Hydroxyproline

(2S,4R)-4-Hydroxyproline, or L-hydroxyproline (C5H9O3N), is a common non-proteinogenic amino acid, abbreviated as Hyp, e.g., in Protein Data Bank. (2S,4R)-4-Hydroxyproline, or L-hydroxyproline (C5H9O3N), is a common non-proteinogenic amino acid, abbreviated as Hyp, e.g., in Protein Data Bank. In 1902, Hermann Emil Fischer isolated hydroxyproline from hydrolyzed gelatin. In 1905, Hermann Leuchs synthesized a racemic mixture of 4-hydroxyproline. Hydroxyproline differs from proline by the presence of a hydroxyl (OH) group attached to the gamma carbon atom. Hydroxyproline is produced by hydroxylation of the amino acid proline by the enzyme prolyl hydroxylase following protein synthesis (as a post-translational modification). The enzyme catalyzed reaction takes place in the lumen of the endoplasmic reticulum. Although it is not directly incorporated into proteins, hydroxyproline comprises roughly 4% of all amino acids found in animal tissue, an amount greater than seven other amino acids that are translationally incorporated. Hydroxyproline is a major component of the protein collagen, comprising roughly 13.5% of mammalian collagen. Hydroxyproline and proline play key roles for collagen stability. They permit the sharp twisting of the collagen helix. In the canonical collagen Xaa-Yaa-Gly triad (where Xaa and Yaa are any amino acid), a proline occupying the Yaa position is hydroxylated to give a Xaa-Hyp-Gly sequence. This modification of the proline residue increases the stability of the collagen triple helix. It was initially proposed that the stabilization was due to water molecules forming a hydrogen bonding network linking the prolyl hydroxyl groups and the main-chain carbonyl groups. It was subsequently shown that the increase in stability is primarily through stereoelectronic effects and that hydration of the hydroxyproline residues provides little or no additional stability. In addition to collagen, the mammalian proteins elastin and argonaute 2 have collagen-like domains in which hydroxyproline is formed. Some snail poisons, conotoxins, contain hydroxyproline, but lack collagen-like sequences. Hydroxylation of proline has been shown to be involved in targeting Hypoxia-inducible factor (HIF) alpha subunit (HIF-1 alpha) for degradation by proteolysis. Under normoxia (normal oxygen conditions) EGLN1 protein hydroxylates the proline at the 564 position of HIF-1 alpha, which allows ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) and subsequent targeting for proteasome degradation. Hydroxyproline is found in few proteins other than collagen. For this reason, hydroxyproline content has been used as an indicator to determine collagen and/or gelatin amount. Hydroxyproline rich glycoproteins (HRGPs) are also found in plant cell walls. These hydroxyprolines serve as the attachment points for glycan chains which are added as post-translational modifications.