Amino Acids

, Volume 41, Issue 5, pp 1071–1079

Lantibiotics as probes for phosphatidylethanolamine

Review Article


Phosphatidylethanolamine (PE) is a major component in the mammalian plasma membrane. It is present mainly in the inner leaflet of the membrane bilayer in a viable, typical mammalian cell. However, accumulating evidence indicates that a number of biological events involve PE externalization. For instance, PE is concentrated at the surface of cleavage furrow between mitotic daughter cells and is correlated with the dynamics of contractile ring. In apoptotic cells, PE is exposed to the cell surface, thus providing a molecular marker for detection. In addition, PE is a cofactor in the anticoagulant mechanism, and a distinct distribution profile of PE has been documented at the blood–endothelium interface. These recent discoveries were made possible using PE-specific probes derived from duramycin and cinnamycin, which are members of type B lantibiotics. This review provides an account on the features of these PE-specific lantibiotics in the context of molecular probes for the characterization of PE on a cellular and tissue level. According to the existing data, PE is likely a versatile chemical species that plays a role in the regulation of defined biological and physiological activities. The utilities of lantibiotic-based molecular probes will help accelerate the characterization of PE as an abundant, yet elusive membrane component.


Duramycin Cinnamycin Phosphatidylethanolamine Anticoagulant Apoptosis Cytokinesis Imaging probe 


