colorectal cancer.

Butyrate is under laboratory research for its potential antimicrobial properties mediated through the antimicrobial peptide LL-37, which it induces via HDAC inhibition on histone H3.[40][41][42] In vitro, butyrate increases gene expression of FOXP3 (the transcription regulator for Tregs) and promotes colonic regulatory T cells (Tregs) through the inhibition of class I histone deacetylases;[36][40] through these actions, it increases the expression of interleukin 10, an anti-inflammatory cytokine.[40][36] Butyrate is under basic research to determine if it affects colonic inflammation by inhibiting the IFN-γSTAT1 signaling pathways, which is mediated partially through histone deacetylase inhibition. While transient IFN-γ signaling is generally associated with normal host immune response, chronic IFN-γ signaling is often associated with chronic inflammation. It has been shown that butyrate inhibits activity of HDAC1 that is bound to the Fas gene promoter in T cells, resulting in hyperacetylation of the Fas promoter and up-regulation of Fas receptor on the T-cell surface.[43]

Similar to other HCA2 agonists studied in vitro, butyrate also produces anti-inflammatory effects in a variety of tissues, including the brain, gastrointestinal tract, skin, and vascular tissue.[44][45][46] Butyrate binding at FFAR3 induces neuropeptide Y release and promotes the functional homeostasis of colonic mucosa and the enteric immune system.[47]

Butyric acid is involved as an energy (ATP) source for cells lining the mammalian colon (colonocytes). Without butyric acid for energy, colon cells undergo upregulated autophagy (i.e., self-digestion).[48]

Cancer[edit]

In laboratory research, butyrate produces different effects in healthy and cancerous cells; this is known as the "butyrate paradox". In particular, butyrate inhibits colonic tumor cells and promotes healthy colonic epithelial cells.[49] The signaling mechanism is not well understood.[50] The production of volatile fatty acids such as butyrate from fermentable fibers may contribute to the role of dietary fiber in colon cancer.[25] Short-chain fatty acids, which include butyric acid, are produced by beneficial colonic bacteria (probiotics) that feed on, or ferment prebiotics, which are plant products that contain dietary fiber. These short-chain fatty acids benefit the colonocytes by increasing energy production and cell proliferation, and may protect against colon cancer.[51]

Conversely, some researchers have sought to eliminate butyrate and consider it a potential cancer driver.[52] Studies in mice indicate it drives transformation of MSH2-deficient colon epithelial cells.[53]

Diabetes[edit]

A review on the relationship between the microbiome and diabetes asserted that butyrate can induce "profound immunometabolic effects" in animal models and humans with type 2 diabetes, although there is no such use in clinical practice and further research is needed.[39]

Addiction[edit]

Butyric acid is a HDAC inhibitor.[54] HDACs are enzymes that can cause histone deacetylation and repression of gene expression. HDACs are regulators of synaptic formation, synaptic plasticity, and long-term memory formation. Several HDACs also appear to play roles in various models of drug abuse and addiction.[55]

See also[edit]

Notes[edit]

  1. ^ Most of the butyrate that is absorbed into blood plasma from the colon enters the circulatory system via the portal vein;[34] most of the butyrate that enters the circulatory system by this route is taken up by the liver.[34]

References[edit]

 This article incorporates text from a publication now in the public domainChisholm, Hugh, ed. (1911). "Butyric Acid". Encyclopædia Britannica (11th ed.). Cambridge University Press.

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