Pantothenic acid biological activity

R)-Pantothenic acid (1) contains two subunits, (R)-pantoic acid and P-alanine. The chemical abstract name is A/-(2,4-dihydroxy-3,3-dimethyl-l-oxobutyl)-P-alanine (11). Only (R)-pantothenic acid is biologically active. Pantothenic acid is unstable under alkaline or acidic conditions, but is stable under neutral conditions. Pantothenic acid is extremely hygroscopic, and there are stabiUty problems associated with the sodium salt of pantothenic acid. The major commercial source of this vitamin is thus the stable calcium salt (3) (calcium pantothenate). 

Figure 1 shows the structure of pantothenic acid ((R)-(+)-N-(2,4-dihydroxy-3,3 -dimethyl-1 -oxobuty 1-13-alanine). Only D(+)-pantothenic acid occurs naturally and is biologically active. The alcohol (R)-pantothenol (= (D)-panthenol) shows biological activity as well. 

The hydrogenation of ketones with O or N functions in the a- or / -position is accomplished by several rhodium compounds [46 a, b, e, g, i, j, m, 56], Many of these examples have been applied in the synthesis of biologically active chiral products [59]. One of the first examples was the asymmetric synthesis of pantothenic acid, a member of the B complex vitamins and an important constituent of coenzyme A. Ojima et al. first described this synthesis in 1978, the most significant step being the enantioselective reduction of a cyclic a-keto ester, dihydro-4,4-dimethyl-2,3-furandione, to D-(-)-pantoyl lactone. A rhodium complex derived from [RhCl(COD)]2 and the chiral pyrrolidino diphosphine, (2S,4S)-N-tert-butoxy-carbonyl-4-diphenylphosphino-2-diphenylphosphinomethyl-pyrrolidine ((S, S) -... 

Some enzymes associate with a nonprotein cofactor that is needed for enzymic activity. Commonly encountered cofactors include metal ions such as Zn2+ or Fe2+, and organic molecules, known as coenzymes, that are often derivatives of vitamins. For example, the coenzyme NAD+contains niacin, FAD contains riboflavin, and coenzyme A contains pantothenic acid. (See pp. 371-379 for the role of vitamins as precursors of coenzymes.) Holoenzyme refers to the enzyme with its cofactor. Apoenzyme refers to the protein portion of the holoenzyme. In the absence of the appropriate cofactor, the apoenzyme typically does not show biologic activity. A prosthetic group is a tightly bound coenzyme that does not dissociate from the enzyme (for example, the biotin bound to carboxylases, see p. 379). 

The process of racemization has a number of practical application in the laboratory and in industry. Thus, in the synthesis of an optical isomer it is frequently possible to racemize the unwanted isomer and to separate additional quantities of the desired isomer. By repeating this process a number of times it is theoretically possible to approach a 100% yield of Synthetic product consisting of only one optical isomer, An example of the utilization of such a process is found in the production of pantothenic acid and its salts, In this process the mixture of D- and L-2-hydroxy-3,3-butyrolactones are separated. The D-lactone is condensed with the salt of beta-alanine to give the biologically active salt of pantothenic acid, The remaining L-lactone is racemized and recycled. 

The coenzymes, CoA, acyl-coenzyme A, and ACP, are the biologically active forms of pantothenic acid (185,186). Recent reviews of the absorption and metabolism of pantothenate are available (185,186). 

The biologically active R- or 5 -pantothenic acid can be obtained upon hydrolysis of coenzyme A with a combiaation of two enzymes, alkaline phosphatase and pantotheiaase (13) (Fig. 1). The phosphatase catalyzes the selective cleavage of the phosphate bond ia coenzyme A to afford adenosin-3 5 -diphosphate (6) and 4-phosphopantetheiae (7). The latter substance is dephosphorylated enzymatically to yield pantetheiae (8), which is rapidly converted by pantotheiaase to pantothenic acid (1). Table 1 Hsts some physical properties of pantothenic acid and its derivatives. 

Since pantothenic acid contains an asymmetric carbon atom, chemical synthesis yields the racemic mixture. On the other hand, when enzymatic synthesis is used, only the biologically active form of pantothenic acid is produced. 

Pantolactone (PL) [(i )-(-)-3-hydroxy-4,4-dimethyltetrahydofuran-2-on], 1 (Scheme 7.23.), is an intermediate in the preparation of several biologically important molecules such as D-(+)-pantothenic acid, 2, which is a member of B vitamins (Vitamin B5) and is an important constituent of coenz5me A. The biosynthesis of 2 involves the asymmetric reduction of ketopantolactone, i, (KPL) (4,4-dimethyltetrahydrofuran-2,3-dion) to R- -)-PL, because only the 7 -(-)-enantiomer is biologically active. 

PUutothenie acid is a widely distributed compound in animals and plants, consisting of 2,4-dihydroxy-33-dimethylbutync acid (pantoic acid) linked to alanine by an amide bond Most organisms have the abili to synthesize pantoic acid from valine, and P-alanine from asparate, but humans lack the enzyme, pantothenate synthetase, which catalyses the condensation of p-alanine and pantoic acid to form pantothenic add Only the n(-i-)-form of pantothenic add is biologically active. It is required for the synthesis of Coenzyme A (see). Non-experimental human defi-dency states have not been observed, so pantothenic add is presumably present in suffident quantity in all diets. 