  1. Aoki Y, Uenaka T, Aoki J, Umeda M, Inoue K (1994) A novel peptide probe for studying the transbilayer movement of phosphatidylethanolamine. J Biochem 116:291–297PubMedGoogle Scholar
  2. Berard M, Chantome R, Marcelli A, Boffa MC (1996) Antiphosphatidylethanolamine antibodies as the only antiphospholipid antibodies. I. Association with thrombosis and vascular cutaneous diseases. J Rheumatol 23:1369–1374PubMedGoogle Scholar
  3. Bevers EM, Comfurius P, Zwaal RF (1996) Regulatory mechanisms in maintenance and modulation of transmembrane lipid asymmetry: pathophysiological implications. Lupus 5:480–487PubMedGoogle Scholar
  4. Bevers EM, Comfurius P, Dekkers DW et al (1999) Lipid translocation across the plasma membrane of mammalian cells. Biochim Biophys Acta 1439:317–330PubMedGoogle Scholar
  5. Bi EF, Lutkenhaus J (1991) FtsZ ring structure associated with division in Escherichia coli. Nature 354:161–164PubMedCrossRefGoogle Scholar
  6. Blankenberg FG, Katsikis PD, Tait JF, Davis RE, Naumovski L, Ohtsuki K, Kopiwoda S, Abrams MJ, Darkes M, Robbins RC, Maecker HT, Strauss HW (1998) In vivo detection and imaging of phosphatidylserine expression during programmed cell death. Proc Natl Acad Sci USA 95:6349–6354PubMedCrossRefGoogle Scholar
  7. Bleeker-Rovers CP, Boerman OC, Rennen HJ, Corstens FH, Oyen WJ (2004) Radiolabeled compounds in diagnosis of infectious and inflammatory disease. Curr Pharm Des 10:2935–2950PubMedCrossRefGoogle Scholar
  8. Brötz H, Josten M, Wiedemann I, Schneider U, Götz F, Bierbaum G, Sahl HG (1998) Role of lipid-bound peptidoglycan precursors in the formation of pores by nisin, epidermin and other lantibiotics. Mol Microbiol 30:317–3127PubMedCrossRefGoogle Scholar
  9. Chandran KB (1993) Flow dynamics in the human aorta. J Biomech Eng 115:611–616PubMedCrossRefGoogle Scholar
  10. Choung SY, Kobayashi T, Inoue J, Takemoto K, Ishitsuka H, Inoue K (1988) Hemolytic activity of a cyclic peptide Ro09–0198 isolated from Streptoverticillium. Biochim Biophys Acta 940:171–179PubMedCrossRefGoogle Scholar
  11. Devaux PF (1991) Static and dynamic lipid asymmetry in cell membranes. Biochemistry 30:1163–1173PubMedCrossRefGoogle Scholar
  12. Emoto K, Umeda M (2000) An essential role for a membrane lipid in cytokinesis. Regulation of contractile ring disassembly by redistribution of phosphatidylethanolamine. J Cell Biol 149:1215–1224PubMedCrossRefGoogle Scholar
  13. Emoto K, Kobayashi T, Yamaji A, Aizawa H, Yahara I, Inoue K, Umeda M (1996) Redistribution of phosphatidylethanolamine at the cleavage furrow of dividing cells during cytokinesis. Proc Natl Acad Sci USA 93:12867–12872PubMedCrossRefGoogle Scholar
  14. Emoto K, Toyama-Sorimachi N, Karasuyama H, Inoue K, Umeda M (1997) Exposure of phosphatidylethanolamine on the surface of apoptotic cells. Exp Cell Res 232:430–434PubMedCrossRefGoogle Scholar
  15. Emoto K, Inadome H, Kanaho Y, Narumiya S, Umeda M (2005) Local change in phospholipid composition at the cleavage furrow is essential for completion of cytokinesis. J Biol Chem 280:37901–37907PubMedCrossRefGoogle Scholar
  16. Esmon NL, Smirnov MD, Esmon CT (1997a) Lupus anticoagulants and thrombosis: the role of phospholipids. Haematologica 82:474–477PubMedGoogle Scholar
  17. Esmon NL, Smirnov MD, Esmon CT (1997b) Thrombogenic mechanisms of antiphospholipid antibodies. Thromb Haemost 78:79–82PubMedGoogle Scholar
  18. Esmon NL, Smirnov MD, Safa O, Esmon CT (1999) Lupus anticoagulants, thrombosis and the protein C system. Haematologica 84:446–451PubMedGoogle Scholar
  19. Hachulla E, Harle JR, Sie P, Boffa MC (2007) Antiphosphatidylethanolamine antibodies are associated with an increased odds ratio for thrombosis. A multicenter study with the participation of the European Forum on antiphospholipid antibodies. Thromb Haemost 97:949–954PubMedGoogle Scholar
  20. Hayashi F, Nagashima K, Terui Y, Kawamura Y, Matsumoto K, Itazaki H (1990) The structure of PA48009: the revised structure of duramycin. J Antibiot 43:1421–1430PubMedGoogle Scholar
  21. Hosoda K, Ohya M, Kohno T, Maeda T, Endo S, Wakamatsu K (1996) Structure determination of an immunopotentiator peptide, cinnamycin, complexed with lysophosphatidylethanolamine by 1H-NMR1. J Biochem 119:226–230PubMedGoogle Scholar
