Abstract
Proline is unique among proteinogenic amino acids because a pyrrolidine ring links its amino group to its side chain. This heterocycle constrains the conformations of the main chain and thus templates particular secondary structures. Proline residues undergo posttranslational modification at the 4-position to yield 4-hydroxyproline, which is especially prevalent in collagen. Interest in characterizing the effects of this modification led to the use of 4-fluoroprolines to enhance inductive properties relative to the hydroxyl group of 4-hydroxyproline and to eliminate contributions from hydrogen bonding. The strong inductive effect of the fluoro group has three main consequences: enforcing a particular pucker upon the pyrrolidine ring, biasing the conformation of the preceding peptide bond, and accelerating cis–trans prolyl peptide bond isomerization. These subtle yet reliable modulations make 4-fluoroproline incorporation a complement to traditional genetic approaches for exploring structure–function relationships in peptides and proteins, as well as for endowing peptides and proteins with conformational stability.
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MacArthur MW, Thornton JM (1991) J Mol Biol 218:397
Brandts JF, Halvorson HR, Brennan M (1975) Biochemistry 14:4953
Shoulders MD, Raines RT (2009) Annu Rev Biochem 78:929
Fischer E (1901) Z Physiol Chem 33:151
Fischer E (1902) Chem Ber 35:2660
Gorres KL, Raines RT (2010) Crit Rev Biochem Mol Biol 45:106
Winter AD, Page AP (2000) Mol Cell Biol 20:4084
Friedman L, Higgin JJ, Moulder G, Barstead R, Raines RT, Kimble J (2000) Proc Natl Acad Sci U S A 97:4736
Holster T, Pakkanen O, Soininen R, Sormunen R, Nokelainen M, Kivirikko KI, Myllyharju J (2007) J Biol Chem 282:2512
Mauger AB, Witkop B (1966) Chem Rev 66:47
Gottlieb AA, Fujita Y, Udenfriend S, Witkop B (1965) Biochemistry 4:2507
Bakerman S, Martin RL, Burgstahler AW, Hayden JW (1966) Nature 212:849
Takeuchi T, Prockop DJ (1969) Biochim Biophys Acta 175:142
Takeuchi T, Rosenbloom J, Prockop DJ (1969) Biochim Biophys Acta 175:156
Uitto J, Prockop DJ (1974) Biochim Biophys Acta 336:234
Hutton JJ Jr, Marglin A, Witkop B, Kurtz J, Berger A, Udenfriend S (1968) Arch Biochem Biophys 125:779
Dieglemann RF, Ondrejickova O, Katz E (1969) Arch Biochem Biophys 131:276
Yoder NC, Kumar K (2002) Chem Soc Rev 31:335
Salwiczek M, Nyakatura EK, Gerling UI, Ye S, Koksch B (2012) Chem Soc Rev 41:2135
Merkel L, Budisa N (2012) Org Biomol Chem 10:7241
Odar C, Winkler M, Wiltschi B (2015) Biotechnol J 10:427
Demange L, Ménez A, Dugave C (1998) Tetrahedron Lett 39:1169
Doi M, Nishi Y, Kiritoshi N, Iwata T, Nago M, Nakano H, Uchiyama S, Nakazawa T, Wakamiya T, Kobayashi Y (2002) Tetrahedron 58:8453
Chorghade MS, Mohapatra DK, Sahoo G, Gurjar MK, Mandlecha MV, Bhoite N, Moghe S, Raines RT (2008) J Fluor Chem 129:781
Kronenthal DR, Mueller RH, Kuester PL, Kissick TP, Johnson EJ (1990) Tetrahedron Lett 31:1241
Hudlický M, Merola JS (1990) Tetrahedron Lett 31:7403
Avent AG, Bowler AN, Doyle PM, Marchand CM, Young DW (1992) Tetrahedron Lett 33:1509
Hudlický M (1993) J Fluor Chem 60:193
Thomas KM, Naduthambi D, Tririya G, Zondlo NJ (2005) Org Lett 7:2397
Pandey AK, Naduthambi D, Thomas KM, Zondlo NJ (2013) J Am Chem Soc 135:4333
