D-Amino Acids in Peptides from Animals, Including Human: Occurrence, Structure, Bioactivity and Pharmacology

Elsie    C.    Jimenez
Abstract

All life forms typically possess homochirality, with rare exceptions. In the case of peptides and proteins, only L-amino acids are known to be encoded by genes. Nevertheless, D-amino acids have been identified in a variety of peptides, synthesized by animal cells. They include neuroexcitatory and neuroprotective peptides, cardioexcitatory peptides, hyperglycemic hormones, opioid peptides, antimicrobial peptides, natriuretic and defensin-like peptides, and fibrinopeptides. This article is a review of their occurrence, structure and bioactivity. It further explores the pharmacology and potential medical applications of some of the peptides.
Keywords: D-amino acid, achatin, conotoxin, agatoxin, crustacean hyperglycemic hormone, dermorphin and deltorphin, natriuretic and defensin-like peptides, fibrinopeptide.
Graphical Abstract

[1] 
Kleinkauf, H.; von Döhren, H. Nonribosomal biosynthesis of peptide antibiotics. Eur. J. Biochem.,  1990, 192(1), 1-15.
[http://dx.doi.org/10.1111/j.1432-1033.1990.tb19188.x] [PMID:  2205497] 
[2] 
Richter, K.; Egger, R.; Kreil, G. D-alanine in the frog skin peptide dermorphin is derived from L-alanine in the precursor. Science,  1987, 238(4824), 200-202.
[http://dx.doi.org/10.1126/science.3659910] [PMID:  3659910] 
[3] 
Yasuda-Kamatani, Y.; Nakamura, M.; Minakata, H.; Nomoto, K.; Sakiyama, F. A novel cDNA sequence encoding the precursor of the D-amino acid-containing neuropeptide fulicin and multiple α-amidated neuropeptides from Achatina fulica. J. Neurochem.,  1995, 64(5), 2248-2255.
[http://dx.doi.org/10.1046/j.1471-4159.1995.64052248.x] [PMID:  7722509] 
[4] 
Matsuo, R.; Kobayashi, S.; Morishita, F.; Ito, E. Expression of Asn-d-Trp-Phe-NH2 in the brain of the terrestrial slug Limax valentianus. Comp. Biochem. Physiol. B Biochem. Mol. Biol.,  2011, 160(2-3), 89-93.
[http://dx.doi.org/10.1016/j.cbpb.2011.06.007] [PMID:  21749929] 
[5] 
Heck, S.D.; Siok, C.J.; Krapcho, K.J.; Kelbaugh, P.R.; Thadeio, P.F.; Welch, M.J.; Williams, R.D.; Ganong, A.H.; Kelly, M.E.; Lanzetti, A.J.; Gray, W.R.; Phillips, D.; Parks, T.N.; Jackson, H.; Ahlijanian, M.K.; Saccomano, N.A.; Volkmann, R.A. Functional consequences of posttranslational isomerization of Ser46 in a calcium channel toxin. Science,  1994, 266(5187), 1065-1068.
[http://dx.doi.org/10.1126/science.7973665] [PMID:  7973665s] 
[6] 
Heck, S.D.; Faraci, W.S.; Kelbaugh, P.R.; Saccomano, N.A.; Thadeio, P.F.; Volkmann, R.A. Posttranslational amino acid epimerization: enzyme-catalyzed isomerization of amino acid residues in peptide chains. Proc. Natl. Acad. Sci. USA,  1996, 93(9), 4036-4039.
[http://dx.doi.org/10.1073/pnas.93.9.4036] [PMID:  8633012] 
[7] 
Bansal, P.S.; Torres, A.M.; Crossett, B.; Wong, K.K.; Koh, J.M.; Geraghty, D.P.; Vandenberg, J.I.; Kuchel, P.W. Substrate specificity of platypus venom L-to-D-peptide isomerase. J. Biol. Chem.,  2008, 283(14), 8969-8975.
[http://dx.doi.org/10.1074/jbc.M709762200] [PMID:  18158286] 
[8] 
Jilek, A.; Mollay, C.; Lohner, K.; Kreil, G. Substrate specificity of a peptidyl-aminoacyl-L/D-isomerase from frog skin. Amino Acids,  2012, 42(5), 1757-1764.
[http://dx.doi.org/10.1007/s00726-011-0890-6] [PMID:  21424715] 
[9] 
Soyez, D.; Toullec, J.Y.; Ollivaux, C.; Géraud, G. L to D amino acid isomerization in a peptide hormone is a late post-translational event occurring in specialized neurosecretory cells. J. Biol. Chem.,  2000, 275(48), 37870-37875.
[http://dx.doi.org/10.1074/jbc.M007302200] [PMID:  10993902] 
[10] 
Bai, L.; Romanova, E.V.; Sweedler, J.V. Distinguishing endogenous D-amino acid-containing neuropeptides in individual neurons using tandem mass spectrometry. Anal. Chem.,  2011, 83(7), 2794-2800.
[http://dx.doi.org/10.1021/ac200142m] [PMID:  21388150] 
[11] 
Tao, Y.; Quebbemann, N.R.; Julian, R.R. Discriminating D-amino acid-containing peptide epimers by radical-directed dissociation mass spectrometry. Anal. Chem.,  2012, 84(15), 6814-6820.
[http://dx.doi.org/10.1021/ac3013434] [PMID:  22812429] 
[12] 
Jia, C.; Lietz, C.B.; Yu, Q.; Li, L. Site-specific characterization of (D)-amino acid containing peptide epimers by ion mobility spectrometry. Anal. Chem.,  2014, 86(6), 2972-2981.
