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Chapter: Introduction to Human Nutrition: The Vitamins

Metabolic functions of vitamin C

Ascorbic acid has specific roles in two groups of enzymes: the copper-containing hydroxylases and the 2-oxoglutarate-linked iron-containing hydroxylases.

Metabolic functions of vitamin C 

Ascorbic acid has specific roles in two groups of enzymes: the copper-containing hydroxylases and the 2-oxoglutarate-linked iron-containing hydroxylases. It also increases the activity of a number of other enzymes in vitro, although this is a non-specific reducing action rather than reflecting any metabolic function of the vitamin. In addition, it has a number of non-enzymic effects due to its action as a reducing agent and oxygen radical quencher.

Copper-containing hydroxylases

Dopamine β-hydroxylase is a copper-containing enzyme involved in the synthesis of the catechol-amines norepinephrine (noradrenaline) and epi-nephrine (adrenaline) from tyrosine in the adrenal medulla and central nervous system. The enzyme contains Cu+, which is oxidized to Cu2+ during the hydroxylation of the substrate; reduction back to Cu+ specifically requires ascorbate, which is oxidized to monodehydroascorbate.

Some peptide hormones have a carboxy-terminal amide that is hydroxylated on the α-carbon by a copper-containing enzyme, peptidylglycine hydroxy-lase. The α-hydroxyglycine residue then decomposes non-enzymically to yield the amidated peptide and glyoxylate. The copper prosthetic group is oxidized in the reaction, and, as in dopamine β-hydroxylase, ascorbate is specifically required for reduction back to Cu+.

Oxoglutarate-linked iron-containing hydroxylases

Several iron-containing hydroxylases share a common reaction mechanism, in which hydroxylation of the substrate is linked to decarboxylation of 2-oxoglutarate. Many of these enzymes are involved in the modification of precursor proteins to yield the final, mature, protein. This is a process of postsyn-thetic modification of an amino acid residue after it has been incorporated into the protein during synthe-sis on the ribosome.

      Proline and lysine hydroxylases are required for the postsynthetic modification of procollagen in the formation of mature, insoluble, collagen, and proline hydroxylase is also required for the post-synthetic modification of the precursor proteins of osteocalcin and the C1q component of complement.


      Aspartate β-hydroxylase is required for the postsyn-thetic modification of the precursor of protein C, the vitamin K-dependent protease that hydrolyzes activated factor V in the blood-clotting cascade.


      Trimethyl-lysine and γ-butyrobetaine hydroxylases are required for the synthesis of carnitine.

Ascorbate is oxidized during the reaction of these enzymes, but not stoichiometrically with the decar-boxylation of 2-oxoglutarate and hydroxylation of the substrate. The purified enzyme is active in the absence of ascorbate, but after some 5–10 s (about 15–30 cycles of enzyme action) the rate of reaction begins to fall. At this stage the iron in the catalytic site has been oxi-dized to Fe3+, which is catalytically inactive; activity is restored only by ascorbate, which reduces it back to Fe2+. The oxidation of Fe2+ is the consequence of a side-reaction rather than the main reaction of the enzyme, which explains how 15–30 cycles of enzyme activity can occur before there is significant loss of activity in the absence of ascorbate, and why the con-sumption of ascorbate is not stoichiometric.

Pro-oxidant and antioxidant roles of ascorbate

Ascorbate can act as a radical-trapping antioxidant, reacting with superoxide and a proton to yield hydro-gen peroxide, or with the hydroxy radical to yield water. In each instance the product is the monodehy-droascorbate radical. Thus, as well as reducing the tocopheroxyl radical formed by interaction of α-tocopherol in membranes with lipid peroxides, ascorbate acts to trap the oxygen radicals that would otherwise react to form lipid peroxides.

At high concentrations, ascorbate can reduce molecular oxygen to superoxide, being oxidized to monodehydroascorbate. At physiological concentra-tions of ascorbate, both Fe3+ and Cu2+ ions are reduced by ascorbate, yielding monodehydroascorbate. Fe2+ and Cu+ are readily reoxidized by reaction with hydro-gen peroxide to yield hydroxide ions and hydroxyl radicals. Cu+ also reacts with molecular oxygen to yield superoxide. Thus, as well as its antioxidant role, ascorbate has potential pro-oxidant activity. However, because at high levels of intake the vitamin is excreted quantitatively, is it unlikely that tissue concentrations will rise high enough for there to be significant for-mation of oxygen radicals.

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