Donohue J, Trueblood KN (1952) Acta Crystallogr 5:419
Matheison AM, Welsh HK (1952) Acta Crystallogr 5:599
Mitsui Y, Tsuboi M, Iitaka Y (1969) Acta Crystallogr B25:2182
Higashijima T, Tasumi M, Miyazawa T (1977) Biopolymers 16:1259
Allen FH (2002) Acta Crystallogr B58:380
DeRider ML, Wilkens SJ, Waddell MJ, Bretscher LE, Weinhold F, Raines RT, Markley JL (2002) J Am Chem Soc 124:2497
Improta R, Benzi C, Barone V (2001) J Am Chem Soc 123:12568
Grieg JT, McLeod RS (1973) J Am Chem Soc 95:5725
Karplus M (1959) J Chem Phys 30:11
Panasik N Jr, Eberhardt ES, Edison AS, Powell DR, Raines RT (1994) Int J Pept Prot Res 44:262
Bretscher LE, Jenkins CL, Taylor KM, DeRider ML, Raines RT (2001) J Am Chem Soc 123:777
Jakobsche CE, Choudhary A, Miller SJ, Raines RT (2010) J Am Chem Soc 132:6651
Hinderaker MP, Raines RT (2003) Protein Sci 12:1188
Bartlett GJ, Choudhary A, Raines RT, Woolfson DN (2010) Nat Chem Biol 6:615
Bürgi HD, Dunitz JD, Shefter E (1974) Acta Crystallogr B30:1517
Newberry RW, VanVeller B, Guzei IA, Raines RT (2013) J Am Chem Soc 135:7843
Bartlett GJ, Newberry RW, Vanveller B, Raines RT, Woolfson DN (2013) J Am Chem Soc 135:18682
Newberry RW, Bartlett GJ, Vanveller B, Woolfson DN, Raines RT (2014) Protein Sci 23:284
Jenkins CL, Lin G, Duo J, Rapolu D, Guzei IA, Raines RT, Krow GR (2004) J Org Chem 69:8565
Choudhary A, Gandla D, Krow GR, Raines RT (2009) J Am Chem Soc 131:7244
Steiner T, Hess P, Bae JH, Wiltschi B, Moroder L, Budisa N (2008) PLoS One 3:e1680
Holzberger B, Obeid S, Welte W, Diederichs K, Marx A (2012) Chem Sci 3:2924
Rubini M, Schärer MA, Capitani G, Glockshuber R (2013) ChemBioChem 14:1053
Siebler C, Maryasin B, Kuemin M, Erdmann RS, Rigling C, Grünenfelder C, Ochsenfeld C, Wennemers H (2015) Chem Sci 6:6725
Eberhardt ES, Panasik N Jr, Raines RT (1996) J Am Chem Soc 118:12261
Shoulders MD, Kamer KJ, Raines RT (2009) Bioorg Med Chem Lett 19:3859
Rich A, Crick FHC (1961) J Mol Biol 3:483
Ramshaw JAM, Shah NK, Brodsky B (1998) J Struct Biol 122:86
Sakakibara S, Inouye K, Shudo K, Kishida T, Kobayashi Y, Prockop DJ (1973) Biochim Biophys Acta 303:198
Berg RA, Prockop DJ (1973) Biochem Biophys Res Commun 52:115
Bella J, Eaton M, Brodsky B, Berman HM (1994) Science 266:75
Bella J, Brodsky B, Berman HM (1995) Structure 3:893
Hodges JA, Raines RT (2005) J Am Chem Soc 127:15923
Hodges JA, Raines RT (2003) J Am Chem Soc 125:9262
Holmgren SK, Bretscher LE, Taylor KM, Raines RT (1999) Chem Biol 6:63
Doi M, Nishi Y, Uchiyama S, Nishiuchi Y, Nakazawa T, Ohkubo T, Kobayashi Y (2003) J Am Chem Soc 125:9922
Doi M, Nishi Y, Uchiyama S, Nishiuchi Y, Nishio H, Nakazawa T, Ohkubo T, Kobayashi Y (2005) J Pept Sci 11:609
Holmgren SK, Taylor KM, Bretscher LE, Raines RT (1998) Nature 392:666
Dunitz JD, Taylor R (1997) Chem Eur J 3:89
Mooney SD, Kollman PA, Klein TE (2002) Biopolymers 64:63
Kotch FW, Guzei IA, Raines RT (2008) J Am Chem Soc 130:2952
Persikov AV, Ramshaw JAM, Kirkpatrick A, Brodsky B (2003) J Am Chem Soc 125:11500
Malkar NB, Lauer-Fields JL, Borgia JA, Fields GB (2002) Biochemistry 41:6054
Chattopadhyay S, Murphy CJ, McAnulty JF, Raines RT (2012) Org Biomol Chem 10:5892
Chattopadhyay S, Raines RT (2014) Biopolymers 101:821
Chattopadhyay S, Guthrie KM, Teixeira L, Murphy CJ, Dubielzig RR, McAnulty JF, Raines RT (2015) J Tissue Eng Regen Med. doi:10.1002/term.1886
