Butyric acid

Butyric acid

Butyric acid
Skeletal structure of butyric acid
Flat structure of butyric acid
Space filling model of butyric acid
Names
IUPAC name
Butanoic acid
Other names
Butyric acid, 1-Propanecarboxylic acid, Propanecarboxylic acid, C4:0 (Lipid numbers)
Identifiers
 Y
ChEBI  Y
ChEMBL  Y
ChemSpider  Y
DrugBank  Y
EC number 203-532-3
Jmol-3D images Image
Image
KEGG  Y
MeSH
PubChem
RTECS number ES5425000
UNII  Y
UN number 2820
Properties
C4H8O2
Molar mass 88.11 g·mol−1
Appearance Colorless liquid
Odor Unpleasant and obnoxious
Density 1.135 g/cm3 (−43 °C)[1]
0.9528 g/cm3 (25 °C)[2]
Melting point −5.1 °C (22.8 °F; 268.0 K)[2]
Boiling point 163.75 °C (326.75 °F; 436.90 K)[2]
Sublimes at −35 °C
ΔsublHo = 76 kJ/mol[3]
Miscible
Solubility Slightly soluble in CCl4[4]
Miscible with ethanol, ether
log P 0.79[4]
Vapor pressure 0.112 kPa (20 °C)[5]
0.74 kPa (50 °C)
9.62 kPa (100 °C)[3]
5.35·10−4 L·atm/mol[4]
Acidity (pKa) 4.82[4]
Thermal conductivity 1.46·105 W/m·K
1.398 (20 °C)[2]
Viscosity 1.814 cP (15 °C)[6]
1.426 cP (25 °C)[4]
Structure
Monoclinic (−43 °C)[1]
C2/m[1]
a = 8.01 Å, b = 6.82 Å, c = 10.14 Å[1]
α = 90°, β = 111.45°, γ = 90°
0.93 D (20 °C)[6]
Thermochemistry
178.6 J/mol·K[3][4]
222.2 J/mol·K[6]
−533.9 kJ/mol[3]
2183.5 kJ/mol[3]
Hazards
Safety data sheet External MSDS
GHS pictograms The corrosion pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)[7]
GHS signal word Danger
H314[7]
P280, P305+351+338, P310[7]
Harmful Xn Corrosive C
R-phrases R20/21/22, R34, R36/37/38
S-phrases S26, S36, S45
NFPA 704
2
3
0
Flash point 71 to 72 °C (160 to 162 °F; 344 to 345 K)[5][7]
440 °C (824 °F; 713 K)[7]
Explosive limits 2.2–13.4%[5]
Lethal dose or concentration (LD, LC):
LD50 (Median dose)
2000 mg/kg (oral, rat)
Related compounds
Other anions
Butyrate
Propionic acid
Acrylic acid
Succinic acid
Malic acid
Tartaric acid
Crotonic acid
Fumaric 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  (: Y/N?)

Butyric acid (from Greek βούτῡρον, meaning "butter"), also known under the systematic name butanoic acid, abbreviated BTA,[5] 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). It has an unpleasant smell and acrid taste, with a sweetish aftertaste (similar to ether). It can be detected by mammals with good scent detection abilities (such as dogs) at 10 parts per billion, whereas humans can detect it in concentrations above 10 parts per million.

Butyric acid is present in, and is the main distinctive smell of, human vomit.[8]

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.[9] The name of butyric acid comes from the Latin word for butter, butyrum (or buturum), the substance in which butyric acid was first found.

Contents

  • Chemistry 1
    • Safety 1.1
  • Production 2
  • Uses 3
  • Biochemistry 4
    • Biosynthesis 4.1
  • Pharmacology 5
    • Pharmacodynamics 5.1
    • Pharmacokinetics 5.2
  • Research 6
    • Peripheral therapeutic effects 6.1
      • Immunomodulation and inflammation 6.1.1
      • Cancer 6.1.2
      • Diabetes 6.1.3
    • Neuroepigenetic effects 6.2
      • Addiction 6.2.1
      • Cognitive deficits and memory 6.2.2
  • See also 7
  • References 8
  • External links 9

Chemistry

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.[10]

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

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.[10]

Production

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.

