Metabolism and Turnover

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The primary role of pantothenic acid is in acyl group activation for lipid metabolism, involving thiol acylation of CoA or of ACP, both of which contain 4-phosphopantotheine, the active group of which is ^-mercaptoethylamine. CoA is essential for oxidation of fatty acids, pyruvate and a-oxogutarate, for metabolism of sterols, and for acetylation of other molecules, so as to modulate their transport characteristics or functions. Acyl carrier protein, which is synthesized from apo-ACP and coenzyme A, is involved specifically in fatty acid synthesis. Its role is to activate acetyl, malonyl, and intermediate chain fatty acyl groups during their anabolism by the biotin-dependent fatty acid synthase complex (i.e., acyl-CoA: malonyl-CoA-acyl transferase (decarboxylating, oxoacyl and enoyl-redu-cing, and thioester-hydrolyzing), EC 2.3.1.85).

The organ with the highest concentration of pan-tothenate is liver, followed by adrenal cortex, because of the requirement for steroid hormone metabolism in these tissues. Ninety-five per cent of the CoA within each tissue is found in the mitochondria. However, the initial stages of activation of pantothenate and conversion to CoA occur in the cytosol. It was originally believed that the final stages of CoA synthesis must occur within the mitochondria, but later evidence indicated that transport across the mitochondrial membrane is, after all, possible. ^-oxidation within the peroxisomes is also CoA-dependent, and is downregu-lated by pantothenate deficiency.

The pathways of conversion of pantothenic acid to CoA and to ACP are summarized in Figure 2. There are three ATP-requiring reactions and one CTP-requir-ing reaction in the synthesis of CoA. The rate of CoA synthesis is under close metabolic control by energy-yielding substrates, such as glucose and free fatty acids (via CoA and acyl CoA) at the initial activation step, which is catalyzed by pantothenate kinase (ATP: pan-tothenate 4-phosphotransferase, EC 2.7.1.33). This feedback control is thought to be a mechanism for conservation of cofactor requirements. There are also direct and indirect effects of insulin, corticosteroids, and glucagon, which result in important changes in tissue distribution, uptake, etc. in persons with diabetes. The mechanisms involved here are complex and not yet fully understood; however insulin represses and glucagon induces the enzyme.

A rare genetic disease, Hallervorden-Spatz syndrome, has recently been shown to result from deficiency of pantothenate kinase, and is now alternatively known as pantothenate kinase-associated neurodegeneration (PKAN). Dystonia, involuntary movements, and spasticity occur, and although there is no cure, some palliative treatment is possible.

In genetically normal people, fasting results in a reduction of fatty acid synthase activity with loss of the coenzyme of ACP, which thus achieves the desired objective of a shift away from fatty acid synthesis, towards breakdown. This interconversion of apo-ACP and holo-ACP is thus a very important process for the short-term regulation of fatty acid synthesis.

Deficiency of sulfur amino acids can result in reduced CoA synthesis; likewise copper overload can (by interfering with sulfur amino acid function) also reduce CoA synthesis.

Excretion of free pantothenate in the urine is the primary excretion route in humans; in other mammals

Pantothenic acid kinase

Pantothenic acid

4'-phosphopantothenic acid

4 '-phosphopantothenoylcysteine synthetase CTP, cysteine

CDP, phosphate 4'-phosphopantothenoylcysteine

4 -phosphopantothenoylcysteine decarboxylase

ATP: pantetheine-4 -phosphate adenylyltransferase

Dephospho-CoA kinase

4'-phosphopantetheine ATP ■

pyrophosphate 4'-dephospho-coenzyme A ATP ■

CoA:apo[acyl-carrier protein] pantetheinephosphotransferase

CoA hydrolase

Apo-(acyl-carrier protein) .

Holo-(acyl-carrier protein)

(with phosphopantetheine as the active group)

Figure 2 Synthetic pathway between pantothenic acid, coenzyme A, and acyl carrier protein.

the glucuronide or glucoside may be excreted. There is little evidence of degradation to simpler products, and pantothenic acid appears to be very efficiently conserved in animals. Some bacteria can cleave it to yield pantoic acid and ^-alanine. A potentially useful breakdown product of CoA is taurine, formed via cystea-mine. This amino acid is an essential nutrient for some carnivorous animals such as cats.

When dietary intakes are low, the majority of the circulating vitamin, which is filtered in the kidney tubules, is absorbed by the same type of sodium-dependent active transport process that also occurs at most other sites in the body. Retention of a test dose of pantothenate is, as expected, greater in partially depleted subjects, than in saturated ones. Secretion into breast milk is proportional to intake and to blood levels of the vitamin; therefore, dietary supplements taken by the lactating mother generally increase the breast milk content of the vitamin.

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Supplements For Diabetics

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