Nishi Y, Uchiyama S, Doi M, Nishiuchi Y, Nakazawa T, Ohkubo T, Kobayashi Y (2005) Biochemistry 44:6034
Marsh EN, Suzuki Y (2014) ACS Chem Biol 9:1242
Kawahara K, Nemoto N, Motooka D, Nishi Y, Doi M, Uchiyama S, Nakazawa T, Nishiuchi Y, Yoshida T, Ohkubo T, Kobayashi Y (2012) J Phys Chem B 116:6908
Gorres KL, Edupuganti R, Krow GR, Raines RT (2008) Biochemistry 47:9447
Gorres KL, Raines RT (2009) Anal Biochem 386:181
Adzhubei AA, Sternberg MJE (1993) J Mol Biol 229:472
Shi Z, Chen K, Liu Z, Kallenbach NR (2006) Chem Rev 106:1877
Wilhelm P, Lawandowski B, Trapp N, Wennemers H (2014) J Am Chem Soc 136:15829
Siebler C, Erdmann RS, Wennemers H (2013) Chimia 67:891
Kuemin M, Engel J, Wennemers H (2010) J Pept Sci 16:596
Horng JC, Raines RT (2006) Protein Sci 15:74
Chiang YC, Lin YJ, Horng JC (2009) Protein Sci 18:1967
Lin YJ, Horng JC (2014) Amino Acids 46:2317
Lin L-N, Brandts JF (1980) Biochemistry 19:3055
Berisio R, Vitagliano L (2012) Curr Protein Pept Sci 13:855
Feng S, Chen JK, Yu H, Simon JA, Schreiber SL (1994) Science 266:1241
Ruzza P, Siligardi G, Donella-Deana A, Calderan A, Hussain R, Rubini C, Cesaro L, Osler A, Guiotto A, Pinna LA, Borin G (2006) J Pept Sci 12:462
Tang HC, Lin YJ, Horng JC (2014) Proteins 82:67
Wintjens R, Wieruszeski JM, Drobecq H, Rousselot-Pailley P, Buée L, Lippens G, Landrieu I (2001) J Biol Chem 276:25150
Naduthambi D, Zondlo NJ (2006) J Am Chem Soc 128:12430
Neidigh JW, Fesinmeyer RM, Andersen NH (2002) Nat Struct Biol 9:425
Boulègue C, Milbradt AG, Renner C, Moroder L (2006) J Mol Biol 358:846
Pokidysheva E, Milbradt AG, Meier S, Renner C, Häussinger D, Bächinger HP, Moroder L, Grzesiek S, Holstein TW, Özbek S, Engel J (2004) J Biol Chem 279:30395
Barth D, Musiol HJ, Schütt M, Fiori S, Milbradt AG, Renner C, Moroder L (2003) Chem Biol 9:3692
Scholz S, Liebler EK, Eickmann B, Fritz HJ, Diederichsen U (2012) Amino Acids 43:289
Rice PA, Yang S-W, Mizuuchi K, Nash HA (1996) Cell 87:1295
Merkel L, Schauer M, Antranikian G, Budisa N (2010) ChemBioChem 11:1505
Lepthien S, Merkel L, Budisa N (2010) Angew Chem Int Ed 49:5446
Hoesl MG, Acevedo-Rocha CG, Nehring S, Royter M, Wolschner C, Wiltschi B, Budisa N, Antranikian G (2011) ChemCatChem 3:213
Hoesl MG, Budisa N (2011) ChemBioChem 12:552
Oldach F, Al Toma R, Kuthning A, Caetano T, Mendo S, Budisa N, Sussmuth RD (2012) Angew Chem Int Ed 51:415
Larregola M, Moore S, Budisa N (2012) Biochem Biophys Res Commun 421:646
Nilsson BL, Soellner MB, Raines RT (2005) Annu Rev Biophys Biomol Struct 34:91
Renner C, Alefelder S, Bae JH, Budisa N, Huber R, Moroder L (2001) Angew Chem Int Ed 40:923
Golbik R, Yu C, Weyher-Stingl E, Huber R, Moroder L, Budisa N, Schiene-Fischer C (2005) Biochemistry 44:16026
Kim W, George A, Evans M, Conticello VP (2004) ChemBioChem 5:928
Debelle L, Tamburro AM (1999) Int J Biochem Cell Biol 31:261
Kim W, McMillian RA, Snyder JP, Conticello VP (2005) J Am Chem Soc 127:18121
Crespo MD, Rubini M (2011) PLoS One 6:e19425
Komander D, Rape M (2012) Annu Rev Biochem 81:203
Vijay-Kumar S, Bugg CE, Cook WJ (1987) J Mol Biol 194:531
Edwardraja S, Sriram S, Govindan R, Budisa N, Lee SG (2011) Mol Biosyst 7:258
Deepankumar K, Nadarajan SP, Ayyadurai N, Yun H (2013) Biochem Biophys Res Commun 440:509
Holzberger B, Marx A (2010) J Am Chem Soc 132:15708
