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Proline

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For other uses, see Proline (disambiguation).
Proline
Physiological model of proline
Structural formula of proline
Names
IUPAC name
Proline
Systematic IUPAC name
Pyrrolidine-2-carboxylic acid[1]
Identifiers
3D model (JSmol)
80812
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.009.264 Edit this at Wikidata
EC Number
  • 210-189-3
26927
KEGG
MeSH Proline
RTECS number
  • TW3584000
UNII
  • InChI=1S/C5H9NO2/c7-5(8)4-2-1-3-6-4/h4,6H,1-3H2,(H,7,8) checkY
    Key: ONIBWKKTOPOVIA-UHFFFAOYSA-N checkY
  • InChI=1/C5H9NO2/c7-5(8)4-2-1-3-6-4/h4,6H,1-3H2,(H,7,8)
  • OC(=O)C1CCCN1
  • C1CC(NC1)C(=O)O
Properties
C5H9NO2
Molar mass 115.132 g·mol−1
Appearance Transparent crystals
Melting point 205 to 228 °C (401 to 442 °F; 478 to 501 K) (decomposes)
Solubility 1.5g/100g ethanol 19 degC[2]
log P -0.06
Acidity (pKa) 1.99 (carboxyl), 10.96 (amino)[3]
Supplementary data page
Proline (data page)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Proline (abbreviated as Pro or P; encoded by the codons CCU, CCC, CCA, and CCG) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated >NH2+ form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −COO− form under biological conditions), and a side chain pyrrolidine, classifying it as a nonpolar(at physiological pH), aliphatic amino acid. It is non-essential in humans, meaning the body can synthesize it from the non-essential amino acid L-glutamate.

Proline is the only amino acid with a secondary amine. Furthermore, it is unique in that the alpha-amino group is attached directly to the side chain, making the α carbon a direct substituent of the side chain.

History and etymology

Proline was first isolated in 1900 by Richard Willstätter who obtained the amino acid while studying N-methylproline. The year after Emil Fischer published the synthesis of proline from phthalimide propylmalonic ester.[4] The name proline comes from pyrrolidine, one of its constituents.[5]

Biosynthesis

Proline is biosynthetically derived from the amino acid L-glutamate. Glutamate-5-semialdehyde is first formed by glutamate 5-kinase (ATP-dependent) and glutamate-5-semialdehyde dehydrogenase (which requires NADH or NADPH). This can then either spontaneously cyclize to form 1-pyrroline-5-carboxylic acid, which is reduced to proline by pyrroline-5-carboxylate reductase (using NADH or NADPH), or turned into ornithine by ornithine aminotransferase, followed by cyclisation by ornithine cyclodeaminase to form proline.[6]

Zwitterionic structure of both proline enantiomers: (S)-proline (left) and (R)-proline

Biological activity

L-Proline has been found to act as a weak agonist of the glycine receptor and of both NMDA and non-NMDA (AMPA/kainate) ionotropic glutamate receptors.[7][8][9] It has been proposed to be a potential endogenous excitotoxin.[7][8][9] In plants, proline accumulation is a common physiological response to various stresses but is also part of the developmental program in generative tissues (e.g. pollen).[10]

Proline is a phosphorylation marker and is commonly found right before the amino acid serine and threonine to mark them as phosphorylation spots. As a result, Proline preceding these amino acids in an amino acid chain is highly evolutionarily conserved.

Properties in protein structure

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.

Peptide bond formation with incoming Pro-tRNAPro is considerably slower than with any other tRNAs, which is a general feature of N-alkylamino acids.[11] 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.[12]

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 thermophilic organisms. Protein secondary structure can be described in terms of the dihedral angles φ, ψ and ω of the protein backbone. The cyclic structure of proline's side chain locks the angle φ at approximately −65°.[13]

Proline acts as a structural disruptor in the middle of regular secondary structure elements such as alpha helices and beta sheets; however, proline is commonly found as the first residue of an alpha helix and also in the edge strands of beta sheets. Proline is also commonly found in 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.

Multiple prolines and/or hydroxyprolines 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.[14] 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 ascorbate (vitamin C) cofactor.

