Pantothenate-synthesizing enzyme

Pantothenic acid (8.48), a hydroxyamide, occurs mainly in liver, yeast, vegetables, and milk, but also in just about every other food source, as its name implies [pantos (Greek) = everywhere]. It is part of coenzyme A, the acyl-transporting enzyme of the Krebs cycle and lipid syntheses, as well as a constituent of the acyl carrier protein in the fatty-acid synthase enzyme complex. 

Vitamins are chemically unrelated organic compounds that cannot be synthesized by humans and, therefore, must must be supplied by the diet. Nine vitamins (folic acid, cobalamin, ascorbic acid, pyridoxine, thiamine, niacin, riboflavin, biotin, and pantothenic acid) are classified as water-soluble, whereas four vitamins (vitamins A, D, K, and E) are termed fat-soluble (Figure 28.1). Vitamins are required to perform specific cellular functions, for example, many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism. In contrast to the water-soluble vitamins, only one fat soluble vitamin (vitamin K) has a coenzyme function. These vitamins are released, absorbed, and transported with the fat of the diet. They are not readily excreted in the urine, and significant quantities are stored in Die liver and adipose tissue. In fact, consumption of vitamins A and D in exoess of the recommended dietary allowances can lead to accumulation of toxic quantities of these compounds. 

All tissues are capable of forming CoA from pantothenic acid, by the pathway shown in Figure 12.2 (Tahiliani and Beinlich, 1991 Begley et al., 2001). The first three enzymes catalyzing the formation of phosphopantetheine from pantothenic acid are found only in the cytosol. Although phosphopantetheine crosses the mitochondrial irmer membrane, CoA does not, but must be synthesized in situ. 

The serum level of pantothenic add is about 1 to 5 lM (Lopaschuk d ai, 1987). The vitamin in the bloodstream is transported into various tissues, where it is then converted to coenzyme A. Coenzyme A is synthesized from pantothenic add, ATP, and cysteine. The pathway of coenzyme A synthesis is shown in Figure 9,77. The cofactor of fatty add synthase is synthesized from coenzyme A and does not involve the direct participation of pantothenic acid. A specific enzyme catalyzes... 

Pantothenic acid has also been called vitamin Bf. Excellent sources of the vitamin ore liver. egg.s. and cereals. It is found, however, in the form of CoA. This coenzyme cannot be absorbed directly from the gut. Although no experiments have been conducted in humans, studies on animals indicate that the coenzyme must be hydrolyzed to panthenene and pantothenate. " which arc absorbed by passive diffusion. Human intestinal cells contain enzymes tltat can hydrolyze the coenzyme. Pantothenate is the major form circulating in the blood and is absorbed by individual cells. Once inside ihe cell. CoA is synthesized. 

Investigations with different carbon sources (Table IV) showed that although the amounts of the two pyrazines varied according to the carbon source used, the ratio of the isopropyl to secbutyl pyra-zine remained relatively constant. This suggested that either availability of precursor followed a set ratio, or else enzyme specificity for the different side chains played a role in determining the relative amounts of each compound synthesized. Accordingly, strains auxotrophic for leucine (leu-), isoleucine (ilu-), or leucine, valine, isoleucine, and pantothenic acid (leu"> val-, ilu-, pant-) were isolated from cultures treated with... 

Coenzyme A (CoA), biotin, and pyridoxal phosphate are also activation-transfer coenzymes synthesized from vitamins. CoA (CoASH), which is synthesized from the vitamin pantothenate, contains an adenosine 3, 5 -bisphosphate which binds reversibly, but tightly, to a site on an enzyme (Fig. 8.12A). Its functional group, a sulfhydryl group at the other end of the molecule, is a nucleophile that always... 

Fig. 8.12. CoA and biotin, activation-transfer coenzymes. A. Coenzyme A (CoA or CoASH) and phosphopantetheine are synthesized from the vitamin pantothenate (pantothenic acid). The active sulfhydryl group, shown in blue, binds to acyl groups (e.g., acetyl, succinyl, or fatty acyl) to form thioesters. B. Biotin activates and transfers CO2 to compounds in car-boxylation reactions. The reactive N is shown in blue. Biotin is covalently attached to a lysine residue in the carboxylase enzyme.

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. 

Thiamine, biotin, pantothenic acid, riboflavin and vitamin B12 are involved in propionic acid fermentation. Biotin forms the prosthetic group of methyl-malonyl-CoA transcarboxylase pantothenate is a constituent of CoA thiamine is not the coenzyme (co-carboxylase) of the enzyme carboxylase like in other organisms, for acetaldehyde has not been detected in propionibacteria (although traces were recently found), but it may function as a component of dehydrogenases in oxidative phosphorylation of a-keto acids. Riboflavin is a constituent of FAD and FMN. Propionibacteria can synthesize vitamins B2 and B in considerable amounts (see below), but the other three vitamins must be supplied. Some strains can grow in synthetic media without thiamine (Silverman and Workman, 1939 Delwiche, 1949), in some other strains thiamine can be replaced by / -aminobenzoic acid. 

Pantothenic acid is synthesized in plants and some microorganisms from pantoic acid and p-alanine. Pantoic acid is formed from 2-oxopantoic acid (4-hydroxy-3,3-dimethyl-2-oxobutyric acid) and 2-oxoisovaleric acid (3-methyl-2-oxobu-tyric acid), a precursor of valine. P-Alanine is formed by decarboxylation of l-aspartic acid. Enzymes involved include pantothenate synthetase (EC 6.3.2.1), oxopantoate reductase (EC 1.1.1.169), oxopantoate hydroxymethyltransferase (EC 4.1.2.12), and aspartate 1-decarboxylase (EC 4.1.1.12). 

Glycinamide ribonucleotide kinosynthetase is the name applied to the partially purified enzyme that forms GAR from glycine, ATP, and PRA (99). It is of interest that the sjmthesis of the amide bond of GAR resulted in the formation of ADP and P after interaction of ATP with the substrates. This process is similar to the events in glutamine (100-103) and glutathione (104) S3mthesis. Other amide bond syntheses such as amino acid activation (105) and pantothenic acid biof thesis (106) are characterized by the formation of AMP and PP from ATP during the synthetic event. 

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