Torbeev VY, Hilvert D (2013) Proc Natl Acad Sci U S A 110:20051
Trinh CH, Smith DP, Kalverda AP, Phillips SE, Radford SE (2002) Proc Natl Acad Sci U S A 99:9771
Jahn TR, Parker MJ, Homans SW, Radford SE (2006) Nat Struct Mol Biol 13:195
Eichner T, Radford SE (2011) FEBS J 278:3868
Park BK, Kitteringham NR, O’Neill PM (2001) Annu Rev Pharmacol Toxicol 41:443
Tran TT, Patino N, Condom R, Frogier T, Guedj R (1997) J Fluor Chem 82:125
Staas DD, Savage KL, Sherman VL, Shimp HL, Lyle TA, Tran LO, Wiscount CM, McMasters DR, Sanderson PE, Williams PD, Lucas BJ Jr, Krueger JA, Lewis SD, White RB, Yu S, Wong BK, Kochansky CJ, Anari MR, Yan Y, Vacca JP (2006) Bioorg Med Chem 14:6900
Tucker TJ, Brady SF, Lumma WC, Lewis SD, Gardell SJ, Naylor-Olsen AM, Yan Y, Sisto JT, Stauffer KJ, Lucas BJ, Lynch JJ, Cook JJ, Stranieri MT, Holahan MA, Lyle EA, Baskin EP, Chen I-W, Dancheck KB, Krueger JA, Cooper CM, Vacca JP (1998) J Med Chem 41:3210
Mandal PK, Ren Z, Chen X, Kalurachchi K, Liao WS-L, McMurray JS (2013) Int J Pept Prot Res 19:3
White JF, Noinaj N, Shibata Y, Love J, Kloss B, Xu F, Gvozdenovic-Jeremic J, Shah P, Shiloach J, Tate CG, Grisshammer R (2012) Nature 490:508
Held C, Hübner H, Kling R, Nagel YA, Wennemers H, Gmeiner P (2013) ChemMedChem 8:772
Zhuang W, Zhao X, Zhao G, Guo L, Lian Y, Zhou J, Fang D (2009) Bioorg Med Chem 17:6540
van der Ley M (1983) J Label Compd Radiopharm 20:453
Hamacher K (1999) J Label Compd Radiopharm 42:1135
Mazza SM (2000) J Label Compd Radiopharm 43:1047
Azad BB, Ashique R, Labiris NR, Chirakal R (2012) J Labelled Cpd Radiopharm 55:23
Wester H-J, Herz M, Senekowitsch-Schmidtke R, Schwaiger M, Stöcklin G, Hamacher K (1999) Nucl Med Biol 26:259
Börner AR, Langen K-J, Herzog H, Hamacher K, Müller-Mattheis V, Schmitz T, Ackermann R, Coenen HH (2001) Nucl Med Biol 28:287
Langen K-J, Mühlensiepen H, Schmieder S, Hamacher K, Bröer S, Börner AR, Schneeweiss FHA, Coenen HH (2002) Nucl Med Biol 29:685
Langen K-J, Jarosch M, Hamacher K, Mühlensiepen H, Weber F, Floeth F, Pauleit D, Herzog H, Coenen HH (2004) Nucl Med Biol 31:67
Langen KJ, Hamacher K, Bauer D, Bröer S, Pauleit D, Herzog H, Floeth F, Zilles K, Coenen HH (2005) J Cereb Blood Flow Metab 25:607
Zimny M, Klosterhalfen B, Conze J, Hamacher K, Fehler S, Schumpelick V, Coenen HH, Buell U (2002) Nucl Med Commun 23:695
Skovgaard D, Kjaer A, Heinemeier KM, Brandt-Larsen M, Madsen J, Kjaer M (2011) PLoS One 6:e16678
Acknowledgments
This paper is dedicated to the memory of Grant R. Krow (1942–2015), our long-time collaborator on research on 4-fluoroprolines and their analogs. R.W.N. was supported by Biotechnology Training Grant T32 GM008349 (NIH), the Nelson J. Leonard Graduate Fellowship of the ACS Division of Organic Chemistry sponsored by Organic Syntheses, and an Eastman Summer Research Award from the Eastman Chemical Company. Work on 4-fluoroprolines in the Raines laboratory was supported by Grant R01 AR044276 (NIH).
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Newberry, R.W., Raines, R.T. (2016). 4-Fluoroprolines: Conformational Analysis and Effects on the Stability and Folding of Peptides and Proteins. In: Lubell, W. (eds) Peptidomimetics I. Topics in Heterocyclic Chemistry, vol 48. Springer, Cham. https://doi.org/10.1007/7081_2015_196
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