Pantothenic acid

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Not to be confused with pantethine.

Pantothenic acid
Skeletal formula of (R)-pantothenic acid
Pantothenic acid molecule
Names
Preferred IUPAC name
3-[(2R)-2,4-Dihydroxy-3,3-dimethylbutanamido]propanoic acid
Systematic IUPAC name
3-[(2R)-(2,4-Dihydroxy-3,3-dimethylbutanoyl)amino]propanoic acid
Identifiers
3D model (
JSmol
)
3DMet
1727062, 1727064 (R)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard
 100.009.061 Edit this at Wikidata
EC Number
  • 209-965-4
KEGG
MeSH Pantothenic+Acid
RTECS number
  • RU4729000
UNII
  • InChI=1S/C9H17NO5/c1-9(2,5-11)7(14)8(15)10-4-3-6(12)13/h7,11,14H,3-5H2,1-2H3,(H,10,15)(H,12,13) ☒N
    Key: GHOKWGTUZJEAQD-UHFFFAOYSA-N ☒N
  • CC(C)(CO)C(C(=O)NCCC(=O)O)O
  • (R): CC(C)(CO)[C@H](C(=O)NCCC(=O)O)O
  • (S): CC(C)(CO)[C@@H](C(=O)NCCC(=O)O)O
Properties
C9H17NO5
Molar mass 219.237 g·mol−1
Appearance Yellow oil
Colorless crystals (Ca2+ salt)
Odor Odorless
Density 1.266 g/cm3
1.32 g/cm3 (Ca2+ salt)[1]
Melting point 183.833 °C (362.899 °F; 456.983 K)
196–200 °C (385–392 °F; 469–473 K)
decomposes (Ca2+ salt)[1][3][5]
Very soluble[2]
2.11 g/mL (Ca2+ salt)[1]
Solubility Very soluble in C6H6, ether[2]
Ca2+ salt:
Slightly soluble in alcohol, CHCl3[3]
log P −1.416[4]
Acidity (pKa) 4.41[5]
Basicity (pKb) 9.698
+37.5°
+24.3° (Ca2+ salt)[5]
Hazards
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
2
1
0
Lethal dose or concentration (LD, LC):
> 10 mg/g (Ca2+ salt)[3]
Related compounds
Related alkanoic acids
 Arginine
Hopantenic acid
4-(γ-Glutamylamino)butanoic acid
Related compounds
 Panthenol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Pantothenic acid (vitamin B5) is a

essential nutrient.[6] All animals need pantothenic acid in order to synthesize coenzyme A (CoA), which is essential for cellular energy production and for the synthesis and degradation of proteins, carbohydrates, and fats.[6][7]

Pantothenic acid is the combination of

β-alanine. Its name comes from the Greek πάντοθεν pantothen, meaning "from everywhere", because pantothenic acid, at least in small amounts, is in almost all foods.[6][8][7] Deficiency of pantothenic acid is very rare in humans.[6][7] In dietary supplements and animal feed, the form commonly used is calcium pantothenate, because chemically it is more stable, and hence makes for longer product shelf-life, than sodium pantothenate and free pantothenic acid.[1]

Definition

Structure of coenzyme A: 1: 3′-phosphoadenosine. 2: diphosphate, organophosphate anhydride. 3: pantoic acid. 4: β-alanine. 5: cysteamine.

Pantothenic acid is a water-soluble

B vitamins. It is synthesized from the amino acid β-alanine and pantoic acid (see biosynthesis and structure of coenzyme A figures). Unlike vitamin E or vitamin K, which occurs in several chemically related forms known as vitamers, pantothenic acid is only one chemical compound. It is a starting compound in the synthesis of coenzyme A (CoA), a cofactor for many enzyme processes.[7][9][10]

Use in biosynthesis of coenzyme A

Details of the biosynthetic pathway of CoA synthesis from pantothenic acid

Pantothenic acid is a precursor to CoA via a five-step process. The biosynthesis requires pantothenic acid, cysteine, and four equivalents of ATP (see figure).[11]

