(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 am ...

, 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, cry ...

Structure and discovery

In 1902,

Hermann Emil Fischer Hermann Emil Louis Fischer (; 9 October 1852 – 15 July 1919) was a German chemist and 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He also developed the Fischer projection, a symbolic way of dra ...

isolated hydroxyproline from hydrolyzed

gelatin Gelatin or gelatine (from la, gelatus meaning "stiff" or "frozen") is a translucent, colorless, flavorless food ingredient, commonly derived from collagen taken from animal body parts. It is brittle when dry and rubbery when moist. It may also ...

. In 1905, Hermann Leuchs synthesized a racemic mixture of 4-hydroxyproline. Hydroxyproline differs from

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...

by the presence of a hydroxyl (OH) group attached to the gamma carbon atom. Betain-Hydroxyprolin

Production and function

Hydroxyproline is produced by

hydroxylation In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...

of the amino acid

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 ribosome ...

). The enzyme catalyzed reaction takes place in the lumen of the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough 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, respo ...

collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...

, 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

and/or

amount. However, the mammalian proteins

elastin Elastin is a protein that in humans is encoded by the ''ELN'' gene. Elastin is a key component of the extracellular matrix in gnathostomes (jawed vertebrates). It is highly elastic and present in connective tissue allowing many tissues in the bod ...

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 Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They are only present in parahoxozoan animals. Discovery The HIF transcriptional complex w ...

(HIF) alpha subunit (HIF-1 alpha) for degradation by

proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...

. 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 The term ''von'' () is used in German language surnames either as a nobiliary particle indicating a noble patrilineality, or as a simple preposition used by commoners that means ''of'' or ''from''. Nobility directories like the ''Almanach de ...

(pVHL) and subsequent targeting for

proteasome Proteasomes are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are part of a major mechanism by w ...

degradation.

Plants

Hydroxyproline rich

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...

s (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 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 ribosomes ...

Clinical significance

Proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...

hydroxylation requires

ascorbic acid 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) an ...

(

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) an ...

). The most obvious, first effects (gingival and hair problems) of absence of

in humans come from the resulting defect in

residues of

, 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 Scurvy is a disease resulting from a lack of vitamin C (ascorbic acid). Early symptoms of deficiency include weakness, feeling tired and sore arms and legs. Without treatment, decreased red blood cells, gum disease, changes to hair, and bleeding ...

. 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 A diatom (Neo-Latin ''diatoma''), "a cutting through, a severance", from el, διάτομος, diátomos, "cut in half, divided equally" from el, διατέμνω, diatémno, "to cut in twain". is any member of a large group comprising sev ...

cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mech ...

s 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 one ...

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 result ...

'' 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