Well Established Metabolic Functions of Vitamin C that are Impaired in Deficiency

Studies of guinea pigs (and other species requiring a dietary source of vitamin C) have revealed that, when deprived of the vitamin, characteristic lesions of growing bones, failure of wound-healing of skin and bones, capillary defects, and other lesions arise, all of which point to a failure of the new synthesis of, or repair processes for, connective tissues and especially the protein collagen, which is the major extracellular protein and comprises a third of all the protein in the body (Table 1). As the biochemical pathway of collagen biosynthesis became better understood, during the middle years of the twentieth century, it became clear that certain unusual and characteristic hydroxylated amino-acids, comprising two different hydroxylated forms of proline and one of lysine, occurred uniquely in collagen. These were not coded for by the genome or inserted by the amino-acid-assembly machinery of the cell but instead were created by 'post-translational' amino-acid hydroxylation processes that took place after the nascent pro-collagen polypeptide chain had been synthesized on the polysomal messenger RNA. Some of the prolyl residues of the pro-collagen molecule were then hydroxylated to hydroxyprolyl residues, and some of the lysyl residues were hydroxylated to hydroxylysyl residues. The hydroxylated prolyl residues are essential for subsequent collagen triple-helix formation and hence for the secretion of nascent collagen; the hydroxylated lysyl residues form part of the essential pyridinoline-type crosslinks that stabilize the collagen fibers, especially those in bone. In the absence of sufficient vitamin C, these hydro-xylation reactions rapidly fail, because the iron at the active center of the 'mixed function oxidase' enzymes that catalyze them is rapidly inactivated by oxidation. Vitamin C, specifically, is needed to keep the essential ferrous residues at the hydroxy-lase-enzyme active centers in the reduced, active, form. In the absence of the vitamin, these enzymes are inactivated after only a few cycles of hydroxylation.

The essential function of vitamin C in collagen maturation can go a long way towards explaining many of the clinical lesions of scurvy (Table 2). However, recent evidence indicates that the vitamin may also act directly on the transcription and translation of collagen mRNA and on the synthesis of other parts of the cell machinery that are needed for the formation of normal connective tissues. Parts of this process have yet to be clarified.

Vitamin C also plays a cofactor-like role in the reactions of several other enzymes that split molecular oxygen, notably members of the group of enzymes that are classified as 'mixed-function oxidases.' Two enzymes containing ferrous iron that are involved in carnitine biosynthesis (trimethyl lysine hydroxylase and 7-butyrobetaine hydroxylase) fall into this category. Aspartate /3-hydoxylase, which is needed for the post-synthetic modification of protein kinase C, also requires vitamin C. Another enzyme that requires vitamin C is the copper enzyme dopamine ^-hydroxylase, and, in this reaction, ascorbic acid is needed to reduce cupric copper to the cuprous form at the active site. Pepti-dyl glycine hydroxylase (peptidyl a-amidase) is also a copper enzyme that requires vitamin C as cosub-strate. Vitamin C can increase the activities of several other enzymes, by a non-specific reducing or protective action that is shared by other cellular reductants. This action is, however, distinct from the functions described above, which are more specific to vitamin C.

In the course of its functional roles, ascorbic acid is oxidized in two successive one-electron reversible steps, and it is thought that most, if not all, of its essential biological actions are centred around this key redox cycle. The first oxidation product is the free-radical form of the vitamin, which is known variously as 'mono-dehydroascorbate,' 'semidehydroascorbate,' or 'ascorbate free radical' (AFR). Although this intermediate shares with most other free radicals the properties of having a relatively short half life and a high degree of chemical reactivity, it is, nevertheless, more stable than many other free radicals, contrasting with the highly reactive and damaging radicals such as hydroxyl or superoxide radical that are derived from molecular oxygen. By reacting with, and thus quenching, these damaging oxygen free radicals, ascorbate can act as a free-radical chain terminator and can thereby protect vulnerable macromolecules such as DNA, lipids, and proteins from oxidative damage by free-radical chain reactions. Such reactions would otherwise cause extensive damage, including genetic damage (to DNA), the formation of potentially atherogenic oxidized lipids, and oxidative inactivation of enzymes. For this reason, ascorbic acid is thought to possess important 'protective' antioxidant properties that are not directly connected with its other cofactor-like or cosubstrate-like roles in enzyme reactions. Ascorbate probably also protects host tissues against damage by oxi-dants such as hypochlorous acid that are produced in the normal course of bacterial killing by white cells.

The second one-electron oxidation step in ascor-bate oxidation produces dehydroascorbate from the free-radical intermediate AFR. Both of these oxidized forms can be recycled to ascorbate either by non-enzymatic reactions with glutathione as the reductant (electron acceptor) or by pyridine nucleo-tide-dependent enzymatically catalyzed reactions. Thus, the two sequential one-electron oxidation steps from ascorbate to dehydroascorbate are fully reversible in vivo. However, the subsequent spontaneous non-enzymatic reaction comprising hydrolysis of the 1,4-lactone ring is not reversible, so that the product of this reaction, diketogulonic acid, has no provitamin activity. Normally, about 3% of the vitamin C in the body is degraded every day, and this loss must be replaced from the diet. Nevertheless, many weeks at or near zero intake are usually needed to reach scorbutic levels, if the tissues are reasonably well supplied to begin with.

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