Cis-trans isomerization

Peptide bonds to proline, and to other N-substituted amino acids (such as sarcosine), are able to populate both the cis and 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 Cα atom than does the following Cα 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.

From a kinetic standpoint, cis-trans proline isomerization 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 enzymes 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.

Uses

Proline and its derivatives are often used as asymmetric catalysts in proline organocatalysis reactions. The CBS reduction and proline catalysed aldol condensation are prominent examples.

L-Proline is an osmoprotectant and therefore is used in many pharmaceutical, biotechnological applications.

In brewing, proteins rich in proline combine with polyphenols to produce haze (turbidity).[15]

Specialties

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.

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.

History

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.[16]

See also

Synthesis

Racemic proline can be synthesized from diethyl malonate and acrylonitrile:[17]

References

  1. ^ http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=614&loc=ec_rcs
  2. ^ H.-D. Belitz; W. Grosch; P. Schieberle. Food Chemistry. p. 15. ISBN 978-3-540-69933-0.
  3. ^ Nelson, D.L., Cox, M.M., Principles of Biochemistry. NY: W.H. Freeman and Company.
  4. ^ "Proline".
  5. ^ "proline". American Heritage Dictionary of the English Language, 4th edition. Retrieved 2015-12-06.
  6. ^ Lehninger, Albert L.; Nelson, David L.; Cox, Michael M. (2000). Principles of Biochemistry (3rd ed.). New York: W. H. Freeman. ISBN 1-57259-153-6..
  7. ^ a b Ion Channel Factsbook: Extracellular Ligand-Gated Channels. Academic Press. 16 November 1995. pp. 126–. ISBN 978-0-08-053519-7.
  8. ^ a b Henzi V, Reichling DB, Helm SW, MacDermott AB (1992). "L-proline activates glutamate and glycine receptors in cultured rat dorsal horn neurons". Mol. Pharmacol. 41 (4): 793–801. PMID 1349155.
  9. ^ a b Orhan E. Arslan (7 August 2014). Neuroanatomical Basis of Clinical Neurology, Second Edition. CRC Press. pp. 309–. ISBN 978-1-4398-4833-3.
  10. ^ Verbruggen N, Hermans C (2008). "Proline accumulation in plants: a review". Amino Acids. 35 (4): 753–759. doi:10.1007/s00726-008-0061-6. PMID 18379856.
  11. ^ Pavlov, Michael Y; Watts, Richard E; Tan, Zhongping; Cornish, Virginia W; Ehrenberg, Måns; Forster, Anthony C (2010), "Slow peptide bond formation by proline and other N-alkylamino acids in translation", PNAS, 106 (1): 50–54, doi:10.1073/pnas.0809211106, PMC 2629218, PMID 19104062.
  12. ^ Buskirk, Allen R.; Green, Rachel (2013). "Getting Past Polyproline Pauses". Science. 339 (6115): 38–39. doi:10.1126/science.1233338.
  13. ^ Morris, Anne (1992). "Stereochemical quality of protein structure coordinates". Proteins: Structure, Function, and Bioinformatics. 12: 345–364. PMID 1579569. {{cite journal}}: |access-date= requires |url= (help)
  14. ^ Szpak, Paul (2011). "Fish bone chemistry and ultrastructure: implications for taphonomy and stable isotope analysis". Journal of Archaeological Science. 38 (12): 3358–3372. doi:10.1016/j.jas.2011.07.022.
  15. ^ K.J. Siebert, "Haze and Foam",[1] Accessed July 12, 2010.
  16. ^ R.H.A. Plimmer (1912) [1908], R.H.A. Plimmer & F.G. Hopkins (ed.), The chemical composition of the proteins, Monographs on biochemistry, vol. Part I. Analysis (2nd ed.), London: Longmans, Green and Co., p. 130, retrieved September 20, 2010
  17. ^ Vogel, Practical Organic Chemistry 5th edition

Further reading

  • Balbach, J.; Schmid, F. X. (2000), "Proline isomerization and its catalysis in protein folding", in Pain, R. H. (ed.), Mechanisms of Protein Folding (2nd ed.), Oxford University Press, pp. 212–49, ISBN 0-19-963788-1.
  • 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). 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 OMMBID blog.
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