Pantothenic acid was discovered in 1933 (Williams et al. 1933). Its name originates from the Greek pantos meaning everywhere , and small quantities of pantothenic acid are found in nearly every food. It was first isolated from liver cells in 1938 and first synthesized in 1940 (Stiller et al. 1940). The principal biologically active forms of pantothenic acid are coenzyme A (CoA) (Lipmann et al. 1950) and 4 -phosphopantetheine in acyl carrier protein (Majerus et al. 1965). 

An alcohol related to pantothenic acid (and referred to as o-panthenol or D-pantothenyl alcohol) also possesses vitamin activity (Figure 8.7) because it is readily oxidized to form pantothenic acid in organisms. Only o-panthenol is biologically active. The lUPAC name is (27 )-2,4-dihydroxy-iV-(3-hydroxy-propyl)-3,3-dimethylbutanamide and the CAS number is 81-13-0. It is... 

Synthetic pantothenic acid is a racemic compound comprising d(- -) and l(—) forms. Pantothenic acid occurs naturally as the d(+) isomer and is biologically active. l(—)-Pantothenic acid is biologically inactive and the racemic compound, oL-pantothenic acid, has half the biologieal activity of D(+)-pantothenic acid. However, large excess administration of l(—)-pantothenic acid to young rats causes growth retardation. 

The structure of pantothenic acid is shown in Figure 21.1. Due to the chirality at the hydroxylated carbon atom of the pantothenic acid moiety, the vitamin is optically active. Only the i/(+)-pantothenic acid enantiomer is biologically active and present in nature. 

Stiller and associatesin the Merck laboratories a little less than a year after the collaboration began isolated the lactone from concentrates, and determined its structure by classical methods to be -hydroxy-/5,/ -dimethyl-y-butyrolactone. This was synthesized and resolved into its optical isomers. The levo-rotatory lactone when condensed with /3-alanine by various pro-ceduresi >22>2 yields dextro-rotatory pantothenic acid with full biological activity. The antipode was found to be inactive. The biologically active form has, according to Hudson s amide rule, the D-configuration24.2s. 

The principal biologically active natural forms of pantothenic acid (vitamin B5), one of the B vitamin complex, are coenzyme A (CoA or CoASH) and acyl-carrier protein (ACP). In solid pharmaceuticals, foods, and feeds, because of simple handling and increased stability, the pantothenic acid sodium and calcium salt are often used as additives. Panthenol is usually used in liquid pharmaceutical preparations and in cosmetics. 

Pantothenic acid occurs in nature only as the d-(+)- or the (/ )-enantiomer the L-(-)- or (5)-form has no vitamin activity, as biological effects of this group of compounds are specific and connected solely with the optically active dextforo-tatory forms. 

GLC was the first chromatographic method to enable the resolution of enantiomers of pantothenic acid and hence the specific determination of the biologically active form of pantothenic acid. 

Reported levels of pantothenic acid in biological samples obtained by the pantolactone GLC approach pertain not only to the free acid but always to all other active forms, such as CoA, acetyl-CoA, etc. 

Vitamin B5 occurs in three biologically active forms in foods [1] pantothenic acid, coenzyme A (CoA), and acyl carrier protein (ACP). Calcium or sodium pantothenate are the forms generally used as supplements in infant formula [4], The total quantification of vitamin B5 requires the release of pantothenic acid from CoA and ACR Since it consists of pantoic acid linked through an amide linkage to p-alanine, chemical hydrolysis cannot be used. The only alternative to free pantothenic acid from CoA is the digestion with a number of enzymes (pepsin, alkaline phosphatase, pantetheinase) nevertheless, this treatment is unable to release the vitamin from ACP [27,28]. For the extraction of free pantothenic acid from milk and calcium pantothenate from infant formula an acidic deproteination is often used, followed by centrifugation and filtration [29,30]. 

Pantothenic acid (formerly also known as vitamin Bj, 5-68) occurs in nature only as the (-l-)-D-form, that is the (ft)-enantiomer. (ft)-Pantothenic acid is composed of (-l-)-D-pantoic acid, also known as (ft)-pantoic acid, the systematic name of which is (ft)-2,4-dihydroxy-3,3-dimethylbutanoic acid. Pantoic acid is linked by an amide bond to the 3-aminopropionic acid (P-alanine). The (S)-enantiomer of pantothenic acid, which is the (-)-L-isomer, is not biologically active and is an antimetabohte of (ft)-pantothenic acid, as are some other structural analogues. The main biologically... 

Pantothenic acid can be accompanied by its biologically active higher homologue known as homopantothenic acid (5-71), which contains 4-aminobutanoic acid (y-aminobutyric acid) instead of P-alanine and acts as an antagonist of pantothenic acid. 

Panthenol is broadly used in cosmetic products and has become an essential ingredient in skin- and hair-care products. Its main functions are improved wound healing, anti-inflanamation and hydrating activities. Panthenol is often called pro-vitamin B5 in advertising literature. Panthenol is the stable biologically active form of vitamin B5 or pantothenic acid. This vitamin is essential for growth and normal maintenance of skin and hair. Pantothenic acid is an essential constituent of coenzyme A, which plays a central role in the metabolism. 

Table XIV records the effects with various analogs of pantothenic acid, when the non-nitrogenous portion is varied by condensing different hydroxy acids with /3-alanine. Only very slight activity is found with any of these compounds, showing that even slight modifications of the molecular structure very greatly decrease the biological activity. The same general picture is found with higher animals for which pantothenic acid has metabolic importance.

The vitamin precursor of CoASH is pantothenate. We have seen that CoASH is used in biological systems to activate carboxylic acids by converting them into thioesters, which are much more reactive toward nucleophilic acyl substitution reac-... 

---