Butyric acid

Butyric acid (from Ancient Greek: βούτῡρον, meaning "butter"), also known under the systematic name butanoic acid is a carboxylic acid with the structural formula CH3CH2CH2CO2H. Classified as a carboxylic acid, it is an oily, colorless liquid that is soluble in water, ethanol, and ether. 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.[7]

Butyric acid
Skeletal structure of butyric acid
Flat structure 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
3H
7COOH
Molar mass 88.106 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 CCl4Miscible with ethanol, ether
log P 0.79
Vapor pressure 0.112 kPa (20 °C)
0.74 kPa (50 °C)
9.62 kPa (100 °C)[4]
5.35·10−4 L·atm/mol
Acidity (pKa) 4.82
-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)[5]
1.426 cP (25 °C)
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)[5]
Thermochemistry
178.6 J/mol·K[4]
222.2 J/mol·K[5]
Std enthalpy of
formation (ΔfH⦵298)
 −533.9 kJ/mol[4]
Std enthalpy of
combustion (ΔcH⦵298)
 2183.5 kJ/mol[4]
Hazards
Safety data sheet External MSDS
GHS pictograms [6]
GHS Signal word Danger
GHS hazard statements
 H314[6]
P280, P305+351+338, P310[6]
NFPA 704 (fire diamond)
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 code
2
3
0
Flash point 71 to 72 °C (160 to 162 °F; 344 to 345 K)[6]
440 °C (824 °F; 713 K)[6]
Explosive limits 2.2–13.4%
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).
Y verify (what is YN ?)
Infobox references

Occurrence

Triglycerides of butyric acid compose 3–4% of butter. When butter goes rancid, butyric acid is liberated from the glyceride by hydrolysis. It is one of the fatty acid subgroup called short-chain fatty acids. Butyric acid is a medium-strong acid that reacts with bases and affects many metals.[8] Butyric acid is found in animal fat and plant oils, bovine milk, breast milk,[9] butter, parmesan cheese, and as a product of anaerobic fermentation (including in the colon and as body odor, and vomit).[10] Butyric acid 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.

In humans, butyric acid is one of two primary endogenous agonists of human hydroxycarboxylic acid receptor 2 (HCA2), a Gi/o-coupled G protein-coupled receptor.[11][12]

Butyric acid or fermentation butyric acid is also present as the ester octyl butyrate in parsnip (Pastinaca sativa)[13] and in the seed of the ginkgo tree.[14]

Preparation and isolation

Butyric acid is prepared industrially by oxidation of butyraldehyde.[7]

It can be separated from aqueous solutions by saturation with salts such as calcium chloride. The calcium salt, Ca(C4H7O2)2·H2O, is less soluble in hot water than in cold.

History

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.[15] By 1817, he published some of his findings regarding the properties of butyric acid and named it.[16] However, it was not until 1823 that he presented the properties of butyric acid in detail.[17] The name of butyric acid comes from the Latin word for butter, butyrum (or buturum), the substance in which butyric acid was first found.

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, parts, and coatings, and is more resistant to degradation than cellulose acetate.[18] However, CAB can degrade with exposure to heat and moisture, releasing butyric acid.[19]

Low-molecular-weight esters of butyric acid, such as methyl butyrate, have mostly pleasant aromas or tastes.[7] 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.[20] 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.[21] The substance has also been used as a stink bomb by Sea Shepherd Conservation Society to disrupt Japanese whaling crews.[22]

Biochemistry
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.

Microbial biosynthesis

Butyrate is produced by several fermentation processes performed by obligate anaerobic bacteria.[23] 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 (CO2) and two molecules of elemental hydrogen (H2) are formed as waste products. Subsequently, 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

Other pathways to butyrate include succinate reduction and crotonate disproportionation.

ActionResponsible enzyme
Acetyl coenzyme A converts into acetoacetyl coenzyme Aacetyl-CoA-acetyl transferase
Acetoacetyl coenzyme A converts into β-hydroxybutyryl CoAβ-hydroxybutyryl-CoA dehydrogenase
β-hydroxybutyryl CoA converts into crotonyl CoAcrotonase
Crotonyl CoA converts into butyryl CoA (CH3CH2CH2C=O-CoA)butyryl CoA dehydrogenase
A phosphate group replaces CoA to form butyryl phosphatephosphobutyrylase
The phosphate group joins ADP to form ATP and butyratebutyrate 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

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.[10][24] One study found that resistant starch consistently produces more butyrate than other types of dietary fiber.[25] The production of SCFA from fibers in ruminant animals such as cattle is responsible for the butyrate content of milk and butter.[9][26]

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),[27] 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.[28][29]

Pharmacology
Human enzyme and GPCR binding[30][31]
Inhibited enzymeIC50 (nM)Entry note
HDAC116,000
HDAC212,000
HDAC39,000
HDAC42,000,000Lower bound
HDAC52,000,000Lower bound
HDAC62,000,000Lower bound
HDAC72,000,000Lower bound
HDAC815,000
HDAC92,000,000Lower bound
CA1511,000
CA21,032,000
GPCR targetpEC50Entry note
FFAR22.9–4.6Full agonist
FFAR33.8–4.9Full agonist
HCA22.8Agonist

