Absorption transport and metabolism of pantothenic acid Domina

Absorption, transport and metabolism of pantothenic acid Domina Petric, MD

Absorption of pantothenic acid I. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 2

Hydrolysis of coenzyme forms Pantothenic acid occurs in most foods and feedstuffs as Co. A and the acyl-carrier protein (ACP). The utilization of the vitamin in foods depends on the hydrolytic digestion of these protein complexes to release the free vitamin. Both Co. A and ACP are degraded in the lumen of the intestine to release the vitamin as 4´-phosphopantetheine. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 3

Hydrolysis of coenzyme forms 4´-phosphopantetheine is dephosphorylated to yield pantetheine, which is rapidly converted by the intestinal pantetheinase to pantothenic acid. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 4

Carrier-mediated uptake Pantothenic acid is absorbed by a saturable, Na+dependent, energy-requiring process that shows highest rates in the jejunum. At high levels, it is also absorbed by simple diffusion throughout the small intestine. The alcohol form, panthenol, which is oxidized to pantothenic acid in vivo, appears to be absorbed somewhat faster than the acid form. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 5

Transport of pantothenic acid II. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 6

Free in plasma Pantothenic acid is transported in both the plasma and erythrocytes. Plasma contains the vitamin only in the free acid form, which erythrocytes take up by passive diffusion. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 7

Free in plasma • While erythrocytes carry some of the vitamin unchanged, they convert some of the vitamin to 4'-phosphopantothenic acid and pantetheine. • Erythrocytes carry most of the vitamin in the blood. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 8

Cellular uptake • Pantothenic acid is transported into other cells in its free acid form by a Na+ co-transporter. • The pantothenic acid transport also appears to transport biotin and to be influenced by hormonal status, and to be mediated by protein kinase C and calmodulin. • Upon cellular uptake, most of the vitamin is converted to Co. A, the predominant tissue form. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 9

Tissue distribution • The greatest concentrations of Co. A are found in the liver, adrenals, kidneys, brain, heart and testes. • Much of this (70% in liver and 95% in heart) is located in the mitochondria. • Tissue Co. A concentrations are not affected by deprivation of the vitamin. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 10

Tissue distribution • Pantothenic acid is reabsorbed by active transport. • At higher concentrations, tubular secretion of pantothenic acid occurs. • Tubular reabsorption appears to be the only mechanism for conserving free pantothenic acid in the plasma. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 11

Tissue distribution • Pantothenic acid is taken up in the choroid plexus by a specific transport process, which, at low concentrations of the vitamin involves the partial phosphorylation of the vitamin. • The cerebrospinal fluid, because it is constantly renewed in the central nervous system, requires a constant supply of pantothenic acid. • Pantothenic acid is as Co. A, involved in the synthesis of the neurotransmitter acetylcholine in brain tissue. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 12

Metabolism of pantothenic acid III. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 13

Coenzyme A biosynthesis All tissues have the ability to synthesize Co. A from pantothenic acid of dietary origin. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 14

In the cytosol Pantothenate kinase catalyzes the ATP-dependent phosphorylation of pantothenic acid to yield 4'-phosphopantothenic acid. This is the rate-limiting step in Co. A synthesis. Under normal conditions, it appears to function far below its maximal capacity. First step Inhibition by Co. A esters appears to be reversed by carnitine. The ethanol metabolite acetaldehyde also inhibits the conversion of pantothenic acid to Co. A. January 30, 2022 It can be induced and appears to be feedback inhibited by 4'-phosphopantothenic acid, Co. A esters (acetyl. Co. A, malonyl-Co. A and propionyl-Co. A) and more weakly by Co. A and long-chain acyl -Co. As. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 15

In the cytosol Phosphopantothenylcysteine synthase catalyzes the ATPdependent condensation of 4'-phosphopantothenic acid with cysteine to yield 4´-phosphopantothenylcysteine. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 16

In the cytosol • Phosphopantothenylcysteine decarboxylase catalyzes the decarboxylation of 4'-phosphopantothenylcysteine to yield 4'-phosphopantetheine in the cytosol, whereupon it is transported into the mitochondria. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 17

In the mitochondrial inner membrane Phosphopantetheine adenyltransferase catalyzes the ATP-dependent adenylation of 4‘-phosphopantetheine to Co. A to yield dephospho-Co. A. Because this reaction is reversible, at low ATP levels dephospho-Co. A can be degraded to yield ATP. January 30, 2022 Dephospho-Co. A kinase catalyzes the ATP dependent phosphorylation of dephospho. Co. A to yield Co. A. Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 18

Acyl-Carrier Protein biosynthesis • The acyl-carrier protein (ACP) is synthesized as the apoprotein lacking the prosthetic group. • That group, 4'-phosphopantetheine, is transferred to ACP from Co. A by the action of 4'-phosphopantetheineapo ACP transferase. • The prosthetic group is bound to the apo-ACP via a phosphoester linkage at a serinyl residue. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 19

Catabolism of Coenzyme A and ACP The pantothenic acid components of both Co. A and ACP are released metabolically ultimately in the free acid form of the vitamin. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 20

Excretion • The vitamin is excreted mainly in the urine as free pantothenic acid, as well as some 4'-phosphopantethenate. • The renal tubular secretion of pantothenic acid results in urinary excretion of the vitamin correlating with dietary intake. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 21

Excretion • An appreciable amount (∼ 15% of daily intake) is oxidized completely and is excreted across the lungs as CO 2. • Humans typically excrete in the urine 0. 8– 8. 4 mg of pantothenic acid per day. January 30, 2022 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 22

Literature • Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. January 30, 2022 23