[http://dx.doi.org/10.1021/ac4033824] [PMID:  24328107] 
[13] 
Koehbach, J.; Gruber, C.W.; Becker, C.; Kreil, D.P.; Jilek, A. MALDI TOF/TOF-based approach for the identification of D-amino acids in biologically active peptides and proteins. J. Proteome Res.,  2016, 15(5), 1487-1496.
[http://dx.doi.org/10.1021/acs.jproteome.5b01067] [PMID:  26985971] 
[14] 
Livnat, I.; Tai, H.C.; Jansson, E.T.; Bai, L.; Romanova, E.V.; Chen, T.T.; Yu, K.; Chen, S.A.; Zhang, Y.; Wang, Z.Y.; Liu, D.D.; Weiss, K.R.; Jing, J.; Sweedler, J.V. A D-amino acid-containing neuropeptide discovery funnel. Anal. Chem.,  2016, 88(23), 11868-11876.
[http://dx.doi.org/10.1021/acs.analchem.6b03658] [PMID:  27788334] 
[15] 
Tai, H.C.; Checco, J.W.; Sweedler, J.V. Non-targeted identification of D-amino acid-containing peptides through enzymatic screening, chiral amino acid analysis, and LC-MS. methods. Methods Mol. Biol.,  2018, 1719, 107-118.
[http://dx.doi.org/10.1007/978-1-4939-7537-2_7] [PMID:  29476507] 
[16] 
Ewing, M.A.; Wang, J.; Sheeley, S.A.; Sweedler, J.V. Detecting D-amino acid-containing neuropeptides using selective enzymatic digestion. Anal. Chem.,  2008, 80(8), 2874-2880.
[http://dx.doi.org/10.1021/ac7025173] [PMID:  18341354] 
[17] 
Kamatani, Y.; Minakata, H.; Kenny, P.T.; Iwashita, T.; Watanabe, K.; Funase, K.; Sun, X.P.; Yongsiri, A.; Kim, K.H.; Novales-Li, P.; Novales, E.T.; Canapi, C.G.; Takeuchi, H.; Nomotol, K. Achatin-I, an endogenous neuroexcitatory tetrapeptide from Achatina fulica Férussac containing a D-amino acid residue. Biochem. Biophys. Res. Commun.,  1989, 160(3), 1015-1020.
[http://dx.doi.org/10.1016/S0006-291X(89)80103-2] [PMID:  2597281] 
[18] 
Kamatani, Y.; Minakata, H.; Iwashita, T.; Nomoto, K. In, Y.; Doi, M.; Ishida, T. Molecular conformation of achatin-I, an endogenous neuropeptide containing D-amino acid residue. X-ray crystal structure of its neutral form. FEBS Lett.,  1990, 276(1-2), 95-97.
[http://dx.doi.org/10.1016/0014-5793(90)80516-L] [PMID:  1979949] 
[19] 
Kimura, T.; Okamura, E.; Matubayasi, N.; Asami, K.; Nakahara, M. NMR study on the binding of neuropeptide achatin-I to phospholipid bilayer: the equilibrium, location, and peptide conformation. Biophys. J.,  2004, 87(1), 375-385.
[http://dx.doi.org/10.1529/biophysj.103.038950] [PMID:  15240472] 
[20] 
Kimura, T.; Ninomiya, K.; Futaki, S. NMR investigation of the electrostatic effect in binding of a neuropeptide, achatin-I, to phosphatidylcholine bilayers. J. Phys. Chem. B,  2007, 111(14), 3831-3838.
[http://dx.doi.org/10.1021/jp067100x] [PMID:  17388516] 
[21] 
Ohta, N.; Kubota, I.; Takao, T.; Shimonishi, Y.; Yasuda-Kamatani, Y.; Minakata, H.; Nomoto, K.; Muneoka, Y.; Kobayashi, M. Fulicin, a novel neuropeptide containing a D-amino acid residue isolated from the ganglia of Achatina fulica. Biochem. Biophys. Res. Commun.,  1991, 178(2), 486-493.
[http://dx.doi.org/10.1016/0006-291X(91)90133-R] [PMID:  1859408] 
[22] 
Fujisawa, Y.; Masuda, K.; Minakata, H. Fulicin regulates the female reproductive organs of the snail, Achatina fulica. Peptides,  2000, 21(8), 1203-1208.
[http://dx.doi.org/10.1016/S0196-9781(00)00260-6] [PMID:  11035206] 
[23] 
Fujita, K.; Minakata, H.; Nomoto, K.; Furukawa, Y.; Kobayashi, M. Structure-activity relations of fulicin, a peptide containing a D-amino acid residue. Peptides,  1995, 16(4), 565-568.
[http://dx.doi.org/10.1016/0196-9781(95)00022-C] [PMID:  7479285] 
[24] 
Yasuda-Kamatani, Y.; Kobayashi, M.; Yasuda, A.; Fujita, T.; Minakata, H.; Nomoto, K.; Nakamura, M.; Sakiyama, F. A novel D-amino acid-containing peptide, fulyal, coexists with fulicin gene-related peptides in Achatina atria. Peptides,  1997, 18(3), 347-354.
[http://dx.doi.org/10.1016/S0196-9781(96)00343-9] [PMID:  9145419] 
[25] 
Morishita, F.; Nakanishi, Y.; Kaku, S.; Furukawa, Y.; Ohta, S.; Hirata, T.; Ohtani, M.; Fujisawa, Y.; Muneoka, Y.; Matsushima, O. A novel D-amino-acid-containing peptide isolated from Aplysia heart. Biochem. Biophys. Res. Commun.,  1997, 240(2), 354-358.
[http://dx.doi.org/10.1006/bbrc.1997.7659] [PMID:  9388481] 
[26] 
Kanemaru, K.; Morishita, F.; Matsushima, O.; Furukawa, Y. Aplysia cardioactive peptide (NdWFamide) enhances the L-type Ca2+ current of Aplysia ventricular myocytes. Peptides,  2002, 23(11), 1991-1998.
