As noted above, the biochemical functions, and hence the basis for the dietary requirement of pan-tothenic acid, arise entirely from its occurrence as an essential component of CoA and of ACP, which cannot be synthesized de novo in mammals from simpler precursors.
In addition to the now well-established roles of CoA in the degradation and synthesis of fatty acids, sterols, and other compounds synthesized from isoprenoid precursors, there are also a number of acetylation and long-chain fatty acylation processes which seem to require CoA as part of their essential biological catalytic sites, and which are still being explored today. The acetylation of amino sugars, and some other basic reactions of acetyl-CoA and succinyl-CoA in intermediary metabolism, have been known since the 1980s. However, the addition of acetyl or fatty acyl groups to certain proteins in order to modify and control their specific and essential properties is a more recent discovery. The first category of these modifications comprises the acetylation of the N-term-inal amino acid in certain proteins, which occurs in at least half of all the known proteins that are found in higher organisms. The specific amino acids that are recipients of these acetyl groups are most commonly methionine, alanine, or serine. The purposes of this terminal acetylation process are not entirely clear and may be multiple, including modifications of function
(e.g., of hormone function), of binding and site recognition, of tertiary peptide structure, and of eventual susceptibility to degradation. Another possible site of protein acetylation is the side chain of certain internal lysine residues, whose side chain e-amino group may become acetylated in some proteins, notably the basic histone proteins of the cell nucleus, and the a-tubulin proteins of the cytoplasmic microtubules, which help to determine cell shape and motility. Its essential role in the synthesis of a-tubulin appears to be a particularly important one.
Proteins can also be modified by acylation with certain long-chain fatty acids, notably the 16-carbon saturated fatty acid, palmitic acid, and the 14-carbon saturated fatty acid, myristic acid. Although structurally very similar to each other, these two fatty acids seek entirely different protein locations for acylation and also have quite different functions. They have recently been explored with particular emphasis on viral and yeast proteins, although proteins in higher animals, in organs such as lung and brain, can also become acylated with palmityl moieties. Palmitoyl CoA is also required for the transport of residues through the Golgi apparatus during protein secretion. It is believed that these protein acylations may enable and control specific protein interactions, especially in relation to cell membranes, and proteins that are pal-mitoylated are generally also found to be associated with the plasma membrane. Signal transduction (e.g., of the human /^-adrenergic receptor) is one process that appears to be controlled by palmitoylation, and other palmitoylated proteins possess some structural importance, for example in the case of the protein-lipid complex of brain myelin. Clearly, these subtle protein modifications, all of which depend on CoA and hence on pantothenic acid, have a wide-ranging significance for many biological processes, which is still being actively explored.
Pantothenic acid is essential for all mammalian species so far studied, namely humans, bovines, pigs, dogs, cats, and rodents, as well as for poultry and fish. Pantothenate deficiency signs in animals are relatively nonspecific and vary among species. Deficiency in young animals results in impaired growth, and requirement estimates based on maximum growth rates are between 8 and 15 mg per kg diet. Rats that are maintained on a diet low in pantothe-nate exhibit reduced growth, scaly dermatitis, alopecia, hair discoloration and loss, porphyrin-caked whiskers, sex organ disruption, congenital malformations, and adrenal necrosis. Deficient chicks are affected by abnormal feather development, locomotor and thymus involution, neurological symptoms including convulsions, and hypoglycemia. Pigs exhibit intestinal problems and abnormalities of dorsal root ganglion cells, and several species suffer nerve demye-lination. Fish exhibit fused gill lamellae, clumping of mitochondria, and kidney lesions. Signs specific for pantothenate depletion are not well characterized for humans. A syndrome that included 'burning feet' has been described in tropical prisoner-of-war camps during World War II, and it was said to respond to pantothenic acid supplements; however this was likely to have been a more complex deficiency. A competitive analog of pantothenate, w-methyl pantothenate, interferes with the activation of pan-tothenic acid; it also produces burning feet symptoms, Reye-like syndrome, cardiac instability, gastrointestinal disturbance, dizziness, paraesthesia, depression, fatigue, insomnia, muscular weakness, loss of immune (antibody) function, insensitivity to adrenocorticotrophic hormone, and increased sensitivity to insulin. Large doses of pantothenate can reverse these changes. One of the earliest functional changes observed in mildly deficient rats was an increase in serum triacylglycerols and free fatty acids, presumably resulting from the impairment in / -oxidation. Paradoxically, CoA levels are relatively resistant to dietary pantothenate deficiency; however there are some inter-organ shifts in pan-tothenate in certain metabolic states.
As noted above, CoA is required for Golgi function, involved in protein transport. Pantothenate deficiency can therefore cause reductions in the amounts of some secreted proteins. Other metabolic responses to deficiency include a reduction in urinary 17-ketosteroids, a reduction in serum cholesterol, a reduction in drug acetylation, a general reduction in immune response, and an increase in upper respiratory tract infection.
Recently, some studies of wound healing and fibroblast growth have indicated that both pantothe-nic acid and ascorbic acid are involved in trace element distribution in the skin and scars of experimental animals, and that pantothenic acid can improve skin and colon wound healing in rabbits. It is not yet known whether these observations are relevant to wound healing in humans.
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