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) and as the octyl ester octyl butyrate in parsnip (Pastinaca sativa); it has also been noticed in skin flora and perspiration.

Uses

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 find use as food and perfume additives. It is also used as an animal feed supplement, due to the ability to reduce pathogenic bacterial colonization.[11] 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.[12] Many of the commercially available flavors used in tench and bitterling.[13]

The substance has also been used as a stink bomb by Sea Shepherd Conservation Society to disrupt Japanese whaling crews,[14] as well as by anti-abortion protesters to disrupt abortion clinics.[15]

Biochemistry

Biosynthesis

Butyrate is produced as end-product of a fermentation process solely performed by 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 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

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.[16] One study found that resistant starch consistently produces more butyrate than other types of dietary fiber.[17] The production of SCFA from fibers in ruminant animals such as cattle is responsible for the butyrate content of milk and butter.[18]

Pharmacology

Pharmacodynamics

Human enzyme and GPCR binding[19][20]
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 15000
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
NIACR1 missing data Full agonist

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 which help regulate energy balance; unlike the other SCFAs, butyrate is also an agonist of niacin receptor 1. Butyric acid 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 histones in cells. Acetylated histones have a lower affinity for DNA than nonacetylated histones, due to the neutralization of electrostatic charge interactions. In general, it is thought that transcription factors will be unable to access regions where histones are tightly associated with DNA (i.e., nonacetylated, e.g., heterochromatin). Therefore, butyric acid is thought to enhance the transcriptional activity at promoters, which are typically silenced or downregulated due to histone deacetylase activity.

Two HDAC inhibitors, sodium butyrate (NaB) and trichostatin A (TSA), increase lifespan in experimental animals.[21]

Pharmacokinetics

Butyric acid is metabolized by various human XM-ligases (ACSM1, ACSM2B, ASCM3, ACSM4, ACSM5, and ACSM6), also known as butyrate–CoA ligase.[8] The metabolite produced by this reaction is butyryl–CoA, and occurs as follows:[8]

Adenosine triphosphate + Butyric acid + Coenzyme A → Adenosine monophosphate + Pyrophosphate + Butyryl-CoA

In humans, the butyrate prodrug tributyrin is metabolized by triacylglycerol lipase into dibutyrin and butyrate through the reaction:[22]

Tributyrin + H20 = Dibutyrin + Butyrate

Research

Peripheral therapeutic effects

Butyrate is known to have numerous beneficial effects in humans on energy homeostasis and related diseases (e.g., diabetes and obesity), immune function, and inflammation, which mediate its antimicrobial and anticarcinogenic properties.[23][24] These effects are all known to occur through one more of its histone-modifying enzyme targets (i.e., the HDACs) or G-protein coupled receptor targets (i.e., FFAR2, FFAR3, and NIACR1).[23]

Immunomodulation and inflammation

Butyrate has established antimicrobial properties in humans which are mediated through the antimicrobial peptide, LL-37, which it induces via HDAC inhibition on histone H3.[25][26][27] 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 which is an NIACR1 ligand.[28] Butyrate increases gene expression of FOXP3 (the transcription regulator for Tregs) and promotes colonic Tregs through the inhibition of class I histone deacetylases;[25][28] through these actions, it increases interleukin 10 expression.[25][28]

Part of butyrate's effects on the immune system are mediated via its G-protein coupled receptor targets: NIACR1 (GPR109A), FFAR2 (GPR43), and FFAR3 (GPR41). Butyrate binding at FFAR3 induces neuropeptide Y release and promotes the functional homeostasis of colonic mucosa and the enteric immune system.[29]

