Editing Hydroxyproline

{{chembox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 451998292
| ImageFile = (2S,4R)-4-Hydroxyprolin.svg
| ImageSize = 
| IUPACName = (2''S'',4''R'')-4-Hydroxypyrrolidine-2-carboxylic acid
| OtherNames = 
|Section1={{Chembox Identifiers
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = RMB44WO89X
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 51-35-4
|  PubChem = 5810
|  ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 5605
|  SMILES = C1[C@H](CN[C@@H]1C(=O)O)O
|  InChI = 1/C5H9NO3/c7-3-1-4(5(8)9)6-2-3/h3-4,6-7H,1-2H2,(H,8,9)/t3-,4+/m1/s1
|  InChIKey = PMMYEEVYMWASQN-DMTCNVIQBF
|  StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C5H9NO3/c7-3-1-4(5(8)9)6-2-3/h3-4,6-7H,1-2H2,(H,8,9)/t3-,4+/m1/s1
|  StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = PMMYEEVYMWASQN-DMTCNVIQSA-N
| MeSHName = Hydroxyproline
  }}
|Section2={{Chembox Properties
| C=5|H=9|N=1|O=3
| Appearance = 
| Density = 
| MeltingPt = 
| BoilingPt = 
  }}
|Section3={{Chembox Hazards
| MainHazards = 
| FlashPt = 
| AutoignitionPt = 
  }}
}}

'''(2''S'',4''R'')-4-Hydroxyproline''', or <small>L</small>-hydroxyproline ([[Carbon|C]]<sub>5</sub>[[Hydrogen|H]]<sub>9</sub>[[Oxygen|O]]<sub>3</sub>[[Nitrogen|N]]), is an [[amino acid]], abbreviated as '''Hyp''' or '''O''', ''e.g.'', in [[Protein Data Bank]].

==Structure and discovery==
In 1902, [[Hermann Emil Fischer]] isolated hydroxyproline from hydrolyzed [[gelatin]]. In 1905, [[Hermann Leuchs]] synthesized a racemic mixture of 4-hydroxyproline.<ref>{{cite book |author= [[R. H. A. Plimmer]] |editor1=R. H. A. Plimmer |editor2=[[F. G. Hopkins]] |title= The chemical composition of the proteins |url= https://books.google.com/books?id=7JM8AAAAIAAJ&pg=PA132 |access-date= January 18, 2010 |edition= 2nd |series= Monographs on biochemistry |volume= Part I. Analysis |orig-year= 1908 |year= 1912 |publisher= Longmans, Green and Co. |location= London|page= 132}}</ref>

Hydroxyproline differs from [[proline]] by the presence of a hydroxyl (OH) group attached to the gamma carbon atom.

[[File:Betain-Hydroxyprolin.png|thumb|right|360px|Zwitterionic structure of (2''S'',4''R'')-4-hydroxyproline (left) and (2''R'',4''S'')-4-hydroxyproline (right)]]

==Production and function==
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 (anatomy)|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.<ref name=gorres>{{cite journal |last1= Gorres |first1= Kelly L. |last2= Raines |first2= Ronald T. |date=April 2010 |title= Prolyl 4-hydroxylase |journal= Critical Reviews in Biochemistry and Molecular Biology |volume= 45 |issue= 2 |pages= 106–124 |pmc= 2841224 |doi= 10.3109/10409231003627991 |pmid= 20199358 }}</ref>

=== Animals ===

==== Collagen ====
Hydroxyproline is a major component of the [[protein]] [[collagen]],<ref name="SzpakJAS">{{Cite journal |last=Szpak |first=Paul |title=Fish bone chemistry and ultrastructure: implications for taphonomy and stable isotope analysis | url=https://www.academia.edu/801925 |journal=[[Journal of Archaeological Science]] |year=2011 |volume=38 |issue=12 |pages=3358–3372 |doi=10.1016/j.jas.2011.07.022 }}</ref> comprising roughly 13.5% of mammalian collagen. Hydroxyproline and proline play key roles for collagen stability.<ref name="Nelson">Nelson, D. L. and Cox, M. M. (2005) Lehninger's Principles of Biochemistry, 4th Edition, W. H. Freeman and Company, New York.</ref> They permit the sharp twisting of the collagen helix.<ref name="Brinckmann">Brinckmann, J., Notbohm, H. and Müller, P.K. (2005) Collagen, Topics in Current Chemistry 247, Springer, Berlin.</ref> 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.<ref name="Bella1994">{{cite journal | last1 = Bella | first1 = J | last2 = Eaton | first2 = M | last3 = Brodsky | first3 = B | last4 = Berman | first4 = HM | title = Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution | journal = Science | volume = 266 | issue = 5182 | pages = 75–81 | year = 1994 | pmid = 7695699 | doi=10.1126/science.7695699}}</ref> It was subsequently shown that the increase in stability is primarily through [[stereoelectronic effect]]s and that hydration of the hydroxyproline residues provides little or no additional stability.<ref name="Kotch2008">{{cite journal | doi = 10.1021/ja800225k | last1 = Kotch | first1 = F.W. | last2 = Guzei | first2 = I.A. | last3 = Raines | first3 = R.T. | year = 2008 | title = Stabilization of the Collagen Triple Helix by O-Methylation of Hydroxyproline Residues | journal = Journal of the American Chemical Society | volume = 130 | issue = 10| pages = 2952–2953 | pmid = 18271593 | pmc = 2802593 }}</ref>