[http://dx.doi.org/10.1016/S0196-9781(02)00186-9] [PMID:  12431737] 
[27] 
Bai, L.; Livnat, I.; Romanova, E.V.; Alexeeva, V.; Yau, P.M.; Vilim, F.S.; Weiss, K.R.; Jing, J.; Sweedler, J.V. Characterization of GdFFD, a D-amino acid-containing neuropeptide that functions as an extrinsic modulator of the Aplysia feeding circuit. J. Biol. Chem.,  2013, 288(46), 32837-32851.
[http://dx.doi.org/10.1074/jbc.M113.486670] [PMID:  24078634] 
[28] 
Yang, C.Y.; Yu, K.; Wang, Y.; Chen, S.A.; Liu, D.D.; Wang, Z.Y.; Su, Y.N.; Yang, S.Z.; Chen, T.T.; Livnat, I.; Vilim, F.S.; Cropper, E.C.; Weiss, K.R.; Sweedler, J.V.; Jing, J. Aplysia Locomotion: Network and Behavioral Actions of GdFFD, a D-Amino Acid-Containing Neuropeptide. PLoS One,  2016, 11(1) e0147335
[http://dx.doi.org/10.1371/journal.pone.0147335] [PMID:  26796097] 
[29] 
Checco, J.W.; Zhang, G.; Yuan, W.D.; Yu, K.; Yin, S.Y.; Roberts-Galbraith, R.H.; Yau, P.M.; Romanova, E.V.; Jing, J.; Sweedler, J.V. Molecular and physiological characterization of a receptor for D-amino acid-containing neuropeptides. ACS Chem. Biol.,  2018a, 13(5), 1343-1352.
[http://dx.doi.org/10.1021/acschembio.8b00167] [PMID:  29543428] 
[30] 
Do, T.D.; Checco, J.W.; Tro, M.; Shea, J.E.; Bowers, M.T.; Sweedler, J.V. Conformational investigation of the structure-activity relationship of GdFFD and its analogues on an achatin-like neuropeptide receptor of Aplysia californica involved in the feeding circuit. Phys. Chem. Chem. Phys.,  2018, 20(34), 22047-22057.
[http://dx.doi.org/10.1039/C8CP03661F] [PMID:  30112548] 
[31] 
Checco, J.W.; Zhang, G.; Yuan, W.D.; Le, Z.W.; Jing, J.; Sweedler, J.V. Aplysia allatotropin-related peptide and its newly identified d amino acid-containing epimer both activate a receptor and a neuronal target. J. Biol. Chem.,  2018b, 293(43), 16862-16873.
[http://dx.doi.org/10.1074/jbc.RA118.004367] [PMID:  30194283] 
[32] 
Tan, K.C.; Wakimoto, T.; Takada, K.; Ohtsuki, T.; Uchiyama, N.; Goda, Y.; Abe, I. Cycloforskamide, a cytotoxic macrocyclic peptide from the sea slug Pleurobranchus forskalii. J. Nat. Prod.,  2013, 76(7), 1388-1391.
[http://dx.doi.org/10.1021/np400404r] [PMID:  23848233] 
[33] 
Fujisawa, Y.; Ikeda, T.; Nomoto, K.; Yasuda-Kamatani, Y.; Minakata, H.; Kenny, P.T.M.; Kubota, I.; Muneoka, Y. The FMRFamide-related decapeptide of Mytilus contains a D-amino acid residue. Comp. Biochem. Physiol. C. Comp. Pharmacol. Toxicol.,  1992, 102(1), 91-95.
[http://dx.doi.org/10.1016/0742-8413(92)90049-D] [PMID:  1358533] 
[34] 
Jimenéz, E.C.; Olivera, B.M.; Gray, W.R.; Cruz, L.J. Contryphan is a D-tryptophan-containing Conus peptide. J. Biol. Chem.,  1996, 271(45), 28002-28005.
[http://dx.doi.org/10.1074/jbc.271.45.28002] [PMID:  8910408] 
[35] 
Jimenez, E.C.; Craig, A.G.; Watkins, M.; Hillyard, D.R.; Gray, W.R.; Gulyas, J.; Rivier, J.E.; Cruz, L.J.; Olivera, B.M. Bromocontryphan: post-translational bromination of tryptophan. Biochemistry,  1997, 36(5), 989-994.
[http://dx.doi.org/10.1021/bi962840p] [PMID:  9033387] 
[36] 
Jacobsen, R.; Jimenez, E.C.; Grilley, M.; Watkins, M.; Hillyard, D.; Cruz, L.J.; Olivera, B.M. The contryphans, a D-tryptophan-containing family of Conus peptides: interconversion between conformers. J. Pept. Res.,  1998, 51(3), 173-179.
[http://dx.doi.org/10.1111/j.1399-3011.1998.tb01213.x] [PMID:  9531419] 
[37] 
Pallaghy, P.K.; Melnikova, A.P.; Jimenez, E.C.; Olivera, B.M.; Norton, R.S. Solution structure of contryphan-R, a naturally occurring disulfide-bridged octapeptide containing D-tryptophan: comparison with protein loops. Biochemistry,  1999, 38(35), 11553-11559.
[http://dx.doi.org/10.1021/bi990685j] [PMID:  10471307] 
[38] 
Pallaghy, P.K.; He, W.; Jimenez, E.C.; Olivera, B.M.; Norton, R.S. Structures of the contryphan family of cyclic peptides. Role of electrostatic interactions in cis-trans isomerism. Biochemistry,  2000, 39(42), 12845-12852.