  1. Pantothenic acid is phosphorylated to 4′-phosphopantothenate by the enzyme pantothenate kinase. This is the committed step in CoA biosynthesis and requires ATP.[12]
  2. A
    phosphopantothenoylcysteine synthetase to form 4'-phospho-N-pantothenoylcysteine (PPC). This step is coupled with ATP hydrolysis.[12]
  3. PPC is
    4′-phosphopantetheine by phosphopantothenoylcysteine decarboxylase
  4. 4′-Phosphopantetheine is adenylated (or more properly,
    AMPylated) to form dephospho-CoA by the enzyme phosphopantetheine adenylyl transferase
  5. Finally, dephospho-CoA is phosphorylated to coenzyme A by the enzyme dephosphocoenzyme A kinase. This final step also requires ATP.[12]

This pathway is suppressed by

end-product inhibition, meaning that CoA is a competitive inhibitor of pantothenate kinase, the enzyme responsible for the first step.[12]

Coenzyme A is necessary in the reaction mechanism of the

acyl group carrier to form acetyl-CoA and other related compounds; this is a way to transport carbon atoms within the cell.[9] CoA is also required in the formation of acyl carrier protein (ACP),[15] which is required for fatty acid synthesis.[9][16] Its synthesis also connects with other vitamins such as thiamin and folic acid.[17]

Dietary recommendations

The US Institute of Medicine (IOM) updated Estimated Average Requirements (EARs) and Recommended Dietary Allowances (RDAs) for B vitamins in 1998. At that time there was not sufficient information to establish EARs and RDAs for pantothenic acid. In instances such as this, the Board sets Adequate Intakes (AIs), with the understanding that at some later date, AIs may be replaced by more exact information.[10][18]

The current AI for teens and adults ages 14 and up is 5 mg/day. This was based in part on the observation that for a typical diet, urinary excretion was approximately 2.6 mg/day, and that bioavailability of food-bound pantothenic acid was roughly 50%.[10] AI for pregnancy is 6 mg/day. AI for lactation is 7 mg/day. For infants up to 12 months the AI is 1.8 mg/day. For children ages 1–13 years the AI increases with age from 2 to 4 mg/day. Collectively the EARs, RDAs, AIs and ULs are referred to as Dietary Reference Intakes (DRIs).[10][18]

Age group Age Adequate intake[10]
Infants 0–6 months 1.7 mg
Infants 7–12 months 1.8 mg
Children 1–3 years 2 mg
Children 4–8 years 3 mg
Children 9–13 years 4 mg
Adult men and women 14+ years 5 mg
Pregnant women (vs. 5) 6 mg
Breastfeeding women (vs. 5) 7 mg

While for many nutrients, the US Department of Agriculture uses food composition data combined with food consumption survey results to estimate average consumption, the surveys and reports do not include pantothenic acid in the analyses.[19] Less formal estimates of adult daily intakes report about 4 to 7 mg/day.[10]

The European Food Safety Authority (EFSA) refers to the collective set of information as Dietary Reference Values, with Population Reference Intake (PRI) instead of RDA, and Average Requirement instead of EAR. AI and UL are defined the same as in the US. For women and men over age 11 the Adequate Intake (AI) is set at 5 mg/day. AI for pregnancy is 5 mg/day, for lactation 7 mg/day. For children ages 1–10 years the AI is 4 mg/day. These AIs are similar to the US AIs.[20]

Safety

As for safety, the IOM sets

Tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of pantothenic acid there is no UL, as there is no human data for adverse effects from high doses.[10] The EFSA also reviewed the safety question and reached the same conclusion as in United States – that there was not sufficient evidence to set a UL for pantothenic acid.[21]

Labeling requirements

For US food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For pantothenic acid labeling purposes 100% of the Daily Value was 10 mg, but as of 27 May 2016 it was revised to 5 mg to bring it into agreement with the AI.[22][23] Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with

US$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales.[24][25] A table of the old and new adult daily values is provided at Reference Daily Intake
.

Sources

Dietary

Food sources of pantothenic acid include animal-sourced foods, including dairy foods and eggs.[6][8] Potatoes, tomato products, oat-cereals, sunflower seeds, avocado are good plant sources. Mushrooms are good sources, too. Whole grains are another source of the vitamin, but milling to make white rice or white flour removes much of the pantothenic acid, as it is found in the outer layers of whole grains.[6][10] In animal feeds, the most important sources are alfalfa, cereal, fish meal, peanut meal, molasses, rice bran, wheat bran, and yeasts.[26]