==== 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|argonaute 2]] have collagen-like domains in which hydroxyproline is formed. Some snail poisons, [[conotoxin]]s, contain hydroxyproline, but lack collagen-like sequences.<ref name="gorres" />

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]][https://www.ncbi.nlm.nih.gov/gene/54583] 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.<ref name="Jaakkola">{{cite journal | doi = 10.1126/science.1059796 | last1 = Jaakkola | first1 = P. | last2 = Mole | first2 = D.R. | last3 = Tian | first3 = Y.M. | last4 = Wilson | first4 = M.I. | last5 = Gielbert | first5 = J. | last6 = Gaskell | first6 = S.J. | last7 = Kriegsheim | first7 = A.V. | last8 = Hebestreit | first8 = H.F. | last9 = Mukherji | first9 = M. | last10 = Schofield | first10 = C. J. | last11 = Maxwell | first11 = P. H. | last12 = Pugh | first12 = C. W. | last13 = Ratcliffe | first13 = P. J. | year = 2001 | title = Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation | journal = Science | volume = 292 | issue = 5516| pages = 468–72 | pmid = 11292861 | bibcode = 2001Sci...292..468J | s2cid = 20914281 | display-authors = 8 | doi-access = free }}</ref>

=== Plants ===
Hydroxyproline rich [[glycoprotein]]s (HRGPs) are also found in [[plant cell walls]].<ref name=":0">{{cite journal | doi = 10.1146/annurev.arplant.49.1.281| pmid = 15012236| title = Plant Cell Wall Proteins| journal = Annual Review of Plant Physiology and Plant Molecular Biology| volume = 49| pages = 281–309| year = 1998| last1 = Cassab| first1 = Gladys I}}</ref> These hydroxyprolines serve as the attachment points for [[Glycan|glycan chains]] which are added as [[Post-translational modification|post-translational modifications]].<ref name=":0" />

==Clinical significance==
[[Proline]] hydroxylation requires [[ascorbic acid]] ([[vitamin C]]). 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 [[chemical stability|stability]] of the collagen molecule, causing [[scurvy]].

Increased serum and urine levels of hydroxyproline have also been demonstrated in [[Paget's disease of bone|Paget's disease]].<ref>{{cite web|url=http://www.wheelessonline.com/ortho/pagets_disease|title=Wheeless' Textbook of Orthopaedics|website=Wheeless Online|date=22 July 2020}}</ref>

[[Mass spectrometry]] analysis showed decreased amount of hydroxyproline [[post-translational modifications]] in non inflamed tissue from [[ulcerative colitis]] patients when compared to tissue from donors without the disease. <ref>{{cite web|url=https://pubs.rsc.org/en/content/articlelanding/2019/mo/c8mo00239h|title=Degradation of the extracellular matrix is part of the pathology of ulcerative colitis}}</ref>

==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 wall]]s<ref name="Nakajima">{{cite journal | doi = 10.1126/science.164.3886.1400 | last1 = Nakajima | first1 = T. | last2 = Volcani | first2 = B.E. | year = 1969 | title = 3,4-Dihydroxyproline: a new amino acid in diatom cell walls | journal = Science | volume = 164 | issue = 3886| pages = 1400–1401 | pmid = 5783709 | bibcode = 1969Sci...164.1400N | s2cid = 23673503 }}</ref> and are postulated to have a role in [[silica]] deposition.  Hydroxyproline is also found in the walls of [[oomycete]]s, fungus-like protists related to diatoms.<ref name="Alexopoulos 1996">{{Cite book | author = Alexopoulos, C.J., Mims C.W. and Blackwell, M. | year = 1996 | title = Introductory Mycology | edition = 4th | pages = 687–688 | location = New York | publisher = John Wiley & Sons | isbn = 978-0-471-52229-4}}</ref> (2''S'',4''S'')-''cis''-4-Hydroxyproline is found in the toxic [[cyclic peptide]]s from ''[[Amanita]]'' mushrooms (''e.g.'', [[phalloidin]]).<ref>{{cite book | author = Wieland, T. | title = Peptides of Poisonous Amanita Mushrooms | publisher = Springer | year = 1986}}</ref>

==See also==
* [[Secondary amino acid]]
* [[Imino acid]]
* [[Hydroxylysine]]

== References ==
{{reflist}}

== External links ==
* [https://simtk.org/home/hydroxyproline Molecular mechanics parameters]

[[Category:Alpha-Amino acids]]
[[Category:Cyclic amino acids]]
[[Category:Pyrrolidines]]
[[Category:Gamma hydroxy acids]]
[[Category:Non-proteinogenic amino acids]]
[[Category:Secondary amino acids]]
[[Category:Substances discovered in the 1900s]]

{{Non-proteinogenic amino acids}}