[http://dx.doi.org/10.1021/bi0010930] [PMID:  11041849] 
[39] 
Jacobsen, R.B.; Jimenez, E.C.; De la Cruz, R.G.; Gray, W.R.; Cruz, L.J.; Olivera, B.M. A novel D-leucine-containing Conus peptide: diverse conformational dynamics in the contryphan family. J. Pept. Res.,  1999, 54(2), 93-99.
[http://dx.doi.org/10.1034/j.1399-3011.1999.00093.x] [PMID:  10461743] 
[40] 
Pi, C.; Liu, Y.; Peng, C.; Jiang, X.; Liu, J.; Xu, B.; Yu, X.; Yu, Y.; Jiang, X.; Wang, L.; Dong, M.; Chen, S.; Xu, A.L. Analysis of expressed sequence tags from the venom ducts of Conus striatus: focusing on the expression profile of conotoxins. Biochimie,  2006a, 88(2), 131-140.
[http://dx.doi.org/10.1016/j.biochi.2005.08.001] [PMID:  16183187] 
[41] 
Hu, H.; Bandyopadhyay, P.K.; Olivera, B.M.; Yandell, M. Characterization of the Conus bullatus genome and its venom-duct transcriptome. BMC Genomics,  2011, 12, 60-74.
[http://dx.doi.org/10.1186/1471-2164-12-60] [PMID:  21266071] 
[42] 
Jimenez, E.C.; Watkins, M.; Juszczak, L.J.; Cruz, L.J.; Olivera, B.M. Contryphans from Conus textile venom ducts. Toxicon,  2001, 39(6), 803-808.
[http://dx.doi.org/10.1016/S0041-0101(00)00210-5] [PMID:  11137539] 
[43] 
Hansson, K.; Ma, X.; Eliasson, L.; Czerwiec, E.; Furie, B.; Furie, B.C.; Rorsman, P.; Stenflo, J. The first gamma-carboxyglutamic acid-containing contryphan. A selective L-type calcium ion channel blocker isolated from the venom of Conus marmoreus. J. Biol. Chem.,  2004, 279(31), 32453-32463.
[http://dx.doi.org/10.1074/jbc.M313825200] [PMID:  15155730] 
[44] 
Grant, M.A.; Hansson, K.; Furie, B.C.; Furie, B.; Stenflo, J.; Rigby, A.C. The metal-free and calcium-bound structures of a gamma-carboxyglutamic acid-containing contryphan from Conus marmoreus, glacontryphan-M. J. Biol. Chem.,  2004, 279(31), 32464-32473.
[http://dx.doi.org/10.1074/jbc.M313826200] [PMID:  15155731] 
[45] 
Gowd, K.H.; Sabareesh, V.; Sudarslal, S.; Iengar, P.; Franklin, B.; Fernando, A.; Dewan, K.; Ramaswami, M.; Sarma, S.P.; Sikdar, S.; Balaram, P.; Krishnan, K.S. Novel peptides of therapeutic promise from Indian Conidae. Ann. N. Y. Acad. Sci.,  2005, 1056, 462-473.
[http://dx.doi.org/10.1196/annals.1352.022] [PMID:  16387709] 
[46] 
Sabareesh, V.; Gowd, K.H.; Ramasamy, P.; Sudarslal, S.; Krishnan, K.S.; Sikdar, S.K.; Balaram, P. Characterization of contryphans from Conus loroisii and Conus amadis that target calcium channels. Peptides,  2006, 27(11), 2647-2654.
[http://dx.doi.org/10.1016/j.peptides.2006.07.009] [PMID:  16945451] 
[47] 
Robinson, S.D.; Safavi-Hemami, H.; McIntosh, L.D.; Purcell, A.W.; Norton, R.S.; Papenfuss, A.T. Diversity of conotoxin gene superfamilies in the venomous snail, Conus victoriae. PLoS One,  2014, 9(2) e87648
[http://dx.doi.org/10.1371/journal.pone.0087648]] [PMID:  24505301] 
[48] 
Drane, S.B.; Robinson, S.D.; MacRaild, C.A.; Chhabra, S.; Chittoor, B.; Morales, R.A.; Leung, E.W.; Belgi, A.; Espino, S.S.; Olivera, B.M.; Robinson, A.J.; Chalmers, D.K.; Norton, R.S. Structure and activity of contryphan-Vc2: Importance of the d-amino acid residue. Toxicon,  2017, 129, 113-122.
[http://dx.doi.org/10.1016/j.toxicon.2017.02.012] [PMID:  28216409] 
[49] 
Vijayasarathy, M.; Basheer, S.M.; Franklin, J.B.; Balaram, P. Contryphan genes and mature peptides in the venom of nine cone snail species by transcriptomic and mass spectrometric analysis. J. Proteome Res.,  2017, 16(2), 763-772.
[http://dx.doi.org/10.1021/acs.jproteome.6b00776] [PMID:  28152596] 
[50] 
Massilia, G.R.; Schininà, M.E.; Ascenzi, P.; Polticelli, F. Contryphan-Vn: a novel peptide from the venom of the Mediterranean snail Conus ventricosus. Biochem. Biophys. Res. Commun.,  2001, 288(4), 908-913.
[http://dx.doi.org/10.1006/bbrc.2001.5833] [PMID:  11688995] 
[51] 
Eliseo, T.; Cicero, D.O.; Romeo, C.; Schininà, M.E.; Massilia, G.R.; Polticelli, F.; Ascenzi, P.; Paci, M. Solution structure of the cyclic peptide contryphan-Vn, a Ca2+-dependent K+ channel modulator. Biopolymers,  2004, 74(3), 189-198.