Pharmacodynamics

Butyric acid is one of two primary endogenous agonists of human hydroxycarboxylic acid receptor 2 (HCA2, aka GPR109A), a Gi/o-coupled G protein-coupled receptor (GPCR),[11][12]

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;[32][33][34] however, among the group of SCFAs, only butyrate is an agonist of HCA2.[32][33][34] Butyric acid is metabolized by mitochondria, particularly in colonocytes and by the liver, to generate adenosine triphosphate (ATP) during fatty acid metabolism.[32] Butyric acid is also an HDAC inhibitor (specifically, HDAC1, HDAC2, HDAC3, and HDAC8),[30][31] a drug that inhibits the function of histone deacetylase enzymes, thereby favoring an acetylated state of histones in cells.[32] Histone acetylation loosens the structure of chromatin by reducing the electrostatic attraction between histones and DNA.[32] 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). Therefore, butyric acid is thought to enhance the transcriptional activity at promoters,[32] which are typically silenced or downregulated due to histone deacetylase activity.

Pharmacokinetics

Butyrate that is produced in the colon through microbial fermentation of dietary fiber is primarily absorbed and metabolized by colonocytes and the liver[note 1] for the generation of ATP during energy metabolism;[32] 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.[32] 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).[35][36] Other transporters that mediate the passage of butyrate across lipid membranes include SLC5A8 (SMCT1), SLC27A1 (FATP1), and SLC27A4 (FATP4).[30][36]

Metabolism

Butyric acid is metabolized by various human XM-ligases (ACSM1, ACSM2B, ASCM3, ACSM4, ACSM5, and ACSM6), also known as butyrate–CoA ligase.[38] The metabolite produced by this reaction is butyryl–CoA, and is produced as follows:[38]

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

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.

In humans, the butyrate prodrug tributyrin is metabolized by triacylglycerol lipase into dibutyrin and butyrate through the reaction:[39]

Tributyrin + H2O → dibutyrin + butyric acid

Research

Peripheral effects

Butyrate has numerous effects on energy homeostasis and related diseases (diabetes and obesity), inflammation, and immune function (e.g., it has pronounced antimicrobial and anticarcinogenic effects) in humans.[33][40] These effects occur through its metabolism 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).[33]

Immunomodulation and inflammation

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: HCA2 (GPR109A), FFAR2 (GPR43), and FFAR3 (GPR41).[34][41] 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.[34] 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 has established antimicrobial properties in humans that are mediated through the antimicrobial peptide LL-37, which it induces via HDAC inhibition on histone H3.[41][42][43] 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;[34][41] through these actions, it increases the expression of interleukin 10, an anti-inflammatory cytokine.[41][34] Butyrate also suppresses colonic inflammation by inhibiting the IFN-γ–STAT1 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.[44]

Similar to other HCA2 agonists studied, butyrate also produces marked anti-inflammatory effects in a variety of tissues, including the brain, gastrointestinal tract, skin, and vascular tissue.[45][46][47] Butyrate binding at FFAR3 induces neuropeptide Y release and promotes the functional homeostasis of colonic mucosa and the enteric immune system.[48]

Butyric acid is an important energy (ATP) source for cells lining the mammalian colon (colonocytes). Without butyric acid for energy, colon cells undergo upregulated autophagy (i.e., self-digestion).[49]

Cancer

Butyrate produces different effects in healthy and cancerous cells; this is known as the "butyrate paradox". In particular, butyrate inhibits colonic tumor cells and stimulates proliferation of healthy colonic epithelial cells.[50] The signaling mechanism is not well understood.[51] The production of volatile fatty acids such as butyrate from fermentable fibers may contribute to the role of dietary fiber in colon cancer.[24] 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 may protect against colon cancer by inhibiting cell proliferation.[52]

Conversely, some researchers have sought to eliminate butyrate and consider it a potential cancer driver.[53] Studies in mice indicate it drives transformation of MSH2-deficient colon epithelial cells.[54]

Addiction

Butyric acid is an HDAC inhibitor that is selective for class I HDACs in humans.[30] HDACs are histone-modifying enzymes that can cause histone deacetylation and repression of gene expression. HDACs are important regulators of synaptic formation, synaptic plasticity, and long-term memory formation. Several HDACs (specifically, class I HDACs) are known to be involved in mediating the development of an addiction.[55][56][57] Butyric acid and other HDAC inhibitors have been used in preclinical research to assess the transcriptional, neural, and behavioral effects of HDAC inhibition in animals addicted to drugs.[57][58][59]

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gollark: Oh, HelloBoi talks about that a lot.
gollark: I have a large 2.5kg gaming laptop which can *technically* be held one-handed.
gollark: * its

See also

Notes
  1. Most of the butyrate that is absorbed into blood plasma from the colon enters the circulatory system via the portal vein;[32] most of the butyrate that enters the circulatory system by this route is taken up by the liver.[32]

References

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

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    Figure 1: Microbial-derived molecules promote colonic Treg differentiation.
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    Table 3: Select human antimicrobial peptides and their proposed targets
    Table 4: Some known factors that induce antimicrobial peptide expression
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