Pantothenate kinase

Pantothenate kinase phosphorylates Vitamin B6, the first and rate controlling step in Coenzyme A biosynthesis. Due to the lack of pantothenate kinase inhibitors and activators, the exact physiological role of this enzyme in metabolism and disease is not yet known. In a recent study aimed at the discovery of antimicrobial agents, a set of novel inhibitors of S. aureus pantothenate kinase were disclosed that also inhibited mammalian (murine) pantothenate kinase with high micromolar IC50 values.235 A team at St. Jude Children s Hospital studied a library of known bioactive compounds to find inhibitors of pantothenate kinase. Several inhibitors with IC50 values below 10 pM were identified.236 

In the previous sections, we have discussed examples of inhibitors of nonprotein kinases for the development of novel therapeutics. Due to their important role in sugar metabolism, sugar kinase inhibitors have potential utility for the treatment of cancer, metabolic disorders diabetes and cardiovascular disease. Nucleoside kinase inhibitors are established oncology targets that operate by inhibition of the salvage pathway. Adenosine kinase inhibitors and lipid kinase inhibitors are highly significant in the development of cancer therapeutics. 

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As a result of the reduced activity of the mutase in vitamin B12 deficiency, there is an accumulation of methyhnalonyl CoA, some of which is hydrolyzed to yield methylmalonic acid, which is excreted in the urine. As discussed in Section 10.10.3, this can be exploited as a means of assessing vitamin B12 nutritional status. There may also be some general metabolic acidosis, which has been attributed to depletion of CoA because of the accumulation of methyl-malonyl CoA. However, vitamin B12 deficiency seems to result in increased synthesis of CoA to maintain normal pools of metabolically useable coenzyme. Unlike coenzyme A and acetyl CoA, neither methylmalonyl CoA nor propionyl CoA (which also accumulates in vitamin B12 deficiency) inhibits pantothenate kinase (Section 12.2.1). Thus, as CoA is sequestered in these metabolic intermediates, there is relief of feedback inhibition of its de novo synthesis. At the same time, CoA may be spared by the formation of short-chain fatty acyl carnitine derivatives (Section 14.1.1), which are excreted in increased amounts in vitamin B12 deficiency. In vitamin Bi2-deficient rats, the urinary excretion of acyl carnitine increases from 10 to 11 nmol per day to 120nmolper day (Brass etal., 1990). 

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.S and dephospho-CoA kinase, EC 2.7.1.24. CoASH, free coenzyme A.

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 ixmo per L. 

Pantothenol, the alcohol ofpantothenic acid (see Figure 12.1), is frequently used in pharmaceutical preparations. Although it is a substrate for pantothenate kinase in vitro, it is more likely that it first undergoes oxidation to pantothenic acid, catalyzed by liver alcohol dehydrogenase, rather than phosphorylation to phosphopantothenol followed by oxidation. 

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. 

Short-chain fatty acyl CoA derivatives are inhibitors of pantothenate kinase in perfused rat hearts, the addition of any of the major energy-yielding... 

Expression of the pantothenate kinase gene is induced by glucagon (which is secreted under conditions when there is an increased need for CoA for fatty acid oxidation) and repressed by insulin (Kirschbaum et al., 1990 Yun et al., 2000). 

Kirschbaum N, Clemons R, Marino KA, Sheedy G, Nguyen ML, and Smith CM (1990) Pantothenate kinase activity in livers of genetically diabetic mice (db/db) and hormonally treated cultured rat hepatocytes./ourna/ of Nutrition 120,1376-86. 

Rock CO, Calder RB, Karim MA, and Jackowski S (2000) Pantothenate kinase regulation of the intracellular concentration of coenzyme A. Journal of Biological Chemistry 275, 1377-83. 

Ynn M, Park CG, Kim JY, Rock CO, Jackowski S, and Park HW (2000) Structural basis for the feedback regulation of Escherichia coli pantothenate kinase by coenzyme A. Journal of Biological Chemistry 275,28093-9. 

Zhou B, Westaway SK, Levinson B, Johnson MA, Gitschier J, and Hayflick SJ (2001) A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nature Genetics 28, 345-9. 

Figure 1 Biosynthesis of CoA from pantothenic acid. El pantothenate kinase (CoaA) E2 phosphopantothenoylcysteine synthetase (CoaB) ...

Pantothenic acid is taken in as dietary CoA compounds and dCphosphopantetheine and hydrolyzed by pyrophosphatase and phosphatase in the intestinal lumen to dephospho-CoA, phosphopantetheine, and pantetheine. This is further hydrolyzed to pantethenic acid. The vitamin is primarily absorbed as pantothenic acid by a saturable process at low concentrations and by simple diffusion at higher ones. The saturable process is facilitated by a sodium-dependent multivitamin transporter, for which biotin and lipoate compete. After absorption, pantothenic acid enters the circulation and is taken up by cells in a manner similar to its intestinal adsorption. The synthesis of CoA from pantothenate is regulated by pantothenate kinase, which itself is subject to negative feedback from the products CoA and acyi-CoA. The steps involved were outlined above. Pantothenic acid is excreted in the urine after hydrolysis of CoA compounds by enzymes that cleave phosphate and the cys-teamine moieties. Only a small fraction of pantothenate is secreted into milk and even less into colostrum. 

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