Butyrate is a major metabolite in colonic lumen arising from bacterial fermentation of dietary fiber and has been shown to be a critical mediator of the colonic inflammatory response. Butyrate possesses both preventive and therapeutic potential to counteract inflammation-mediated ulcerative colitis and colorectal cancer. One mechanism underlying butyrate function in suppression of colonic inflammation is inhibition of the IFN-γSTAT1 signaling pathways, which at least 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.[30] It is thus suggested that Butyrate enhances apoptosis of T cells in the colonic tissue and thereby eliminates the source of inflammation (IFN-γ production).[30]

Cancer

The role of butyrate differs between normal and cancerous cells. This is known as the "butyrate paradox". Butyrate inhibits colonic tumor cells, and promotes healthy colonic epithelial cells;[31] but the signaling mechanism is not well understood.[32] A review suggested the chemopreventive benefits of butyrate depend in part on amount, time of exposure with respect to the tumorigenic process, and the type of fat in the diet.[16] The production of volatile fatty acids such as butyrate from fermentable fibers may contribute to the role of dietary fiber in colon cancer.[16]

Diabetes

A review on the relationship between the microbiome and diabetes asserted that butyrate can induce "profound immunometabolic effects" in animal models of and humans with type 2 diabetes;[24] it also noted a relationship between the presence of obesity or diabetes and a state of marked dysbiosis in a host, which is not yet completely understood.[24] While acknowledging that there is strong evidence for the use of butyrate in such disorders, the review called for more research into the pathophysiology (i.e., biomolecular mechanisms) of these diseases, so as to improve therapeutic approaches to these diseases.[24]

Neuroepigenetic effects

Addiction

Cognitive deficits and memory

See also

References

  • International Chemical Safety Card 1334
  • 2004 review of the scientific evidence on butanoate/butyrate vs. colon cancer

