The Formation of CoA from Pantothenic Acid

Phosphopantothenic acid reacts with cysteine, forming 4 -phosphopant-othenyl cysteine, which is decarboxylated to 4 -phosphopantetheine in a flavin-dependent reaction. In most bacteria, phosphopantetheinyl cysteine synthase and decarboxylase occur as a single bifunctional enzyme, but the human enzymes occur as two separate proteins (Daugherty et al., 2002). 

Phosphopantetheine undergoes adenylyl transfer from ATP to yield de-phospho-CoA, which is then phosphorylated at the 3 position of the ribose moiety to yield CoA. Phosphopantetheine adenylyltransferase and dephos-pho- CoA kinase activities occur in a single bifunctional enzyme, which is found in both cytosol and mitochondria. However, in addition to the bifunctional protein, human tissues also contain a separate dephospho-CoA kinase (Begley et al., 2001 Zhyvoloup et al., 2002). 

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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. 

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). 

However, the latter assumption can not be the only mechanism of action, because pantothenic acid did not exert so favorable effect on the diabetic hyperlipidemia as pantethine ( data not shown ). And some additional action of pantethine should be considered. This has been also supported by the present finding that pantethine did not stimulate COo formation from 1- C-palmitate in the absence of added CoA ( Figs.3 and 4 ). There may be several... 

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