[http://dx.doi.org/10.1002/bip.20025] [PMID:  15150794] 
[52] 
Massilia, G.R.; Eliseo, T.; Grolleau, F.; Lapied, B.; Barbier, J.; Bournaud, R.; Molgó, J.; Cicero, D.O.; Paci, M.; Schininà, M.E.; Ascenzi, P.; Polticelli, F. Contryphan-Vn: a modulator of Ca2+-dependent K+ channels. Biochem. Biophys. Res. Commun.,  2003, 303(1), 238-246.
[http://dx.doi.org/10.1016/S0006-291X(03)00331-0] [PMID:  12646193] 
[53] 
Pi, C.; Liu, J.; Peng, C.; Liu, Y.; Jiang, X.; Zhao, Y.; Tang, S.; Wang, L.; Dong, M.; Chen, S.; Xu, A. Diversity and evolution of conotoxins based on gene expression profiling of Conus litteratus. Genomics,  2006b, 88(6), 809-819.
[http://dx.doi.org/10.1016/j.ygeno.2006.06.014] [PMID:  16908117] 
[54] 
Thakur, S.S.; Balaram, P. Rapid mass spectral identification of contryphans. Detection of characteristic peptide ions by fragmentation of intact disulfide-bonded peptides in crude venom. Rapid Commun. Mass Spectrom.,  2007, 21(21), 3420-3426.
[http://dx.doi.org/10.1002/rcm.3225] [PMID:  17902199] 
[55] 
Lluisma, A.O.; Milash, B.A.; Moore, B.; Olivera, B.M.; Bandyopadhyay, P.K. Novel venom peptides from the cone snail Conus pulicarius discovered through next-generation sequencing of its venom duct transcriptome. Mar. Genomics,  2012, 5, 43-51.
[http://dx.doi.org/10.1016/j.margen.2011.09.002] [PMID:  22325721] 
[56] 
Rajesh, R.P. Novel M-Superfamily and T-Superfamily conotoxins and contryphans from the vermivorous snail Conus figulinus. J. Pept. Sci.,  2015, 21(1), 29-39.
[http://dx.doi.org/10.1002/psc.2715] [PMID:  25420928] 
[57] 
Han, P.; Cao, Y.; Liu, S.; Dai, X.; Yao, G.; Fan, C.; Wu, W.; Chen, J. Contryphan-Bt: A pyroglutamic acid containing conopeptide isolated from the venom of Conus betulinus. Toxicon,  2017, 135, 17-23.
[http://dx.doi.org/10.1016/j.toxicon.2017.05.022] [PMID:  28554718] 
[58] 
Jimenez, E.C.; Shetty, R.P.; Lirazan, M.; Rivier, J.; Walker, C.; Abogadie, F.C.; Yoshikami, D.; Cruz, L.J.; Olivera, B.M. Novel excitatory Conus peptides define a new conotoxin superfamily. J. Neurochem.,  2003, 85(3), 610-621.
[http://dx.doi.org/10.1046/j.1471-4159.2003.01685.x] [PMID:  12694387] 
[59] 
Buczek, O.; Yoshikami, D.; Watkins, M.; Bulaj, G.; Jimenez, E.C.; Olivera, B.M. Characterization of D-amino-acid-containing excitatory conotoxins and redefinition of the I-conotoxin superfamily. FEBS J.,  2005a, 272(16), 4178-4188.
[http://dx.doi.org/10.1111/j.1742-4658.2005.04830.x] [PMID:  16098199] 
[60] 
Buczek, O.; Yoshikami, D.; Bulaj, G.; Jimenez, E.C.; Olivera, B.M. Post-translational amino acid isomerization: a functionally important D-amino acid in an excitatory peptide. J. Biol. Chem.,  2005b, 280(6), 4247-4253.
[http://dx.doi.org/10.1074/jbc.M405835200] [PMID:  15561705] 
[61] 
Buczek, O.; Wei, D.; Babon, J.J.; Yang, X.; Fiedler, B.; Chen, P.; Yoshikami, D.; Olivera, B.M.; Bulaj, G.; Norton, R.S. Structure and sodium channel activity of an excitatory I1-superfamily conotoxin. Biochemistry,  2007, 46(35), 9929-9940.
[http://dx.doi.org/10.1021/bi700797f] [PMID:  17696362] 
[62] 
Fiedler, B.; Zhang, M.M.; Buczek, O.; Azam, L.; Bulaj, G.; Norton, R.S.; Olivera, B.M.; Yoshikami, D. Specificity, affinity and efficacy of iota-conotoxin RXIA, an agonist of voltage-gated sodium channels Na(V)1.2, 1.6 and 1.7. Biochem. Pharmacol.,  2008, 75(12), 2334-2344.
[http://dx.doi.org/10.1016/j.bcp.2008.03.019] [PMID:  18486102] 
[63] 
Pisarewicz, K.; Mora, D.; Pflueger, F.C.; Fields, G.B.; Marí, F. Polypeptide chains containing D-gamma-hydroxyvaline. J. Am. Chem. Soc.,  2005, 127(17), 6207-6215.
[http://dx.doi.org/10.1021/ja050088m] [PMID:  15853325] 
[64] 
Dutertre, S.; Lumsden, N.G.; Alewood, P.F.; Lewis, R.J. Isolation and characterisation of conomap-Vt, a D-amino acid containing excitatory peptide from the venom of a vermivorous cone snail. FEBS Lett.,  2006, 580(16), 3860-3866.
[http://dx.doi.org/10.1016/j.febslet.2006.06.011] [PMID:  16797543] 
[65] 
Han, Y.; Huang, F.; Jiang, H.; Liu, L.; Wang, Q.; Wang, Y.; Shao, X.; Chi, C.; Du, W.; Wang, C. Purification and structural characterization of a D-amino acid-containing conopeptide, conomarphin, from Conus marmoreus. FEBS J.,  2008, 275(9), 1976-1987.
