Pantothenate synthesis and

Pantothenic acid Functional part of CoA and acyl carrier protein fatty acid synthesis and metabolism ... 

Pantothenic acid (vitamin B5) is both present in many nutrientcients and it is also produced by intestinal bacteria. Deficiency is therefore thought to be unlikely. Its active form, 4-phosphopantetheine, is an element of both coenzyme-A and acyl-carrier protein and thus participates in fatty acid synthesis and in the posttranslational modification of proteins. Acetylcoenzyme-A is important for the synthesis of the neurotransmitter acetylcholine. 

Pantothenic acid, as a component of coenzyme A, is involved with the release of energy during gluconeogenesis, in the synthesis and de-... 

In 1940, Hams, Folkers, ct al. reported structure determination and synthesis and crystallization of pantothenic acid. In 1950. Lipmaiin el al. discovered coenzyme A and, in 1951, Lynen characterized the coenzyme A structure,... 

Pantothenic acid is produced commerdally by synthesis involving the condensation of d-pantolactone with salt of -alanine. Some of the dietary supplement forms include caldum pantothenate, dexpanthenol, and panthenol. 

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. 

This is followed by removal of the glutamic acid and the glycine residues, which is followed by acetylation of the remaining cysteine. Essential amino acids are required for the synthesis of the proteins involved, pantothenic acid for coenzyme A synthesis, and phosphorus for synthesis of the ATP needed for glutathione synthesis. Similar scenarios can be developed for glucuronide and sulfate formation, acetylation, and other phase II reaction systems. 

The development of a novel production system for D-pantoyl lactone (which is a lactone compound carrying a chiral hydroxy group and a chiral intermediate for the commercial production of D-pantothenate) by microbial asymmetric reduction has been undertaken. D-pantothenate is mainly used in various pharmaceutical products and as an animal feed additive, the current world production of calcium pantothenate being about 6,000 tons per year. Conventional commercial production of D-pantoyl lactone has depended exclusively on chemical synthesis involving optical resolution of a chemically synthesized racemic pantoyl lactone, which is the most troublesome step of the pantothenate synthesis process. 

Metabolic Control of CoA Synthesis Pantothenate kinase is rate-limiting for the synthesis of CoA, and both regulation of the activity of the existing enzyme protein and changes in its synthesis are important in the control of intracellular concentrations of CoA (Rock et al., 2000). The enzyme has a low Km compared with the normal intracellular concentration of pantothenic acid and is thus insensitive to the availability of substrate, even in deflciency. 

D. Pyruvate dehydrogenase and a-ketoglutarate dehydrogenase require four vitamins for synthesis of their coenzymes (thiamine, pantothenate, niacin, and riboflavin). Niacin is also required for the NAD+ utilized by isocitrate dehydrogenase and malate dehydrogenase. Riboflavin is required for the FAD utilized by succinate dehydrogenase and the FMN of the electron transport chain. Biotin is not required. 

About 6,0001 of the animal feed additive calcium-D-pantothenate are produced annually via D-pantolactone (d-112) (Scheme 35, left side).D-Pantolactone itself is an important chiral intermediate for chemical synthesis and a chiral resolution agent for optically pure amines. Optically pure d-112 is for instance produced by Fuji Chemical Industries by using the D-specific 1,4-lactone hydroxy-acylhydrolase from Fusarium oxysporum [100-102], an enzyme that catalyzes the stereospecific hydrolysis of various kinds of lactones. Treatment of mc-112 leads to an exclusive hydrolysis of d-112 the hydroxy acid d-113 can be easily separated from the remaining lactone l-1 12 and is subsequently chemically con-... 

Figure 3. Branched chain amino acid and pantothenate synthesis. TD and ALS are the enzymes threonine deaminase and acetolactate synthase, respectively.

A typical time course for CoA synthesis by this method is shown in Fig. 2. The amounts of CoA synthesized from pantothenic acid and from pantetheine were about 1 mg/ml and 1.3 mg/ml, respectively. An addition of a surfactant, sodium laurylbenzene-... 

Figure 1. Synthesis of CoA from pantothenic acid and cysteine coupled with ATP-generating system...

M potassium phosphate buffer, pH 7.5. Under the same conditions free, dried cells were completely inactivated within a week. The gel was more stable at high temperatures than were free, dried cells as judged by the total CoA synthesis and by the phosphorylation of pantothenic acid (Fig. 5). 

Isobutyraldehyde is used in the synthesis of cellulose esters, resins, and plasticizers in the preparation of pantothenic acid and valine and in flavors. 

Currently, (J )-pantothenic acid is industrially produced by conventional chemical synthesis and marketed as the calcium salt (calpan). The global market of calpan was valued at approximately 75 million US dollars in sales in 2005 with a world output over 10 000 ton. The key starting material for large-scale chemical processes is (J )-pantolactone. This molecule can be coupled with either calcium P-alanine to form (J )-pantothenate or with 3-aminopropanol to form panthenol, an important ingredient in skin and hair care consumer products. Purification of (7 )-pantolactone from racemic mixtures occurs by chemical or enzymatic racemic resolution [320, 321]. 

Although the growth rate of rats is not affected by the administration of pantothenic acid, the addition of pantothenic acid to the culture media stimulates the growth of myoblasts, fibroblasts, and embryonic skin. Pantothenic acid also reduces some of the effects of 6-mercaptopurine on tissue culture, such as blocking of mitosis, interference with lipid synthesis, and fragmentation of the mitochondria. 

The synthesis and metabolism of CoA is shown in Figure 41.1. Pantothenic acid is an important part for CoA synthesis. In the initial step, pantothenic add is phosphorylated to 4-phosphopantotenic add by the action of pantothenate kinase. The formation of 4 -phosphopantetheine is a two-step process in which 4 -phosphopantothenic acid and cysteine are first converted to 4 -phospho-pantothenoyl-L-cysteine by the formation of a peptide linkage followed by decarboxylation of cysteine. In the final two steps in the pathway, 4 -phos-phopantetheine is adenylated to form dephospho-CoA and dephospho-CoA is... 

The synthesis of coenzyme A can be divided into the synthesis of adenosine (adumbrated above) and the synthesis of pantotheine phosphate. The latter is then conveniently divided into the preparation of pantothenic acid and its subsequent conversion to the desired (pantetheine) thiol. 

There is considerable basis for linking pyridoxine to amino acid metabolism, and the participation of this vitamin in antibody production may be related to such a function. However, in a recent review, Beaton et al. (1954) suggest that pyridoxine is not essential for protein synthesis or maintenance in the rat and that its effect on amino acid metabolism is of a secondary nature. A role for pantothenic acid in protein synthesis has not yet been demonstrated. A relationship between pantothenic acid and peptide bond formation is suggested by the observation of Chantrenne (1944) that coenzyme A, the coenzyme derivative of pantothenic acid, is... 

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