(2''S'',4''R'')-4-Hydroxyproline, or L-hydroxyproline ( C₅ H₉ O₃ N), is an

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...

, abbreviated as Hyp or O, ''e.g.'', in

Protein Data Bank The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids. The data, typically obtained by X-ray crystallography, NMR spectroscopy, or, increasingly, ...

Structure and discovery

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. Betain-Hydroxyprolin

Production and function

Hydroxyproline is produced by hydroxylation of the amino acid proline by the enzyme

prolyl hydroxylase Procollagen-proline dioxygenase, commonly known as prolyl hydroxylase, is a member of the class of enzymes known as alpha-ketoglutarate-dependent hydroxylases. These enzymes catalyze the incorporation of oxygen into organic substrates through a mec ...

following protein synthesis (as a

post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribos ...

). 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.

Animals

Collagen

Hydroxyproline is a major component of the

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...

collagen, comprising roughly 13.5% of mammalian collagen. Hydroxyproline and proline play key roles for collagen stability.Nelson, D. L. and Cox, M. M. (2005) Lehninger's Principles of Biochemistry, 4th Edition, W. H. Freeman and Company, New York. They permit the sharp twisting of the collagen helix.Brinckmann, J., Notbohm, H. and Müller, P.K. (2005) Collagen, Topics in Current Chemistry 247, Springer, Berlin. 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 In the fields of geometry and biochemistry, a triple helix (plural triple helices) is a set of three congruent geometrical helices with the same axis, differing by a translation along the axis. This means that each of the helices keeps the same ...

. 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 effect In chemistry, primarily organic and computational chemistry, a stereoelectronic effectAlabugin, I. V. Stereoelectronic Effects: the Bridge between Structure and Reactivity. John Wiley & Sons Ltd, Chichester, UK, 2016. http://eu.wiley.com/WileyCDA/W ...

s and that hydration of the hydroxyproline residues provides little or no additional stability.

Non-collagen

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. However, the mammalian proteins elastin and argonaute 2 have collagen-like domains in which hydroxyproline is formed. Some snail poisons,

conotoxin A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus ''Conus''. Conotoxins, which are peptides consisting of 10 to 30 amino acid residues, typically have one or more disulfide bonds. Cono ...

s, 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 Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fou ...

by the von Hippel-Lindau tumor suppressor (pVHL) and subsequent targeting for proteasome degradation.

Plants

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.

Clinical significance

Proline hydroxylation requires ascorbic acid (

vitamin C Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits and vegetables, also sold as a dietary supplement and as a topical 'serum' ingredient to treat melasma (dark pigment spots) ...

). The most obvious, first effects (gingival and hair problems) of absence of ascorbic acid in humans come from the resulting defect in hydroxylation of proline residues of collagen, with reduced

stability Stability may refer to: Mathematics *Stability theory, the study of the stability of solutions to differential equations and dynamical systems ** Asymptotic stability ** Linear stability ** Lyapunov stability ** Orbital stability ** Structural sta ...

of the collagen molecule, causing scurvy. Increased serum and urine levels of hydroxyproline have also been demonstrated in Paget's disease.

Other hydroxyprolines

Other hydroxyprolines also exist in nature. The most notable ones are 2,3-''cis''-, 3,4-''trans''-, and 3,4-dihydroxyproline, which occurs in diatom cell walls and are postulated to have a role in

silica Silicon dioxide, also known as silica, is an oxide of silicon with the chemical formula , most commonly found in nature as quartz and in various living organisms. In many parts of the world, silica is the major constituent of sand. Silica is ...

deposition. Hydroxyproline is also found in the walls of

oomycete Oomycota forms a distinct phylogenetic lineage of fungus-like eukaryotic microorganisms, called oomycetes (). They are filamentous and heterotrophic, and can reproduce both sexually and asexually. Sexual reproduction of an oospore is the resul ...

s, fungus-like protists related to diatoms. (2''S'',4''S'')-''cis''-4-Hydroxyproline is found in the toxic cyclic peptides from ''

Amanita The genus ''Amanita'' contains about 600 species of agarics, including some of the most toxic known mushrooms found worldwide, as well as some well-regarded edible species. This genus is responsible for approximately 95% of the fatalities resul ...

'' mushrooms (''e.g.'',

phalloidin Phalloidin belongs to a class of toxins called phallotoxins, which are found in the death cap mushroom ''(Amanita phalloides)''. It is a rigid bicyclic heptapeptide that is lethal after a few days when injected into the bloodstream. The major sy ...

References

External links

Molecular mechanics parameters
Cyclic amino acids Pyrrolidines Hydroxy acids Non-proteinogenic amino acids Secondary amino acids Substances discovered in the 1900s {{Non-proteinogenic amino acids