Pantothenic Acid

Pantothenic acid has a central role in energy-yielding metabolism as the functional moiety of coenzyme A (CoA), in the biosynthesis of fatty acids as the prosthetic group of acyl carrier protein, and through its role in CoA in the mitochondrial elongation of fatty acids; the biosynthesis of steroids, porphyrins, and acetylcholine; and other acyl transfer reactions, including postsynthetic acylation of proteins. Perhaps 4% of all known enzymes utilize CoA derivatives. CoA is also bound by disulfide links to protein cysteine residues in sporulating bacteria, where it may be involved with heat resistance of the spores, and in mitochondrial proteins, where it seems to be involved in the assembly of active cytochrome c oxidase and ATP synthetase complexes.

Pantothenic acid is widely distributed in all foodstuffs. The name is derived from the Greek for from everywhere, as opposed to other vitamins that were originally isolated from individual rich sources.

Deficiency is well documented in chickens, which develop a pantothenic acid-responsive dermatitis. Other experimental animals show a variety of abnormalities from pantothenic acid deficiency. In human beings dietary deficiency has not been reliably documented, although it has been implicated in the burning foot syndrome (nutritional melalgia). Subjects maintained on pantothenic acid-deficient diets or given the antagonist «-methyl pantothenate develop relatively unspecific symptoms that respond to repletion with the vitamin.

12.1 PANTOTHENIC ACID VITAMERS

The only naturally occurring vitamer of pantothenic acid is the D-isomer (as shown in Figure 12.1). It is the peptide of pantoic acid and ^-alanine.

Free pantothenic acid and its sodium salt are chemically unstable, and therefore the usual pharmacological preparation is the calcium salt (calcium h3c oh o

oh ch3 pantothenic acid h3c oh o I I II

o ch2—c—ch—c—nh-ch2-ch2-c—nh—ch2-ch2-sh

h3c oh o

oh ch3 pantothenol

o oh

h3c oh o

o)-methyl pantothenic acid

o oh

o)-methyl pantothenic acid

0H CH3 homopantothenic acid (pantoyl GABA)

Figure 12.1. Pantothenic acid and related compounds and coenzyme A. Relative molecular masses (Mr): pantothenic acid, 219.2 (calcium dipantothenate, 476.5); pantothenol, 214.2; »-methyl pantothenic acid, 213.6; homopantothenic acid, 233.2; and coenzyme A, 767.6. CoASH, free coenzyme A; GABA, y-aminobutyric acid.

dipantothenate). The alcohol, pantothenol, is a synthetic compound that has biological activity because it is oxidized to pantothenic acid in vivo.

»-Methyl pantothenic acid is a potent antagonist of the vitamin that has been used in studies of pantothenic acid deficiency, and the y-aminobutyric acid (GABA) peptide ofpantoic acid, pantoyl GABA or homopantothenic acid, has pharmacological actions in cholinergic neurotransmission and has been used in the treatment of Alzheimer's disease.

12.2 METABOLISM OF PANTOTHENIC ACID

About 85% of dietary pantothenic acid is as CoA or phosphopantetheine. In the intestinal lumen, these undergo hydrolysis to phosphopantetheine, then pantetheine (see Figure 12.2). Intestinal mucosal cells have a high panteth-einase activity and rapidly hydrolyze pantetheine to yield free pantothenic acid.

The intestinal absorption of pantothenic acid is by use of the same sodium-dependent carrier as biotin and lipoic acid (Section 11.1). The carrier is found throughout the intestinal tract, and therefore pantothenic acid synthesized by intestinal bacteria (Section 12.2.4) will, like biotin, be available for absorption (Said et al., 1998; Chatterjee et al., 1999; Ramaswamy, 1999; Said, 1999; Prasad h3c oh o

oh ch3 pantothenic acid atpo

H3C OH

pantothenate kinase

CH2—C—CH—NH—CH2-CH2-COO-CH3 phosphopantothenic acid

ATP-nL— cysteine

J phosphopantothenylcysteine synthase

H3C OH O O

CH2—C—CH—C—NH—CH2-CH2-C—NH—CH—CH2-SH

0 CH3 COO--q_P_q phosphopantothenylcysteine

O"

phosphopantothenylcysteine decarboxylase

H3C OH O O

CH2—C—CH—c—NH—CH2-CH2- C- NH- CH2- CH2- SH

O CH3 phosphopantetheine

H3C OH O O

CH,—C—CH—C—NH—CH2-CH2-C—NH—CH2-CH2-SH

^ CHs coenzyme A (CoASH)

dephospho-CoA kinase ATP

dephospho-CoA kinase ATP

h3c oh o o

ch2—c—ch—c—nh—ch2-ch2-c—nh—ch2-ch2-sh

phosphopantetheine adenyltransferase phosphopantetheine adenyltransferase

dephospho-CoA

Figure 12.2. Biosynthesis of coenzyme A. Pantothenate kinase, EC 2.7.1.33; phosphopantothenylcysteine synthase, EC 6.3.2.5; phosphopantothenylcysteine decarboxylase, EC 4.1.1.36; phosphopantetheine adenyltransferase, EC 2.7.7.3; and dephospho-CoA kinase, EC 2.7.1.24. CoASH, free coenzyme A.

and Ganapathy, 2000). Other tissues take up pantothenic acid from the circulation by the same mechanism. The transport mechanism is not normally saturated, so pantothenate uptake into tissues will increase with plasma concentration.

The first step in pantothenic acid utilization is phosphorylation (see Figure 12.2). Pantothenate kinase is rate-limiting, so that, unlike many vitamins that are accumulated by metabolic trapping, there can be significant accumulation of free pantothenic acid in tissues. Intracellular concentrations may be as high as 200 to 500 ^mol per L.

Red blood cells contain pantothenic acid, 4-phosphopantothenic acid, and pantetheine. These seem to enter by diffusion, and their function is not known; unsurprisingly, because they contain no mitochondria, erythrocytes do not contain CoA (Annous and Song, 1995). The permeability of erythrocytes to pantothenate is normally relatively low, but in red cells infected with malaria parasites, the permeability is increased considerably; the vitamin is taken up and utilized by the parasites, which require CoA (Saliba et al., 1998).

Pantothenic acid is well conserved; over a week after the administration of tracer doses of [14C]pantothenic acid to rats, less than 40% of the dose is recovered in the urine, all as the free vitamin. Pantothenic acid filtered by the kidneys is largely resorbed by a sodium-dependent system in the renal tubule brush border membrane (Barbarat and Podevin, 1986).

Pantothenic acid is largely excreted unchanged by mammals. Some phos-phopantetheine may also be excreted in the urine; after administration of [14C]pantothenic acid, some of the label may be recovered in exhaled CO2. This is probably the result of intestinal bacterial metabolism, because many bacteria have pantothenase, a specific amidase that cleaves pantothenic acid to p-alanine andpantoic acid. Pseudomonas species are capable of using pantothenic acid as their sole carbon source.

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