Pantothenic acid transport

The water-soluble vitamins generally function as cofactors for metabolism enzymes such as those involved in the production of energy from carbohydrates and fats. Their members consist of vitamin C and vitamin B complex which include thiamine, riboflavin (vitamin B2), nicotinic acid, pyridoxine, pantothenic acid, folic acid, cobalamin (vitamin B12), inositol, and biotin. A number of recent publications have demonstrated that vitamin carriers can transport various types of water-soluble vitamins, but the carrier-mediated systems seem negligible for the membrane transport of fat-soluble vitamins such as vitamin A, D, E, and K. 

Pantothenic acid (8.48), a hydroxyamide, occurs mainly in liver, yeast, vegetables, and milk, but also in just about every other food source, as its name implies [pantos (Greek) = everywhere]. It is part of coenzyme A, the acyl-transporting enzyme of the Krebs cycle and lipid syntheses, as well as a constituent of the acyl carrier protein in the fatty-acid synthase enzyme complex. 

Vitamins are chemically unrelated organic compounds that cannot be synthesized by humans and, therefore, must must be supplied by the diet. Nine vitamins (folic acid, cobalamin, ascorbic acid, pyridoxine, thiamine, niacin, riboflavin, biotin, and pantothenic acid) are classified as water-soluble, whereas four vitamins (vitamins A, D, K, and E) are termed fat-soluble (Figure 28.1). Vitamins are required to perform specific cellular functions, for example, many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism. In contrast to the water-soluble vitamins, only one fat soluble vitamin (vitamin K) has a coenzyme function. These vitamins are released, absorbed, and transported with the fat of the diet. They are not readily excreted in the urine, and significant quantities are stored in Die liver and adipose tissue. In fact, consumption of vitamins A and D in exoess of the recommended dietary allowances can lead to accumulation of toxic quantities of these compounds. 

The uptake and accumulation of various amino acids in Lactobacillus arabinosus have been described. Deficiencies of vitamin B6, biotin, and pantothenic acid markedly alter the operation of these transport systems. Accumulation capacity is decreased most severely by a vitamin B6 deficiency. This effect appears to arise indirectly from the synthesis of abnormal cell wall which renders the transport systems unusually sensitive to osmotic factors. Kinetic and osmotic experiments also exclude biotin and pantothenate from direct catalytic involvement in the transport process. Like vitamin B6, they affect uptake indirectly, probably through the metabolism of a structural cell component. The evidence presented supports a concept of pool formation in which free amino acids accumulate in the cell through the intervention of membrane-localized transport catalysts. 

Therefore, the three vitamin deficiencies so far studied in detail appear to affect amino acid transport and accumulation in similar but indirect ways. The accumulation defect is most pronounced in vitamin B6-deficient cells, for which there is also strong evidence implicating an abnormality in cell wall composition as a likely source of the change in transport activity. Direct evidence for a cell wall change in biotin- and pantothenate-deficient cells has not yet been obtained. The possibility remains, therefore, that the change in accumulation activity may be caused by an abnormality in some other structural component such as the peripheral cell membrane. 

It is apparent that at this stage of development definitive conclusions are premature, and that this aspect of amino acid and lipide metabolism will be pursued vigorously in the near future. It is of considerable interest to us that biotin and pantothenic acid deficiencies affect amino acid transport in L. arabinosus, since both vitamins are known to play a prominent role in lipide biosynthesis. We are currently reexamining the turnover of lipide fractions in nutritionally normal and vitamin-deficient cell types to determine whether there is some relation between this aspect of metabolism and amino acid transport. In any case, the nature of the catalytic steps involved in amino acid transport is still unknown to us. They probably occur in the peripheral cell membrane, but even this elementary and widely accepted belief will require additional study before it can be accepted beyond doubt as an established fact. 

Biotin uptake into enterocytes is by a sodium-dependent carrier, which also transports pantothenic acid (Section 12.2) and lipoic acid, but is inhibited by biocytin and dethiobiotin. The carrier is found in both the small intestine and the colon, so both biotin and pantothenic acid synthesized by intestinal bacteria can be absorbed (Chatterjee etal., 1999 Ramaswamy, 1999 Said, 1999 Prasad and Ganapathy, 2000). Even at relatively high intakes (up to 80 /rmol), biotin is more-or-less completely absorbed (Zempleni and Mock, 1999b). 

Saliha Ki, Horner HA, and Kirk K (1998) Transport and metaholism of the essential vitamin pantothenic acid in human erythrocytes infected with the malaria parasite Plasmodium falciparum. Journal of Biological Chemistry 273,10190-5. 

Zempleni J, Steven Stanley J, and Mock DM (2001) Proliferation of peripheral blood mononuclear cells causes increased expression of the sodium-dependent multivitamin transporter gene and increased uptake of pantothenic acid./owma/ of Nutritional Biochemistry 12, 465-73. 

Deficiency of water-soluble vitamins is far less precarious than a deficit of fat-soluble vitamins. While the first condition is generally rare, it can nevertheless often be observed in severe alcoholism. In liver cirrhosis, it was possible to detect a reduced amount of vitamins B2, Bg, Bi2, C and niacin or pantothenic acid in the liver as well as hypofunction of vitamins Bi, B2, Bg, C and folic acid. Hypovitaminosis may develop due to the reduced formation of specific transport proteins or the decreased acti-... 

The serum level of pantothenic add is about 1 to 5 lM (Lopaschuk d ai, 1987). The vitamin in the bloodstream is transported into various tissues, where it is then converted to coenzyme A. Coenzyme A is synthesized from pantothenic add, ATP, and cysteine. The pathway of coenzyme A synthesis is shown in Figure 9,77. The cofactor of fatty add synthase is synthesized from coenzyme A and does not involve the direct participation of pantothenic acid. A specific enzyme catalyzes... 

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. 

Dietary pantothenic acid is consumed as coenzyme A and the intermediates from coenzyme As biosynthesis (Fig. 8.39). These are hydrolyzed to free pantothenic acid. Absorption is by saturable, active transport. 

Thus, the flow of reducing equivalents in the pyruvate dehydrogenase complex is from pyruvate to lipoyl to FAD to NAD+. Conversion of pyruvate to acetyl-CoA requires four vitamins thiamine, pantothenic acid, riboflavin, and niacin. In contrast, in glycolysis, niacin is the only vitamin used. NADH generated in this reaction is oxidized to NAD+ in the electron transport... 

Most organisms, regardless of their ability to produce pantothenic acid, have some transport system that actively mediates pantothenate uptake." The E. coli pantothenate permease (panF gene product) is the best characterized of these transport systems." " Studies have shown that it is a unidirectional sodium-based symporter, which is highly specific for pantothenate (1/ of 0.4p,moll ), and has maximum velocity of... 

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