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| {{Chembox
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| | Verifiedfields = changed
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| | verifiedrevid = 464215484
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| | ImageFileL1 = Prolin - Proline.svg
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| | ImageFileL1_Ref = {{Chemboximage|correct|??}}
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| | ImageSizeL1 = 121
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| | ImageNameL1 = Structural formula of proline
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| | ImageFileR1 = L-proline-3D-balls.png
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| | ImageFileR1_Ref = {{Chemboximage|correct|??}}
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| | ImageSizeR1 = 121
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| | ImageNameR1 = Ball and stick model of (S)-proline
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| | IUPACName = Proline
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| | SystematicName = Pyrrolidine-2-carboxylic acid<ref>http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=614&loc=ec_rcs</ref>
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| | Section1 = {{Chembox Identifiers
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| | CASNo = 609-36-9
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| | CASNo_Ref = {{cascite|correct|CAS}}
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| | CASNo1 = 344-25-2
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| | CASNo1_Ref = {{cascite|correct|CAS}}
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| | CASNo1_Comment = (''R'')
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| | CASNo2 = 147-85-3
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| | CASNo2_Ref = {{cascite|correct|CAS}}
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| | CASNo2_Comment = (''S'')
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| | PubChem = 614
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| | PubChem_Ref = {{Pubchemcite|correct|PubChem}}
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| | PubChem1 = 8988
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| | PubChem1_Ref = {{Pubchemcite|correct|PubChem}}
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| | PubChem1_Comment = (''R'')
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| | PubChem2 = 145742
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| | PubChem2_Ref = {{Pubchemcite|correct|PubChem}}
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| | PubChem2_Comment = (''S'')
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| | ChemSpiderID = 594
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| | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
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| | ChemSpiderID1 = 8640
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| | ChemSpiderID1_Ref = {{chemspidercite|correct|chemspider}}
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| | ChemSpiderID1_Comment = (''R'')
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| | ChemSpiderID2 = 128566
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| | ChemSpiderID2_Ref = {{chemspidercite|correct|chemspider}}
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| | ChemSpiderID2_Comment = (''S'')
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| | UNII = DCS9E77JPQ
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| | UNII_Ref = {{fdacite|correct|FDA}}
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| | EINECS = 210-189-3
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| | DrugBank_Ref = {{drugbankcite|changed|drugbank}}
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| | DrugBank = DB02853
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| | KEGG = C16435
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| | KEGG_Ref = {{keggcite|correct|kegg}}
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| | MeSHName = Proline
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| | ChEBI_Ref = {{ebicite|correct|EBI}}
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| | ChEBI = 26271
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| | ChEMBL = 72275
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| | ChEMBL_Ref = {{ebicite|correct|EBI}}
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| | RTECS = TW3584000
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| | Beilstein = 80812
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| | Gmelin = 26927
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| | SMILES = OC(=O)C1CCCN1
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| | SMILES1 = C1CC(NC1)C(=O)O
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| | StdInChI = 1S/C5H9NO2/c7-5(8)4-2-1-3-6-4/h4,6H,1-3H2,(H,7,8)
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| | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
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| | InChI = 1/C5H9NO2/c7-5(8)4-2-1-3-6-4/h4,6H,1-3H2,(H,7,8)
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| | StdInChIKey = ONIBWKKTOPOVIA-UHFFFAOYSA-N
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| | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
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| }}
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| | Section2 = {{Chembox Properties
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| | C = 5
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| | H = 9
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| | N = 1
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| | O = 2
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| | ExactMass = 115.063328537 g mol<sup>−1</sup>
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| | Appearance = Transparent crystals
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| | MeltingPtCL = 205
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| | MeltingPtCH = 228
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| | Melting_notes = decomposes
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| | LogP = -0.06
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| | pKa=1.99 (carboxyl), 10.96 (amino)<ref>Nelson, D.L., Cox, M.M., Principles of Biochemistry. NY: W.H. Freeman and Company.</ref>
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| | SolubleOther = 1.5g/100g ethanol 19 degC<ref>http://books.google.ch/books?id=xteiARU46SQC&pg=PA15&lpg=PA15&dq=methionine+solubility+in+ethanol&source=bl&ots=HzHueOPPoB&sig=KjMXxDNgjSvG1CddED9lfaYEhKQ&hl=en&sa=X&ei=2-26T-bZK-mX0QWt3I2ACA&redir_esc=y#v=onepage&q=methionine%20solubility%20in%20ethanol&f=false</ref>
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| }}
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| | Section3 = {{Chembox Hazards
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| | SPhrases = {{S22}}, {{S24/25}}
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| }}
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| }}
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| '''Proline''' (abbreviated as '''Pro''' or '''P''') is an α-[[amino acid]], one of the twenty [[DNA]]-encoded amino acids. Its [[codon]]s are CCU, CCC, CCA, and CCG. It is not an [[essential amino acid]], which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the amine nitrogen is bound to not one but two alkyl groups, thus making it a [[secondary amine]]. The more common <small>L</small> form has ''S'' stereochemistry.