Supplements

pantothenol (or panthenol), a shelf-stable analog, which is converted to pantothenic acid once consumed.[7] Calcium pantothenate – a salt – may be used in manufacturing because it is more resistant than pantothenic acid to factors that deteriorate stability, such as acid, alkali or heat.[9][26] The amount of pantothenic acid in dietary supplement products may contain up to 1,000 mg (200 times the Adequate Intake level for adults), without evidence that such large amounts provide any benefit.[7][6] According to WebMD, pantothenic acid supplements have a long list of claimed uses, but there is insufficient scientific evidence to support any of them.[27]

As a dietary supplement, pantothenic acid is not the same as

LDL cholesterol – a risk factor for cardiovascular diseases – but its long-term effects are unknown, requiring that its use be supervised by a physician.[7] Dietary supplementation with pantothenic acid does not have the same effect on LDL.[7]

Fortification

According to the Global Fortification Data Exchange, pantothenic acid deficiency is so rare that no countries require that foods be fortified.[28]

Absorption, metabolism and excretion

When found in foods, most pantothenic acid is in the form of CoA or bound to acyl carrier protein (ACP). For the intestinal cells to absorb this vitamin, it must be converted into free pantothenic acid. Within the lumen of the intestine, CoA and ACP are hydrolyzed into 4'-phosphopantetheine. The 4'-phosphopantetheine is then dephosphorylated into pantetheine. Pantetheinase, an intestinal enzyme, then hydrolyzes pantetheine into free pantothenic acid.[29] Free pantothenic acid is absorbed into intestinal cells via a saturable, sodium-dependent active transport system.[14] At high levels of intake, when this mechanism is saturated, some pantothenic acid may also be additionally absorbed via passive diffusion.[26] As a whole, when intake increases 10-fold, absorption rate decreases to 10%.[14]

Pantothenic acid is excreted in urine. This occurs after its release from CoA. Urinary amounts are on the order of 2.6 mg/day, but decreased to negligible amounts when subjects in multi-week experimental situations were fed diets devoid of the vitamin.[10]

Deficiency

Pantothenic acid deficiency in humans is very rare and has not been thoroughly studied. In the few cases where deficiency has been seen (prisoners of war during World War II, victims of starvation, or limited volunteer trials), nearly all symptoms were reversed with orally administered pantothenic acid.

fatigue, and apathy.[14] Acetylcholine synthesis is also impaired; therefore, neurological symptoms can also appear in deficiency;[30] they include sensation of numbness in hands and feet, paresthesia and muscle cramps. Additional symptoms could include restlessness, malaise, sleep disturbances, nausea, vomiting and abdominal cramps.[30]

In animals, symptoms include disorders of the nervous, gastrointestinal, and immune systems, reduced growth rate, decreased food intake, skin lesions and changes in hair coat, and alterations in lipid and carbohydrate metabolism.[31] In rodents, there can be loss of hair color, which led to marketing of pantothenic acid as a dietary supplement which could prevent or treat graying of hair in humans (despite the lack of any human trial evidence).[9]

Pantothenic acid status can be assessed by measuring either whole blood concentration or 24-hour urinary excretion. In humans, whole blood values less than 1 μmol/L are considered low, as is urinary excretion of less than 4.56 mmol/day.[9]

Animal nutrition

Calcium pantothenate and dexpanthenol (D-panthenol) are European Food Safety Authority (EFSA) approved additives to animal feed.[1] Supplementation is on the order of 8–20 mg/kg for pigs, 10–15 mg/kg for poultry, 30–50 mg/kg for fish and 8–14 mg/kg feed for pets. These are recommended concentrations, designed to be higher than what are thought to be requirements.[1] There is some evidence that feed supplementation increases pantothenic acid concentration in tissues, i.e., meat, consumed by humans, and also for eggs, but this raises no concerns for consumer safety.[1]

No dietary requirement for pantothenic acid has been established in ruminant species. Synthesis of pantothenic acid by ruminal microorganisms appears to be 20 to 30 times more than dietary amounts.[32] Net microbial synthesis of pantothenic acid in the rumen of steer calves has been estimated to be 2.2 mg/kg of digestible organic matter consumed per day. Supplementation of pantothenic acid at 5 to 10 times theoretical requirements did not improve growth performance of feedlot cattle.[33]

Synthesis

Biosynthesis

Pantothenic acid biosynthesis

Bacteria synthesize pantothenic acid from the amino acids aspartate and a precursor to the amino acid valine. Aspartate is converted to