[http://dx.doi.org/10.1111/j.1742-4658.2008.06352.x] [PMID:  18355315] 
[66] 
Zhang, L.; Shao, X.; Chi, C.; Wang, C. Two short D-Phe-containing cysteine-free conopeptides from Conus marmoreus. Peptides,  2010, 31(1), 177-179.
[http://dx.doi.org/10.1016/j.peptides.2009.10.017] [PMID:  19879909] 
[67] 
Wu, X.C.; Zhou, M.; Peng, C.; Shao, X.X.; Guo, Z.Y.; Chi, C.W. Novel conopeptides in a form of disulfide-crosslinked dimer. Peptides,  2010, 31(6), 1001-1006.
[http://dx.doi.org/10.1016/j.peptides.2010.03.010] [PMID:  20307606] 
[68] 
Mendoza, C.B.; Masacupan, D.J.M.; Batoctoy, D.C.R.; Yu, E.T.; Lluisma, A.O.; Salvador-Reyes, L.A. Conomarphins cause paralysis in mollusk: Critical and tunable structural elements for bioactivity. J. Pept. Sci.,  2019, 25(7) e3179
[http://dx.doi.org/10.1002/psc.3179] [PMID:  31309676] 
[69] 
Zhang, Z.Y.; Ma, N.; Tao, L.J.; Gong, X.Y.; Ye, W.C.; Wang, L. Linear peptides containing D-leucine with neuroprotective activities from the leech Whitmania pigra Whitman. J. Nat. Prod.,  2019, 82(8), 2349-2353.
[http://dx.doi.org/10.1021/acs.jnatprod.9b00322] [PMID:  31361480] 
[70] 
Teramoto, T.; Kuwada, M.; Niidome, T.; Sawada, K.; Nishizawa, Y.; Katayama, K. A novel peptide from funnel web spider venom, omega-Aga-TK, selectively blocks, P-type calcium channels. Biochem. Biophys. Res. Commun.,  1993, 196(1), 134-140.
[http://dx.doi.org/10.1006/bbrc.1993.2225] [PMID:  8216284] 
[71] 
Kuwada, M.; Teramoto, T.; Kumagaye, K.Y.; Nakajima, K.; Watanabe, T.; Kawai, T.; Kawakami, Y.; Niidome, T.; Sawada, K.; Nishizawa, Y. Omega-agatoxin-TK containing D-serine at position 46, but not synthetic omega-[L-Ser46]agatoxin-TK, exerts blockade of P-type calcium channels in cerebellar Purkinje neurons. Mol. Pharmacol.,  1994, 46(4), 587-593.
[PMID: 7969037] 
[72] 
Williams, D.H.; Santikarn, S.; De Angelis, F.; Smith, R.J.; Reid, D.G.; Oelrichs, P.B.; MacLeod, J.K. The structure of a toxic octapeptide from the larvae of sawfly. J. Chem. Soc. Perkin Trans.,  1983, 1, 1869-1878.
[http://dx.doi.org/10.1039/p19830001869] 
[73] 
Kannan, R.; Oelrichs, P.B.; Thamsborg, S.M.; Williams, D.H. Identification of the octapeptide lophyrotomin in the European birch sawfly (Arge pullata). Toxicon,  1988, 26(2), 224-226.
[http://dx.doi.org/10.1016/0041-0101(88)90177-8] [PMID:  3363571] 
[74] 
Oelrichs, P.B.; MacLeod, J.K.; Seawright, A.A.; Moore, M.R.; Ng, J.C.; Dutra, F.; Riet-Corŕea, F.; Mendez, M.C.; Thamsborg, S.M. Unique toxic peptides isolated from sawfly larvae in three continents. Toxicon,  1999, 37(3), 537-544.
[http://dx.doi.org/10.1016/S0041-0101(98)00192-5] [PMID:  10080356] 
[75] 
Oelrichs, P.B.; MacLeod, J.K.; Seawright, A.A.; Grace, P.B. Isolation and identification of the toxic peptides from Lophyrotoma zonalis (Pergidae) sawfly larvae. Toxicon,  2001, 39(12), 1933-1936.
[http://dx.doi.org/10.1016/S0041-0101(01)00144-1] [PMID:  11600157] 
[76] 
Soyez, D.; Van Herp, F.; Rossier, J.; Le Caer, J.P.; Tensen, C.P.; Lafont, R. Evidence for a conformational polymorphism of invertebrate neurohormones. D-amino acid residue in crustacean hyperglycemic peptides. J. Biol. Chem.,  1994, 269(28), 18295-18298.
[PMID: 8034574] 
[77] 
Yasuda, A.; Yasuda, Y.; Fujita, T.; Naya, Y. Characterization of crustacean hyperglycemic hormone from the crayfish (Procambarus clarkii): multiplicity of molecular forms by stereoinversion and diverse functions. Gen. Comp. Endocrinol.,  1994, 95(3), 387-398.
[http://dx.doi.org/10.1006/gcen.1994.1138] [PMID:  7821776] 
[78] 
Huberman, A.; Aguilar, M.B.; Brew, K.; Shabanowitz, J.; Hunt, D.F. Primary structure of the major isomorph of the crustacean hyperglycemic hormone (CHH-I) from the sinus gland of the Mexican crayfish Procambarus bouvieri (Ortmann): interspecies comparison. Peptides,  1993, 14(1), 7-16.
[http://dx.doi.org/10.1016/0196-9781(93)90004-Z] [PMID:  8441709] 
[79] 
Aguilar, M.B.; Soyez, D.; Falchetto, R.; Arnott, D.; Shabanowitz, J.; Hunt, D.F.; Huberman, A. Amino acid sequence of the minor isomorph of the crustacean hyperglycemic hormone (CHH-II) of the Mexican crayfish Procambarus bouvieri (Ortmann): presence of a D-amino acid. Peptides,  1995, 16(8), 1375-1383.