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| == Biosynthesis ==
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| Proline is [[Biosynthesis|biosynthetically]] derived from the amino acid <small>L</small>-[[glutamate]] and its immediate precursor is the [[imino acid]] [[1-Pyrroline-5-carboxylic acid|(''S'')-1-pyrroline-5-carboxylate]] (P5C). Enzymes involved in a typical biosynthesis include:<ref>{{Lehninger3rd}}.</ref>
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| # [[Glutamate 5-kinase]], [[Glutamate 1-kinase]] (ATP-dependent)
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| # [[Glutamate dehydrogenase]] (requires NADH or NADPH)
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| # [[Pyrroline-5-carboxylate reductase]] (requires NADH or NADPH)
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| [[File:Betain-Proline.png|thumb|left|260px|[[Zwitterion]]ic structure of both proline enantiomers: (''S'')-proline (left) and (''R'')-proline]]
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| ==Properties in protein structure==
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| The distinctive cyclic structure of proline's side chain gives proline an exceptional conformational rigidity compared to other amino acids. It also affects the rate of peptide bond formation between proline and other amino acids. When proline is bound as an amide in a peptide bond, its nitrogen is not bound to any hydrogen, meaning it cannot act as a [[hydrogen bond]] donor, but can be a hydrogen bond acceptor.
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| Peptide bond formation with incoming Pro-tRNA<sup>Pro</sup> is considerably slower than with any other tRNAs, which is a general feature of N-alkylamino acids.<ref>{{citation | first1 = Michael Y | last1 = Pavlov | first2 = Richard E | last2 = Watts | first3 = Zhongping | last3 = Tan | first4 = Virginia W | last4 = Cornish | first5 = Måns | last5 = Ehrenberg | first6 = Anthony C | title = Slow peptide bond formation by proline and other N-alkylamino acids in translation | year = 2010 | journal = PNAS | volume = 106 | issue = 1 | pages = 50–54 | doi = 10.1073/pnas.0809211106 | pmid = 19104062 | last6 = Forster | pmc = 2629218}}.</ref> Peptide bond formation is also slow between an incoming tRNA and a chain ending in proline; with the creation of proline-proline bonds slowest of all.<ref>{{Cite journal |last=Buskirk |first=Allen R. |last2=Green |first2=Rachel |title=Getting Past Polyproline Pauses | url=http://uwo.academia.edu/PaulSzpak/Papers/827788/Fish_Bone_Chemistry_and_Ultrastructure_Implications_for_Taphonomy_and_Stable_Isotope_Analysis |journal=[[Science]] |year=2013 |volume=339 |issue=6115 |pages=38–39}}</ref>
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| The exceptional conformational rigidity of proline affects the [[secondary structure]] of proteins near a proline residue and may account for proline's higher prevalence in the proteins of [[thermophile|thermophilic]] organisms. [[Protein secondary structure]] can be described in terms of the [[dihedral angle|dihedral angles]] [[Dihedral_angle#Dihedral angles of biological molecules|φ, ψ and ω]] of the protein backbone. The cyclic structure of proline's side chain locks the angle φ at approximately −60°.
