Pantothenic acid synthesis

Enterobacter aerogenes, B. subtilis, P. fluorescens, and Serratia marces-cens produce acetoin by decarboxylation of a-acetolactate. However, yeasts and E. coli form acetoin from the acetaldehyde-TPP complex and free acetaldehyde (Rodopulo et al 1976). These organisms do not decarboxylate a-acetolactate, but use it to produce valine and pantothenic acid. In lactic acid bacteria, a-acetolactate is not used for valine or pantothenic acid synthesis, since these substances are required for growth (Law et al. 1976B Reiter and Oram 1962). In those microorganisms which can synthesize valine, this amino acid inhibits a-acetolactate synthesis (Rodopulo et al 1976). 

The biochemical mode of action of dalapon has not been unequivocally elucidated. The protein precipitating action of chlorinated aliphatic acids, hence of dalapon, is known (Redemann and Hamaker, 1954), and it has also been proved by the investigations of Kemp et al. (1969) that the acid form of dalapon is able to form a hydrogen bond with the amide group of the protein molecule, so that this mechanism, in blocking enzyme activity, may be the cause of the phytotoxic action. Hilton et al. (1959) proved that dalapon inhibits the pantothenic acid synthesis of plants. 

This is compatible with the accepted idea shown above that leucine is formed from the condensation of the isobutyryl moiety of valine with acetate. As Webb notes, interference by aminopterin with pantothenic acid synthesis would impede CoA synthesis, which would further cripple leucine synthesis. 

Biosynthesis of coen2yme A (CoA) ia mammalian cells incorporates pantothenic acid. Coen2yme A, an acyl group carrier, is a cofactor for various en2ymatic reactions and serves as either a hydrogen donor or an acceptor. Pantothenic acid is also a stmctural component of acyl carrier protein (AGP). AGP is an essential component of the fatty acid synthetase complex, and is therefore requited for fatty acid synthesis. Free pantothenic acid is isolated from hver, and is a pale yeUow, viscous, and hygroscopic oil. 

Despite the progress made in the stereoselective synthesis of (R)-pantothenic acid since the mid-1980s, the commercial chemical synthesis still involves resolution of racemic pantolactone. Recent (ca 1997) synthetic efforts have been directed toward developing a method for enantioselective synthesis of (R)-pantolactone by either chemical or microbial reduction of ketopantolactone. Microbial reduction of ketopantolactone is a promising area for future research. 

In bacteria and plants, the individual enzymes of the fatty acid synthase system are separate, and the acyl radicals are found in combination with a protein called the acyl carrier protein (ACP). However, in yeast, mammals, and birds, the synthase system is a multienzyme polypeptide complex that incorporates ACP, which takes over the role of CoA. It contains the vitamin pantothenic acid in the form of 4 -phosphopan-tetheine (Figure 45-18). The use of one multienzyme functional unit has the advantages of achieving the effect of compartmentalization of the process within the cell without the erection of permeability barriers, and synthesis of all enzymes in the complex is coordinated since it is encoded by a single gene. 

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

Rice bran is the richest natural source of B-complex vitamins. Considerable amounts of thiamin (Bl), riboflavin (B2), niacin (B3), pantothenic acid (B5) and pyridoxin (B6) are available in rice bran (Table 17.1). Thiamin (Bl) is central to carbohydrate metabolism and kreb s cycle function. Niacin (B3) also plays a key role in carbohydrate metabolism for the synthesis of GTF (Glucose Tolerance Factor). As a pre-cursor to NAD (nicotinamide adenine dinucleotide-oxidized form), it is an important metabolite concerned with intracellular energy production. It prevents the depletion of NAD in the pancreatic beta cells. It also promotes healthy cholesterol levels not only by decreasing LDL-C but also by improving HDL-C. It is the safest nutritional approach to normalizing cholesterol levels. Pyridoxine (B6) helps to regulate blood glucose levels, prevents peripheral neuropathy in diabetics and improves the immune function. 

BaddUey J. Thain, E.M. (1951) The Synthesis of Pantothenic Acid-2 and -4 Phosphates as Possible Degradation Products of Coenzyme A. Journal of the Chemical Society, 246-251. 