  22. Iwamoto K, Kobayashi S, Fukuda R, Umeda M, Kobayashi T, Ohta A (2004) Local exposure of phosphatidylethanolamine on the yeast plasma membrane is implicated in cell polarity. Genes Cells 9:891–903PubMedCrossRefGoogle Scholar
  23. Johnson LL, Schofield L, Donahay T, Narula N, Narula J (2005) 99mTc-annexin V imaging for in vivo detection of atherosclerotic lesions in porcine coronary arteries. J Nucl Med 46:1186–1193PubMedGoogle Scholar
  24. Kaletta C, Entian KD, Jung G (1991) Prepeptide sequence of cinnamycin (Ro 09–0198): the first structural gene of a duramycin-type lantibiotic. Eur J Biochem 199:411–415PubMedCrossRefGoogle Scholar
  25. Kato U, Emoto K, Fredriksson C, Nakamura H, Ohta A, Kobayashi T, Murakami-Murofushi K, Kobayashi T, Umeda M (2002) A novel membrane protein, Ros3p, is required for phospholipid translocation across the plasma membrane in Saccharomyces cerevisiae. J Biol Chem 277:37855–37862PubMedCrossRefGoogle Scholar
  26. Kiestelaer BL, Reutelingsperger CPM, Heidendal GAK, Daemen MJAP, Mess WH, Hofstra L (2004) Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis. N Engl J Med 350:1472–1473Google Scholar
  27. Li Z, Wells CW, Esmon CT, Zhao M (2009) Phosphatidylethanolamine at the endothelial surface of aortic flow dividers. J Thromb Haemost 7:227–229PubMedCrossRefGoogle Scholar
  28. Li Z, Wells CW, North PE, Kumar S, Duris CB, McIntyre JA, Zhao M (2010) Phosphatidylethanolamine at the luminal endothelial surface—implications in hemostasis and thrombotic autoimmunity. Clin Appl Thromb Hem (in press)Google Scholar
  29. Liu S, Edwards DS (1999) 99mTc-labeled small peptides as diagnostic radiopharmaceuticals. Chem Rev 99:2235–2268PubMedCrossRefGoogle Scholar
  30. Liu Z, Zhao M, Zhu X, Furenlid LR, Chen YC, Barrett HH (2007) In vivo dynamic imaging of myocardial cell death using 99mTc-labeled C2A domain of synaptotagmin I in a rat model of ischemia and reperfusion. Nucl Med Biol 34:907–915PubMedCrossRefGoogle Scholar
  31. Machaidze G, Seelig J (2003) Specific binding of cinnamycin (Ro 09–0198) to phosphatidylethanolamine. Comparison between micellar and membrane environments. Biochemistry 42:12570–12576PubMedCrossRefGoogle Scholar
  32. Marconescu A, Thorpe PE (2008) Coincident exposure of phosphatidylethanolamine and anionic phospholipids on the surface of irradiated cells. Biochim Biophys Acta 1778:2217–2224PubMedCrossRefGoogle Scholar
  33. Maulik N, Kagan VE, Tyurin VA, Das DK (1998) Redistribution of phosphatidylethanolamine and phosphatidylserine precedes reperfusion-induced apoptosis. Am J Physiol 274:H242–H248PubMedGoogle Scholar
  34. Mileykovskaya E, Sun Q, Margolin W, Dowhan W (1998) Localization and function of early cell division proteins in filamentous Escherichia coli cells lacking phosphatidylethanolamine. J Bacteriol 180:4252–4257PubMedGoogle Scholar
  35. Narula J, Acio ER, Narula N, Samuels LE, Fyfe B, Wood D, Fitzpatrick JM, Raghunath PN, Tomaszewski JE, Kelly C, Steinmetz N, Green A, Tait JF, Leppo J, Blankenberg FG, Jain D, Strauss HW (2001) Annexin-V imaging for noninvasive detection of cardiac allograft rejection. Nat Med 7:1347–1352PubMedCrossRefGoogle Scholar
  36. Pag U, Sahl HG (2002) Multiple activities in lantibiotics—models for the design of novel antibiotics? Curr Pharm Des 8:815–833PubMedCrossRefGoogle Scholar
  37. Rouser G, Yamamoto A, Kritchevsky G (1971) Cellular membranes. Structure and regulation of lipid class composition species differences, changes with age, and variations in some pathological states. Arch Intern Med 127:1105–1121PubMedCrossRefGoogle Scholar
  38. Sahl HG, Bierbaum G (1998) Lantibiotics: biosynthesis and biological activities of uniquely modified peptides from gram-positive bacteria. Annu Rev Microbiol 52:41–79PubMedCrossRefGoogle Scholar
  39. Sahu SK, Gummadi SN, Manoj N, Aradhyam GK (2007) Phospholipid scramblases: an overview. Arch Biochem Biophys 462:103–114PubMedCrossRefGoogle Scholar
  40. Sanmarco M, Alessi MC, Harle JR, Sapin C, Aillaud MF, Gentile S, Juhan-Vague I, Weiller PJ (2001) Antibodies to phosphatidylethanolamine as the only antiphospholipid antibodies found in patients with unexplained thromboses. Thromb Haemost 85:800–805PubMedGoogle Scholar
  41. Seelig J (2004) Thermodynamics of lipid-peptide interactions. Biochim Biophys Acta 1666:40–50PubMedCrossRefGoogle Scholar
