Vitamin C (ascorbic acid) is the water-soluble antioxidant vitamin that is the essential cofactor for the prolyl hydroxylase and lysyl hydroxylase enzymes — the enzymes that are required for the synthesis of all collagens in the human body and that are therefore essential for the integrity of all connective tissues, including bone, cartilage, tendon, skin, and the walls of all blood vessels. Without vitamin C, the prolyl and lysyl hydroxylase enzymes cannot function, the hydroxylation of proline and lysine residues in the collagen molecule is impaired, the triple helix of the collagen molecule is unstable at body temperature, the collagen fibres that are synthesised are defective, and the connective tissues that depend on collagen for their mechanical integrity are weakened. This vitamin C-dependent vulnerability of collagen synthesis is the foundation of the clinical syndrome of scurvy — the disease that results from severe vitamin C deficiency and that is characterised by the perifollicular haemorrhages, the petechiae, the ecchymoses, the bleeding gums, the poor wound healing, the bent femur bones in infants (from the weakness of the collagen-based growth plate), and the death from sepsis or from haemorrhage that is the final stage of untreated scurvy.
The Prolyl and Lysyl Hydroxylase Reactions
Prolyl hydroxylase (P4H) and lysyl hydroxylase are the enzymes that catalyse the hydroxylation of proline and lysine residues in the collagen molecule, respectively, and they are the only enzymes in the human body that require vitamin C as a cofactor. Prolyl hydroxylase uses molecular oxygen, Fe2+, ascorbate (vitamin C), and alpha-ketoglutarate as cofactors and substrates, and it hydroxylates the proline residues in the Y-position of the repeating Gly-X-Y sequence to hydroxyproline — the modified amino acid that is essential for the thermal stability of the collagen triple helix. Without hydroxyproline, the collagen triple helix is unstable at body temperature (37C), and the collagen molecule cannot form the stable, organised fibrils that are the foundation of all connective tissues. Lysyl hydroxylase hydroxylates the lysine residues in the collagen molecule to hydroxylysine, and the hydroxylysine residues are the sites at which the oligosaccharide chains are attached (in the GPI aggregation of collagen monomers) and at which the covalent cross-links between adjacent collagen molecules are formed (by lysyl oxidase, which oxidatively deaminates the hydroxylysine residues to form the reactive aldehydes that form the cross-links). Without vitamin C, both the prolyl and lysyl hydroxylase reactions are impaired, and the collagen that is synthesised is defective at every level — from the stability of the triple helix to the cross-linking of the fibrils.
The clinical importance of vitamin C for collagen synthesis is underscored by the scurvy syndrome — one of the most dramatic and recognisable deficiency diseases in all of medicine. Scurvy was first described by the Egyptian physician Ebers papyrus in 1550 BC and was a devastating disease among sailors on long sea voyages from the 15th to the 18th centuries, when fresh fruits and vegetables were not available on board. The disease was eventually conquered by the discovery that citrus fruits (particularly limes and lemons) prevented and cured scurvy — a discovery that saved countless lives and that eventually led to the establishment of the modern science of nutrition. The modern understanding of scurvy is that it is a disease of collagen failure — the perifollicular haemorrhages, the bleeding gums, the poor wound healing, and the bent bones are all the direct result of the defective collagen that is synthesised when vitamin C is not available to support the prolyl and lysyl hydroxylase enzymes.
Vitamin C as an Antioxidant
Beyond its role as a cofactor for the hydroxylase enzymes, vitamin C is also one of the most important water-soluble antioxidants in the body — it directly neutralises the reactive oxygen species (ROS) and the reactive nitrogen species (RNS) that are generated as byproducts of normal cellular metabolism and as products of the inflammatory response. Vitamin C is the primary antioxidant in the plasma and in the extracellular fluid — it protects the plasma lipids (particularly LDL cholesterol) from oxidation, it protects the endothelial cells from oxidative damage, and it regenerates the vitamin E radical back to active vitamin E at the lipid-water interface of cell membranes. This antioxidant function of vitamin C is complementary to its hydroxylase cofactor function, and together these two roles make vitamin C one of the most important nutrients for the maintenance of connective tissue integrity and for the prevention of the oxidative damage that underlies cardiovascular disease, cancer, and the ageing process.
Practical Application
For general vitamin C supplementation, the evidence-based dose is 500-2,000mg of vitamin C daily (as ascorbic acid, the most common supplemental form). The RDA of 75-90mg daily is sufficient to prevent scurvy but is not optimal for the maintenance of the antioxidant defence system or for the support of the hydroxylase enzymes under conditions of metabolic stress. Vitamin C is generally well-tolerated with no significant adverse effects at doses up to 2,000mg daily, though doses above 2,000mg daily can produce diarrhoea, nausea, and kidney stones in susceptible individuals. For comprehensive antioxidant and connective tissue support, vitamin C pairs well with the bioflavonoids (which enhance the absorption and the antioxidant activity of vitamin C — the Citrus fruits and the berries that are the best dietary sources of vitamin C are also the best sources of the bioflavonoids that synergise with vitamin C), with zinc (which is required for collagen synthesis and for the function of the immune system), with the omega-3 fatty acids (which have anti-inflammatory effects and which support the integrity of the skin and of the blood vessel wall), and with the Mediterranean dietary pattern (which is associated with higher vitamin C intake and with better cardiovascular outcomes).
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