Pantothenate kinase, feedback

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). 

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. 

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. 

---