[http://dx.doi.org/10.1016/0196-9781(95)02024-1] [PMID:  8745046] 
[80] 
Salib, M.N.; Molinski, T.F. Cyclic hexapeptide dimers, Antatollamides A and B, from the ascidian Didemnum molle. A tryptophan-derived auxiliary for L- and D-amino acid assignments. J. Org. Chem.,  2017, 82(19), 10181-10187.
[http://dx.doi.org/10.1021/acs.joc.7b01659] [PMID:  28846849] 
[81] 
Montecucchi, P.C.; de Castiglione, R.; Piani, S.; Gozzini, L.; Erspamer, V. Amino acid composition and sequence of dermorphin, a novel opiate-like peptide from the skin of Phyllomedusa sauvagei. Int. J. Pept. Protein Res.,  1981a, 17(3), 275-283.
[http://dx.doi.org/10.1111/j.1399-3011.1981.tb01993.x] [PMID:  7287299] 
[82] 
Montecucchi, P.C.; de Castiglione, R.; Erspamer, V. Identification of dermorphin and Hyp6-dermorphin in skin extracts of the Brazilian frog Phyllomedusa rhodei. Int. J. Pept. Protein Res.,  1981b, 17(3), 316-321.
[http://dx.doi.org/10.1111/j.1399-3011.1981.tb01997.x] [PMID:  7287302] 
[83] 
Richter, K.; Egger, R.; Negri, L.; Corsi, R.; Severini, C.; Kreil, G. cDNAs encoding [D-Ala2]deltorphin precursors from skin of Phyllomedusa bicolor also contain genetic information for three dermorphin-related opioid peptides. Proc. Natl. Acad. Sci. USA,  1990, 87(12), 4836-4839.
[http://dx.doi.org/10.1073/pnas.87.12.4836] [PMID:  2352951] 
[84] 
Mignogna, G.; Severini, C.; Simmaco, M.; Negri, L.; Erspamer, G.F.; Kreil, G.; Barra, D. Identification and characterization of two dermorphins from skin extracts of the Amazonian frog Phyllomedusa bicolor. FEBS Lett.,  1992, 302(2), 151-154.
[http://dx.doi.org/10.1016/0014-5793(92)80427-I] [PMID:  1633846] 
[85] 
Kreil, G.; Barra, D.; Simmaco, M.; Erspamer, V.; Erspamer, G.F.; Negri, L.; Severini, C.; Corsi, R.; Melchiorri, P. Deltorphin, a novel amphibian skin peptide with high selectivity and affinity for delta opioid receptors. Eur. J. Pharmacol.,  1989, 162(1), 123-128.
[http://dx.doi.org/10.1016/0014-2999(89)90611-0] [PMID:  2542051] 
[86] 
Mor, A.; Delfour, A.; Sagan, S.; Amiche, M.; Pradelles, P.; Rossier, J.; Nicolas, P. Isolation of dermenkephalin from amphibian skin, a high-affinity delta-selective opioid heptapeptide containing a D-amino acid residue. FEBS Lett.,  1989, 255(2), 269-274.
[http://dx.doi.org/10.1016/0014-5793(89)81104-4] [PMID:  2551734] 
[87] 
Erspamer, V.; Melchiorri, P.; Falconieri-Erspamer, G.; Negri, L.; Corsi, R.; Severini, C.; Barra, D.; Simmaco, M.; Kreil, G. Deltorphins: a family of naturally occurring peptides with high affinity and selectivity for delta opioid binding sites. Proc. Natl. Acad. Sci. USA,  1989, 86(13), 5188-5192.
[http://dx.doi.org/10.1073/pnas.86.13.5188] [PMID:  2544892] 
[88] 
Kreil, G. Peptides containing a D-amino acid from frogs and molluscs. J. Biol. Chem.,  1994, 269(15), 10967-10970.
[PMID: 8157620] 
[89] 
Barra, D.; Mignogna, G.; Simmaco, M.; Pucci, P.; Severini, C.; Falconieri-Erspamer, G.; Negri, L.; Erspamer, V. [D-Leu2]deltorphin, a 17 amino acid opioid peptide from the skin of the Brazilian hylid frog, Phyllomedusa burmeisteri. Peptides,  1994, 15(2), 199-202.
[http://dx.doi.org/10.1016/0196-9781(94)90002-7] [PMID:  8008623] 
[90] 
Wechselberger, C.; Severini, C.; Kreil, G.; Negri, L. A new opioid peptide predicted from cloned cDNAs from skin of Pachymedusa dacnicolor and Agalychnis annae. FEBS Lett.,  1998, 429(1), 41-43.
[http://dx.doi.org/10.1016/S0014-5793(98)00545-6] [PMID:  9657380] 
[91] 
Amiche, M.; Sagan, S.; Mor, A.; Delfour, A.; Nicolas, P. Dermenkephalin (Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2): a potent and fully specific agonist for the delta opioid receptor. Mol. Pharmacol.,  1989, 35(6), 774-779.
[PMID: 2543911] 
[92] 
Sagan, S.; Amiche, M.; Delfour, A.; Mor, A.; Camus, A.; Nicolas, P. Molecular determinants of receptor affinity and selectivity of the natural delta-opioid agonist, dermenkephalin. J. Biol. Chem.,  1989, 264(29), 17100-17106.
[PMID: 2551895] 
[93] 
Simmaco, M.; Barra, D.; Chiarini, F.; Noviello, L.; Melchiorri, P.; Kreil, G.; Richter, K. A family of bombinin-related peptides from the skin of Bombina variegata. Eur. J. Biochem.,  1991, 199(1), 217-222.