α-ketoisovalerate, which, in turn, forms α-ketopantoate following transfer of a methyl group, then D-pantoate (also known as pantoic acid) following reduction. β-alanine and pantoic acid are then condensed to form pantothenic acid (see figure).[12]

Industrial synthesis

The industrial synthesis of pantothenic acid starts with the

racemic pantolactone. This sequence of reactions was first published in 1904.[34]

Synthesis of the vitamin is completed by resolution of the lactone using quinine, for example, followed by treatment with the calcium or sodium salt of β-alanine.[35]

History

Further information: Vitamin § History

The term vitamin is derived from the word vitamine, which was coined in 1912 by Polish biochemist Casimir Funk, who isolated a complex of water-soluble micronutrients essential to life, all of which he presumed to be amines.[36] When this presumption was later determined not to be true, the "e" was dropped from the name, hence "vitamin".[26] Vitamin nomenclature was alphabetical, with Elmer McCollum calling these fat-soluble A and water-soluble B.[26] Over time, eight chemically distinct, water-soluble B vitamins were isolated and numbered, with pantothenic acid as vitamin B5.[26]

The essential nature of pantothenic acid was discovered by

Fritz Lipmann shared the Nobel Prize in Physiology or Medicine "for his discovery of co-enzyme A and its importance for intermediary metabolism", work he had published in 1946.[38]

References

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    doi:10.2903/j.efsa.2011.2409
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  3. ^ a b c "Calcium D-pantothenate". CHEMICALLAND21, AroKor Holdings Inc. Retrieved 5 September 2014.
  4. ^ "MSDS of D-pantothenic acid" (PDF). Human Metabolome Database. Retrieved 5 September 2014.
  5. ^
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  6. ^ a b c d e f g "Pantothenic acid: Fact Sheet for Health Professionals". Office of Dietary Supplements, US National Institutes of Health. 3 June 2020. Retrieved 27 November 2020.
  7. ^ a b c d e f g h i "Pantothenic acid". Linus Pauling Institute at Oregon State University. Micronutrient Information Center. 1 July 2015. Retrieved 27 November 2020.
  8. ^ a b "Pantothenic acid ordered by nutrient content per 100 g". US Department of Agriculture Agricultural Research Service, Food Data Central. February 2020. Retrieved 3 June 2020.
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  13. ^ Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). "Chapter 2: How Cells Obtain Energy from Food". Molecular Biology of the Cell (4th ed.). Garland Science.
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  18. ^ a b "Nutrient Recommendations: Dietary Reference Intakes (DRI)". National Institutes of Health, Office of Dietary Supplements. Retrieved 30 June 2020.
  19. ^ "TABLE 1: Nutrient Intakes from Food and Beverages" (PDF). What We Eat In America, NHANES 2012–2014 (2016). Retrieved 18 August 2018.
  20. ^ "Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies" (PDF). 2017.
  21. ^ "Tolerable Upper Intake Levels For Vitamins And Minerals" (PDF). European Food Safety Authority. 2006.
  22. ^ "Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels" (PDF).
  23. ^ "Daily Value Reference of the Dietary Supplement Label Database (DSLD)". Dietary Supplement Label Database (DSLD). Archived from the original on 7 April 2020. Retrieved 16 May 2020.
  24. ^ "Changes to the Nutrition Facts Label". U.S. Food and Drug Administration (FDA). 27 May 2016. Retrieved 16 May 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  25. ^ "Industry Resources on the Changes to the Nutrition Facts Label". U.S. Food and Drug Administration (FDA). 21 December 2018. Retrieved 16 May 2020. Public Domain This article incorporates text from this source, which is in the public domain.
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  27. ^ "Pantothenic acid (Vitamin B5)". WebMD. 2018. Retrieved 22 June 2020.
  28. ^ "Map: Count of Nutrients In Fortification Standards". Global Fortification Data Exchange. Retrieved 30 April 2019.
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  33. ^ National Research Council (2001). Nutrient Requirements of Dairy Cattle (7th ed.). Washington, DC: National Academy of Sciences. pp. 162–177.
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  36. ^ Funk C (1912). "The etiology of the deficiency diseases. Beri-beri, polyneuritis in birds, epidemic dropsy, scurvy, experimental scurvy in animals, infantile scurvy, ship beri-beri, pellagra". Journal of State Medicine. 20: 341–68.
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