4hydroxyproline

4-hydroxyproline, commonly called hydroxyproline (Hyp), is a non-proteinogenic amino acid formed by post-translational hydroxylation of proline residues in collagen and other extracellular matrix proteins. In vertebrates, it occurs primarily as the L-enantiomer and is most abundant in collagen, where hydroxyproline residues constitute a significant fraction of the amino acid content. Biosynthesis of Hyp is mediated by prolyl-4-hydroxylase, a non-heme iron(II) enzyme that converts proline to 4-hydroxyproline in the presence of molecular oxygen and ascorbate, within the endoplasmic reticulum during collagen synthesis. The natural product is trans-4-hydroxy-L-proline.

The hydroxy group is at the C4 (gamma) position of the pyrrolidine ring, giving Hyp its distinctive stereochemistry and hydrogen-bonding capacity. In collagen, Hyp stabilizes the triple helix by promoting a network of hydrogen bonds with water and neighboring residues, thereby increasing thermal stability and proper folding. Hyp accounts for roughly 4–5% of collagen’s amino acid residues, and its presence is a hallmark of vertebrate extracellular matrix proteins. Because hydroxyproline is relatively unique to collagen, measurement of tissue hydroxyproline content is a common biochemical marker for collagen content and turnover.

Beyond biology, Hyp serves as a useful chiral building block in organic synthesis and pharmaceutical chemistry, and smaller amounts occur in certain bacterial and plant proteins. The natural, predominant form is L-4-hydroxyproline; other enantiomers are less common.