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) -... 

It is now well known that pantothenic acid is a part of coenzyme A, a substance of unusual biochemical significance in that it is intimately concerned with the utilization of carbohydrates, and both the utilization and synthesis of fats, sterols, steriod hormones, etc. A partial failure of any of the processes in which it is concerned may not produce a specific lesion, but may nevertheless be a serious detriment to the individual experiencing it. 

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. 

FIGURE 21-4 Acyl carrier protein (ACP). The prosthetic group is 4 -phosphopantetheine, which is covalently attached to the hydroxyl group of a Ser residue in ACP. Phosphopantetheine contains the B vitamin pantothenic acid, also found in the coenzyme A molecule. Its —SH group is the site of entry of malonyl groups during fatty acid synthesis. 

The remaining series of reactions of fatty acid synthesis in eukary-l otes is catalyzed by the multifunctional, dimeric enzyme, fatty acid synthase. Each fatty acid synthase monomer is a multicatalytic polypeptide with seven different enzymic activities plus a domain that covalently binds a molecule of 4 -phosphopantetheine. [Note 4-Phosphopantetheine, a derivative of the vitamin pantothenic add (see p. 379), carries acetyl and acyl units on its terminal thiol (-SH)j group during fatty acid synthesis. It also is a component of 00-enzyme A.] In prokaryotes, fatty acid synthase is a multienzyme complex, and the 4 -phosphopantetheine domain is a separate protein, referred to as the acyl carrier protein (ACP). ACP is used below to refer to the phosphopantetheine-binding domain of the eukaryotic fatty acid synthase molecule. The reaction numbers in1 brackets below refer to Figure 16.9. [Note The enzyme activities listed are actually separate catalytic domains present in each mulf-1 catalytic fatty acid synthase monomer.]... 

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

Vitamins and Minerals. Milk is a rich source of vitamins and other organic substances that stimulate microbial growth. Niacin, biotin, and pantothenic acid are required for growth by lactic streptococci (Reiter and Oram 1962). Thus the presence of an ample quantity of B-complex vitamins makes milk an excellent growth medium for these and other lactic acid bacteria. Milk is also a good source of orotic acid, a metabolic precursor of the pyrimidines required for nucleic acid synthesis. Fermentation can either increase or decrease the vitamin content of milk products (Deeth and Tamime 1981 Reddy et al. 1976). The folic acid and vitamin Bi2 content of cultured milk depends on the species and strain of culture used and the incubation conditions (Rao et al. 1984). When mixed cultures are used, excretion of B-complex vita-... 

Two aliphatic acids possess, for grasses, many of the growth-distortion and toxicity effects associated with the synthetic auxins on dicotyledonous plants. Trichloroacetic acid and 2,2-dichloropropionic acid (dalapon), as the sodium salts, have been called grass "hormones or auxins, although Wilkinson184 could find no growth stimulation at low concentrations, and described dalapon as an antiauxin from its interference with indole-3-acetic acid effects. The herbicidal properties of trichloroacetate do not depend on its protein-denaturing ability, and those of 2,2-dichloropropionic acid involve, at least indirectly, the synthesis of pantothenic acid. 

Niacin and pantothenic acid synergistic wilh ACTH in steroid hormone synthesis Vitamin D antagonized directly by AC-TH via cortisol action... 

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. 

Precursors in the biosynthesis of pantothenic acid include a-ketoiso valeric add (pantoic acid), uracil (/J-alanine), and aspartic acid. Intermediates in the synthesis include ketopantoic acid, pantoic acid, and -alanine. 

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. 

Fig. 8. Possible routes for the synthesis of D-pantothenic acid through the enzymatic transformation. PL, pantolactone KPL, ketopantolactone KPA, ketopantoic acid d-PA, D-pantoic acid KPaOEt, ethyl 2 -ketopantothenate KPaCN, 2 -ketopantothenonitrile D-PaOEt, ethyl D-pan-tothenate D-PaCN, D-pantothenonitrile...

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