  42. Smirnov MD, Esmon CT (1994) Phosphatidylethanolamine incorporation into vesicles selectively enhances factor Va inactivation by activated protein C. J Biol Chem 269:816–819PubMedGoogle Scholar
  43. Smirnov MD, Triplett DT, Comp PC, Esmon NL, Esmon CT (1995) On the role of phosphatidylethanolamine in the inhibition of activated protein C activity by antiphospholipid antibodies. J Clin Invest 95:309–316PubMedCrossRefGoogle Scholar
  44. Smirnov MD, Ford DA, Esmon CT, Esmon NL (1999) The effect of membrane composition on the hemostatic balance. Biochemistry 38:3591–3598PubMedCrossRefGoogle Scholar
  45. Song Z, Steller H (1999) Death by design: mechanism and control of apoptosis. Trends Cell Biol 9:M49–M52PubMedCrossRefGoogle Scholar
  46. Sosnovik DE, Schellenberger EA, Nahrendorf M, Novikov MS, Matsui T, Dai G, Reynolds F, Grazette L, Rosenzweig A, Weissleder R, Josephson L (2005) Magnetic resonance imaging of cardiomyocyte apoptosis with a novel magneto-optical nanoparticle. Magn Reson 54:718–724CrossRefGoogle Scholar
  47. Spector AA, Yorek MA (1985) Membrane lipid composition and cellular function. J Lipid Res 26:1015–1035PubMedGoogle Scholar
  48. Sugi T, Katsunuma J, Izumi S, McIntyre JA, Makino T (1999) Prevalence and heterogeneity of antiphosphatidylethanolamine antibodies in patients with recurrent early pregnancy losses. Fertil Steril 71:1060–1065PubMedCrossRefGoogle Scholar
  49. Sugi T, Matsubayashi H, Inomo A, Dan L, Makino T (2004) Antiphosphatidylethanolamine antibodies in recurrent early pregnancy loss and mid-to-late pregnancy loss. J Obstet Gynaecol Res 30:326–332PubMedCrossRefGoogle Scholar
  50. Thimister PW, Hofstra L, Liem IH, Boersma HH, Kemerink G, Reutelingsperger CP, Heidendal GA (2003) In vivo detection of cell death in the area at risk in acute myocardial infarction. J Nucl Med 44:391–396PubMedGoogle Scholar
  51. Tian Y, Jackson P, Gunter C, Wang J, Rock CO, Jackowski S (2006) Placental thrombosis and spontaneous fetal death in mice deficient in ethanolamine kinase 2. J Biol Chem 281:28438–28449PubMedCrossRefGoogle Scholar
  52. Umeda M, Emoto K (1999) Membrane phospholipid dynamics during cytokinesis: regulation of actin filament assembly by redistribution of membrane surface phospholipid. Chem Phys Lipids 101:81–91PubMedCrossRefGoogle Scholar
  53. Vinatier D, Dufour P, Cosson M, Houpeau JL (2001) Antiphospholipid syndrome and recurrent miscarriages. Eur J Obstet Gynecol Reprod Biol 96:37–50PubMedCrossRefGoogle Scholar
  54. Wakamatsu K, Choung SY, Kobayashi T, Inoue K, Higashijima T, Miyazawa T (1990) Complex formation of peptide antibiotic Ro09–0198 with lysophosphatidylethanolamine: 1H NMR analyses in dimethyl sulfoxide solution. Biochemistry 29:113–118PubMedCrossRefGoogle Scholar
  55. Widdick DA, Dodd HM, Barraille P, White J, Stein TH, Chater KF, Gasson MJ, Bibb MJ (2003) Cloning and engineering of the cinnamycin biosynthetic gene cluster from Streptomyces cinnamoneus cinnamoneus DSM 40005. Proc Natl Acad Sci USA 100:4316–4321PubMedCrossRefGoogle Scholar
  56. Williamson P, Schlegel RA (2002) Transbilayer phospholipid movement and the clearance of apoptotic cells. Biochim Biophys 1585:53–63Google Scholar
  57. Wyllie AH (1997) Apoptosis: an overview. Br Med Bull 53:451–465PubMedGoogle Scholar
  58. Zhao M, Beauregard DA, Loizou L, Davletov B, Brindle KM (2001) Non-invasive detection of apoptosis using magnetic resonance imaging and a targeted contrast agent. Nat Med 7:1241–1244PubMedCrossRefGoogle Scholar
  59. Zhao M, Zhu X, Ji S, Zhou J, Ozker KS, Fang W, Molthen RC, Hellman RS (2006) 99mTc-labeled C2A domain of synaptotagmin I as a target-specific molecular probe for noninvasive imaging of acute myocardial infarction. J Nucl Med 47:1367–1374PubMedGoogle Scholar
  60. Zhao M, Li Z, Bugenhagen S (2008) 99mTc-labeled duramycin as a novel phosphatidylethanolamine-binding molecular probe. J Nucl Med 49:1345–1352PubMedCrossRefGoogle Scholar
  61. Zimmermann N, Freund S, Fredenhagen A, Jung G (1993) Solution structures of the lantibiotics duramycin B and C. Eur J Biochem 216:419–428PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  1. 1.Department of BiophysicsMedical College of WisconsinMilwaukeeUSA

Personalised recommendations