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| Proline acts as a structural disruptor in the middle of regular [[secondary structure]] elements such as [[alpha helix|alpha helices]] and [[beta sheet]]s; however, proline is commonly found as the first residue of an [[alpha helix]] and also in the edge strands of [[beta sheet]]s. Proline is also commonly found in [[turn (biochemistry)|turns]] (another kind of secondary structure), and aids in the formation of beta turns. This may account for the curious fact that proline is usually solvent-exposed, despite having a completely [[aliphatic]] side chain.
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| Multiple prolines and/or [[hydroxyproline]]s in a row can create a [[polyproline helix]], the predominant [[secondary structure]] in [[collagen]]. The [[hydroxylation]] of proline by [[prolyl hydroxylase]] (or other additions of electron-withdrawing substituents such as [[fluorine]]) increases the conformational stability of [[collagen]] significantly.<ref name="SzpakJAS">{{Cite journal |last=Szpak |first=Paul |title=Fish bone chemistry and ultrastructure: implications for taphonomy and stable isotope analysis | url=http://uwo.academia.edu/PaulSzpak/Papers/827788/Fish_Bone_Chemistry_and_Ultrastructure_Implications_for_Taphonomy_and_Stable_Isotope_Analysis |journal=[[Journal of Archaeological Science (journal)|Journal of Archaeological Science]] |year=2011 |volume=38 |issue=12 |pages=3358–3372 |doi=10.1016/j.jas.2011.07.022 }}</ref> Hence, the hydroxylation of proline is a critical biochemical process for maintaining the [[connective tissue]] of higher organisms. Severe diseases such as [[scurvy]] can result from defects in this hydroxylation, e.g., mutations in the enzyme prolyl hydroxylase or lack of the necessary [[vitamin C|ascorbate (vitamin C)]] cofactor.
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| Sequences of proline and [[2-Aminoisobutyric acid|2-aminoisobutyric acid]] (Aib) also form a helical turn structure.{{Citation needed|date=February 2007}}
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| ==Cis-trans isomerization==
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| [[Peptide bond]]s to proline, and to other ''N''-substituted amino acids (such as [[sarcosine]]), are able to populate both the ''[[Cis-trans isomerism|cis]]'' and ''[[trans isomer|trans]]'' isomers. Most peptide bonds overwhelmingly adopt the ''trans'' isomer (typically 99.9% under unstrained conditions), chiefly because the amide hydrogen (''trans'' isomer) offers less steric repulsion to the preceding <math>\mathrm{C}^{\alpha}</math> atom than does the following <math>\mathrm{C}^{\alpha}</math> atom (''cis'' isomer). By contrast, the ''cis'' and ''trans'' isomers of the X-Pro peptide bond (where X represents any amino acid) both experience steric clashes with the neighboring substitution and are nearly equal energetically. Hence, the fraction of X-Pro peptide bonds in the ''cis'' isomer under unstrained conditions ranges from 10-40%; the fraction depends slightly on the preceding amino acid, with aromatic residues favoring the ''cis'' isomer slightly.
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| From a kinetic standpoint, ''cis''-''trans'' proline [[isomer]]ization is a very slow process that can impede the progress of [[protein folding]] by trapping one or more proline residues crucial for folding in the non-native isomer, especially when the native protein requires the ''cis'' isomer. This is because proline residues are exclusively synthesized in the [[ribosome]] as the ''trans'' isomer form. All organisms possess [[prolyl isomerase]] [[enzyme]]s to catalyze this isomerization, and some [[bacteria]] have specialized prolyl isomerases associated with the ribosome. However, not all prolines are essential for folding, and protein folding may proceed at a normal rate despite having non-native conformers of many X-Pro peptide bonds.
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| ==Uses==
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| Proline and its derivatives are often used as asymmetric catalysts in organic reactions. The [[CBS reduction]] and proline catalysed [[aldol condensation]] are prominent examples.
