Vitamin C and collagen hydroxylation in scurvy
Hydroxylation (adding OH groups) of proline and lysine, amino acids in the collagen chain, stabilises the triple helix (a rope-like coil of the collagen chains) and needs vitamin C.
Remember
Without vitamin C, proline and lysine in collagen are poorly hydroxylated, so the helix is unstable and the collagen weak: that is scurvy, the disease of vitamin C deficiency.
Memory aid
Hydroxylation is the step that tightens the rope, and without vitamin C the rope is loosely wound.
Picture the triple helix as a rope: the OH groups tighten it, and without vitamin C it stays loosely wound.
Collagen supports skin, gums, blood vessel walls and joints. Fibroblasts, the connective tissue cells that make it, build each chain on a ribosome and feed it into the lumen (the space inside) of the endoplasmic reticulum.
There, enzymes called prolyl hydroxylase and lysyl hydroxylase add hydroxyl (OH) groups to proline and lysine residues, which are single amino acids within the chain. The change is called hydroxylation, and it makes hydroxyproline and hydroxylysine, which are the proline and lysine residues once they carry the OH group. The extra OH groups allow more hydrogen bonding between the three chains. That stabilises the triple helix, the right-handed, rope-like coil that gives collagen its tensile strength (resistance to being pulled apart).
Both enzymes need vitamin C as a cofactor, a helper molecule that keeps the iron in their active site in its working form. Without it, hydroxylation is poor, the helix is unstable and the collagen is weak. That is scurvy, the disease of vitamin C deficiency. A diet without fruit and vegetables is the usual cause.
In scurvy, capillaries (the smallest blood vessels) are fragile and leak, which gives the bruising and bleeding gums, and wounds heal poorly. The chains are still made but badly modified, so the defect lies in how the protein is modified, not in how the gene is read.
The other steps inside the cell, such as removal of the signal peptide (a short leading sequence that sends a new protein into the endoplasmic reticulum), glycosylation (attaching sugar units) and formation of disulphide bonds (links between sulphur atoms), do not need vitamin C. Outside the cell, lysyl oxidase later links neighbouring collagen molecules together, and it depends on copper, not vitamin C.
Key facts
- Where
- proline and lysine are hydroxylated in the lumen of the endoplasmic reticulum, before the helix forms.
- Enzymes
- prolyl hydroxylase and lysyl hydroxylase add the OH groups.
- Effect
- the OH groups add hydrogen bonding between the three chains, which stabilises the triple helix.
- Cofactors
- both enzymes need vitamin C and iron.
- Scurvy
- features include bleeding gums, easy bruising and slow wound healing, after long-term dietary lack of vitamin C.
- Treatment
- oral vitamin C, with improvement within days.
Exam traps
- Cross-linking by lysyl oxidase (linking neighbouring collagen molecules together) is not the step that fails in scurvy, because it happens outside the cell and depends on copper rather than vitamin C.
- Glycosylation (attaching sugar units) of hydroxylysine is a genuine step, but it is not the main stabiliser of the helix: sugar units modify the surface of the chains and do not add the extra hydrogen bonding, and hydroxylation comes first and makes the hydroxylysine sites the sugars attach to.
- Transcription of collagen genes is not what fails in scurvy, because vitamin C does not control it, and the chains are still made but under-hydroxylated.
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