[http://dx.doi.org/10.1111/j.1432-1033.1991.tb16112.x] [PMID:  1712299] 
[94] 
Mignogna, G.; Simmaco, M.; Kreil, G.; Barra, D. Antibacterial and haemolytic peptides containing D-alloisoleucine from the skin of Bombina variegata. EMBO J.,  1993, 12(12), 4829-4832.
[http://dx.doi.org/10.1002/j.1460-2075.1993.tb06172.x] [PMID:  8223491] 
[95] 
Mijiddorj, B.; Kaneda, S.; Sato, H.; Kitahashi, Y.; Javkhlantugs, N.; Naito, A.; Ueda, K.; Kawamura, I. The role of d-allo-isoleucine in the deposition of the anti-Leishmania peptide bombinin H4 as revealed by 31P solid-state NMR, VCD spectroscopy, and MD simulation. Biochim. Biophys. Acta. Proteins Proteomics,  2018, 1866(7), 789-798.
[http://dx.doi.org/10.1016/j.bbapap.2018.01.005] [PMID:  29337209] 
[96] 
de Plater, G.M.; Martin, R.L.; Milburn, P.J. A C-type natriuretic peptide from the venom of the platypus (Ornithorhynchus anatinus): structure and pharmacology. Comp. Biochem. Physiol. C Pharmacol. Toxicol. Endocrinol.,  1998, 120(1), 99-110.
[http://dx.doi.org/10.1016/S0742-8413(98)00030-9] [PMID:  9827022] 
[97] 
Torres, A.M.; Menz, I.; Alewood, P.F.; Bansal, P.; Lahnstein, J.; Gallagher, C.H.; Kuchel, P.W. D-Amino acid residue in the C-type natriuretic peptide from the venom of the mammal, Ornithorhynchus anatinus, the Australian platypus. FEBS Lett.,  2002, 524(1-3), 172-176.
[http://dx.doi.org/10.1016/S0014-5793(02)03050-8] [PMID:  12135762] 
[98] 
Torres, A.M.; Wang, X.; Fletcher, J.I.; Alewood, D.; Alewood, P.F.; Smith, R.; Simpson, R.J.; Nicholson, G.M.; Sutherland, S.K.; Gallagher, C.H.; King, G.F.; Kuchel, P.W. Solution structure of a defensin-like peptide from platypus venom. Biochem. J.,  1999, 341(Pt 3), 785-794.
[http://dx.doi.org/10.1042/bj3410785] [PMID:  10417345] 
[99] 
Torres, A.M.; Tsampazi, C.; Geraghty, D.P.; Bansal, P.S.; Alewood, P.F.; Kuchel, P.W. D-amino acid residue in a defensin-like peptide from platypus venom: effect on structure and chromatographic properties. Biochem. J.,  2005, 391(Pt 2), 215-220.
[http://dx.doi.org/10.1042/BJ20050900] [PMID:  16033333] 
[100] 
Ha, S.; Kim, I.; Takata, T.; Kinouchi, T.; Isoyama, M.; Suzuki, M.; Fujii, N. Identification of ᴅ-amino acid-containing peptides in human serum. PLoS One,  2017, 12(12) e0189972
[http://dx.doi.org/10.1371/journal.pone.0189972] [PMID:  29253022] 
[101] 
Hotchkiss, R.D.; Dubos, R.J. The isolation of bactericidal substances from cultures of Bacillus brevis. J. Biol. Chem.,  1941, 141, 155-162.
[102] 
Lipmann, F.; Hotchkiss, R.D.; Dubos, R.J. The occurrence of D-amino acids in gramicidin and tyrocidine. J. Biol. Chem.,  1941, 141, 163-169.
[103] 
Wallace, B.A. Structure of gramicidin A. Biophys. J.,  1986, 49(1), 295-306.
[http://dx.doi.org/10.1016/S0006-3495(86)83642-6] [PMID:  2420381] 
[104] 
Loll, P.J.; Upton, E.C.; Nahoum, V.; Economou, N.J.; Cocklin, S. The high resolution structure of tyrocidine A reveals an amphipathic dimer. Biochim. Biophys. Acta,  2014, 1838(5), 1199-1207.
[http://dx.doi.org/10.1016/j.bbamem.2014.01.033] [PMID:  24530898] 
[105] 
Broccardo, M.; Erspamer, V.; Falconieri Erspamer, G.; Improta, G.; Linari, G.; Melchiorri, P.; Montecucchi, P.C. Pharmacological data on dermorphins, a new class of potent opioid peptides from amphibian skin. Br. J. Pharmacol.,  1981, 73(3), 625-631.
[http://dx.doi.org/10.1111/j.1476-5381.1981.tb16797.x] [PMID:  7195758] 
[106] 
Basso, N.; Marcelli, M.; Ginaldi, A.; De Marco, M. Intrathecal dermorphine in postoperative analgesia. Peptides,  1985, 6(Suppl. 3), 177-179.
[http://dx.doi.org/10.1016/0196-9781(85)90371-7] [PMID:  3831962] 
[107] 
Hesselink, J.M.K.; Schatman, M.E. Rediscovery of old drugs: the forgotten case of dermorphin for postoperative pain and palliation. J. Pain Res.,  2018, 11, 2991-2995.
[http://dx.doi.org/10.2147/JPR.S186082] [PMID:  30538538] 
[108] 
Liebregts, R.; Keppel Hesselink, J.M.; Kopsky, D.J. Dermorphin: A missed palliative care opportunity for intrathecal therapy in oncological patients? Pain Med.,  2019, 20(10), 2077-2079.
[http://dx.doi.org/10.1093/pm/pnz080] [PMID:  30986300] 
Cite As
Current Protein & Peptide Science

D-Amino Acids in Peptides from Animals, Including Human: Occurrence, Structure, Bioactivity and Pharmacology

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