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| <small>L</small>-Proline is an [[osmoprotectant]] and therefore is used in many pharmaceutical, biotechnological applications.
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| In brewing, proteins rich in proline combine with polyphenols to produce haze (turbidity).<ref>K.J. Siebert, "Haze and Foam",[http://www.nysaes.cornell.edu/fst/faculty/siebert/haze.html] Accessed July 12, 2010.</ref>
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| ==Specialties==
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| Proline is one of the two amino acids that do not follow along with the typical [[Ramachandran plot]], along with [[glycine]]. Due to the ring formation connected to the beta carbon, the ψ and φ angles about the peptide bond have fewer allowable degrees of rotation. As a result it is often found in "turns" of proteins as its free entropy (ΔS) is not as comparatively large to other amino acids and thus in a folded form vs. unfolded form, the change in entropy is less. Furthermore, proline is rarely found in α and β structures as it would reduce the stability of such structures, because its side chain α-N can only form one hydrogen bond.
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| Additionally, proline is the only amino acid that does not form a blue/purple colour when developed by spraying with [[ninhydrin]] for uses in [[chromatography]]. Proline, instead, produces an orange/yellow colour.
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| ==History==
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| [[Richard Willstätter]] synthesized proline by the reaction of sodium salt of [[diethyl malonate]] with [[1,3-dibromopropane]] in 1900. In 1901, [[Hermann Emil Fischer]] isolated proline from casein and the decomposition products of γ-phthalimido-propylmalonic ester.<ref>{{Citation |author= R.H.A. Plimmer |editor= R.H.A. Plimmer & F.G. Hopkins |title= The chemical composition of the proteins |url= http://books.google.com/?id=7JM8AAAAIAAJ&pg=PA130 |accessdate= September 20, 2010 |edition= 2nd |series= Monographs on biochemistry |volume= Part I. Analysis |origyear= 1908 |year= 1912 |publisher= Longmans, Green and Co. |location= London|page= 130}}</ref>
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| ==See also==
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| * [[Hyperprolinemia]]
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| * [[Inborn error of metabolism]]
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| * [[Prolidase deficiency]]
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| * [[Prolinol]]
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| ==Synthesis==
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| [[Racemic]] proline can be synthesized from [[diethyl malonate]] and [[acrylonitrile]]:<ref>Vogel, ''Practical Organic Chemistry'' 5th edition</ref>
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| :[[File:DL-Proline synth.png|500px]]{{clear-left}}
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| ==References==
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| {{reflist}}
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| == Further reading ==
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| * {{citation | last1 = Balbach | first1 = J. | last2 = Schmid | first2 = F. X. | year = 2000 | contribution = Proline isomerization and its catalysis in protein folding | title = Mechanisms of Protein Folding | edition = 2nd | editor-first = R. H. | editor-last = Pain | publisher = Oxford University Press | pages = 212–49 | isbn = 0-19-963788-1}}.
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| * For a thorough scientific overview of disorders of proline and hydroxyproline metabolism, one can consult chapter 81 of OMMBID [[Charles Scriver]], Beaudet, A.L., Valle, D., Sly, W.S., Vogelstein, B., Childs, B., Kinzler, K.W. (Accessed 2007). [http://www.ommbid.com The Online Metabolic and Molecular Bases of Inherited Disease]. New York: McGraw-Hill. - Summaries of 255 chapters, full text through many universities. There is also the [http://books.mcgraw-hill.com/medical/ommbid/blog/ OMMBID blog].
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| == External links ==
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| * [http://www.chem.qmul.ac.uk/iubmb/enzyme/reaction/AminoAcid/Pro.html Proline biosynthesis]
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| * [http://www.biocarta.com/pathfiles/prolinePathway.asp Proline biosynthesis]
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| {{Amino acids}}
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| {{Amino acid metabolism intermediates}}
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| [[Category:Proteinogenic amino acids]]
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| [[Category:Glucogenic amino acids]]
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| [[Category:Cyclic amino acids]]
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| [[Category:Pyrrolidines]]
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