External links

  1. ^ a b c d Strieter FJ, Templeton DH (1962). "Crystal structure of butyric acid". Acta Crystallographica 15 (12): 1240.  
  2. ^ a b c d Lide, David R., ed. (2009).  
  3. ^ a b c d e Butanoic acid in Linstrom, P.J.; Mallard, W.G. (eds.) NIST Chemistry WebBook, NIST Standard Reference Database Number 69. National Institute of Standards and Technology, Gaithersburg MD. http://webbook.nist.gov (retrieved 2014-06-13)
  4. ^ a b c d e f CID 264 from PubChem
  5. ^ a b c d "Butanoic Acid". http://www.caslab.com. ALS Environmental. Retrieved 2014-06-13. 
  6. ^ a b c http://chemister.ru/Database/properties-en.php?dbid=1&id=1985
  7. ^ a b c d e Sigma-Aldrich Co., Butyric acid. Retrieved on 2014-06-13.
  8. ^ a b c "Butyric acid". Human Metabolome Database. University of Alberta. Retrieved 15 August 2015. 
  9. ^ Unfortunately, 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. This led to problems because 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 susbstance that's responsible for the smell of butter: 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, vol. 94, pages 73–79; in a footnote spanning pages 75–76, he mentions that he had found a substance that is responsible for the smell of butter. By 1817, he published some of his findings regarding the properties of butyric acid: 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, vol. 3, pages 79–81. However, it was not until 1823 that he presented the properties of butyric acid in detail: 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.
  10. ^ a b ICSC 1334 – BUTYRIC ACID. Inchem.org (1998-11-23). Retrieved on 2014-03-31.
  11. ^ Supplementation of Coated Butyric Acid in the Feed Reduces Colonization and Shedding of Salmonella in Poultry. Ps.fass.org. Retrieved on 2014-03-31.
  12. ^ Freezer Baits, nutrabaits.net
  13. ^ Kasumyan AO, Døving KB (2003). "Taste preferences in fishes". Fish and Fisheries 4 (4): 289–347.  
  14. ^ Japanese Whalers Injured by Acid-Firing Activists, newser.com, February 10, 2010
  15. ^ National Abortion Federation, HISTORY OF VIOLENCE Butyric Acid Attacks. Prochoice.org. Retrieved on 2014-03-31.
  16. ^ a b c Lupton JR (Feb 2004). "Microbial degradation products influence colon cancer risk: the butyrate controversy". The Journal of Nutrition 134 (2): 479–82.  
  17. ^ Cummings JH, Macfarlane GT, Englyst HN (Feb 2001). "Prebiotic digestion and fermentation". The American Journal of Clinical Nutrition 73 (2 Suppl): 415S–420S.  
  18. ^ Grummer RR (Sep 1991). "Effect of feed on the composition of milk fat" (PDF). Journal of Dairy Science 74 (9): 3244–57.  
  19. ^ "Butyric acid". IUPHAR. IUPHAR/BPS Guide to PHARMACOLOGY. Retrieved 23 May 2015. 
  20. ^ "butanoic acid, 4 and Sodium; butyrate". BindingDB. The Binding Database. Retrieved 23 May 2015. 
  21. ^ Zhang M, Poplawski M, Yen K, Cheng H, Bloss E, Zhu X, Patel H, Mobbs CV (Nov 2009). Dillin A, ed. "Role of CBP and SATB-1 in aging, dietary restriction, and insulin-like signaling". PLoS Biology 7 (11): e1000245.  
  22. ^ "triacylglycerol lipase - Homo sapiens". BRENDA. Technische Universität Braunschweig. Retrieved 25 May 2015. 
  23. ^ a b Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura I (2015). "Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation". Nutrients 7 (4): 2839–49.  
  24. ^ a b c d Tilg H, Moschen AR (September 2014). "Microbiota and diabetes: an evolving relationship". Gut 63 (9): 1513–1521.  
  25. ^ a b c Wang G (2014). "Human antimicrobial peptides and proteins". Pharmaceuticals (Basel) 7 (5): 545–94.  
    Table 3: Select human antimicrobial peptides and their proposed targets
    Table 4: Some known factors that induce antimicrobial peptide expression
  26. ^ Yonezawa H, Osaki T, Hanawa T, Kurata S, Zaman C, Woo TD, Takahashi M, Matsubara S, Kawakami H, Ochiai K, Kamiya S (2012). "Destructive effects of butyrate on the cell envelope of Helicobacter pylori". J. Med. Microbiol. 61 (Pt 4): 582–9.  
  27. ^ McGee DJ, George AE, Trainor EA, Horton KE, Hildebrandt E, Testerman TL (2011). "Cholesterol enhances Helicobacter pylori resistance to antibiotics and LL-37". Antimicrob. Agents Chemother. 55 (6): 2897–904.  
  28. ^ a b c Hoeppli RE, Wu D, Cook L, Levings MK (February 2015). "The environment of regulatory T cell biology: cytokines, metabolites, and the microbiome". Front Immunol 6: 61.  
    Figure 1: Microbial-derived molecules promote colonic Treg differentiation.
  29. ^ Farzi A, Reichmann F, Holzer P (2015). "The homeostatic role of neuropeptide Y in immune function and its impact on mood and behaviour". Acta Physiol (Oxf) 213 (3): 603–27.  
  30. ^ a b Zimmerman MA, Singh N, Martin PM, Thangaraju M, Ganapathy V, Waller JL, Shi H, Robertson KD, Munn DH, Liu K (2012). "Butyrate suppresses colonic inflammation through HDAC1-dependent Fas upregulation and Fas-mediated apoptosis of T cells". Am. J. Physiol. Gastrointest. Liver Physiol. 302 (12): G1405–15.  
  31. ^ Vanhoutvin SA, Troost FJ, Hamer HM, Lindsey PJ, Koek GH, Jonkers DM, Kodde A, Venema K, Brummer RJ (2009). Bereswill S, ed. "Butyrate-induced transcriptional changes in human colonic mucosa". PloS One 4 (8): e6759.  
  32. ^ Klampfer L, Huang J, Sasazuki T, Shirasawa S, Augenlicht L (Aug 2004). "Oncogenic Ras promotes butyrate-induced apoptosis through inhibition of gelsolin expression" (PDF). The Journal of Biological Chemistry 279 (35): 36680–8.