Inhibition of pantothenate kinase

Biosynthesis of CoA from pantothenic acid in the supernatant fraction of the liver. All enzymes required for the biosynthesis of CoA from pantothenic acid have been isolated from the soluble fraction of the cell (8). By using the vitro system of Abiko (cf. 8) for the synthesis of CoA from pantothenic acid, we found the capacity for CoA-biosynthesis to be markedly increased after treatment with clofibrate (2). Dephospho-CoA kinase was not significantly (or only very slightly) increased, but the activity of pantothenate kinase was more than doubled. CoA will exert feed-back inhibition of pantothenate kinase (8), and the extent of this inhibition was not changed by clofibrate (2). 

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... 

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). 

Virga, K.G., Zhang, Y.M., Leonardi, R., et al. (2006) Structure-activity relationships and enzyme inhibition of pantothenamide-type pantothenate kinase inhibitors. Bioorg. Med. Chem. 14, 1007-1020. 

Spry, C., Chai, C. L., Kirk, K., and Saliba, K. J. (2005). A class of pantothenic acid analogs inhibits Plasmodium falciparum pantothenate kinase and represses the proliferation of malaria parasites. Antimicrob. Agents Chemother. 49, 4649-4657. 

Table 5 shows that pantothenate kinase in the liver supernatant from clofibrate-treated animals had about twice the activity of normal. We found feed-back inhibition of CoA at this step, as previously reported by Abiko (8). The extent of this feed-back inhibition was not significantly changed by treatment with clofibrate (2). ... 

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