title: Cytotoxic Lipopeptide Muscotoxin A, Isolated from Soil  Cyanobacterium Desmonostoc muscorum, Permeabilizes  Phospholipid Membranes by Reducing Their Fluidity.
abstract: There is mounting evidence that cyanobacterial lipopeptides can kill mammalian cells, presenting a hazard to human health. Unfortunately, their mechanism of toxicity is poorly understood. We have isolated new cyclic undecalipopeptides muscotoxin A and B containing unique lipophilicresidue 3-amino-2,5-dihydroxydecanoic acid (5-OH Ahdoa). Muscotoxin B was not used for biological studies due to its poor yield. Muscotoxin A was cytotoxic to YAC-1, Sp/2, and HeLa cancer cell lines (LC(50) ranged from 9.9 to 13.2 μM after 24 h of exposure), causing membrane damage and influx of calcium ions. Subsequently, we studied this lytic mechanism using synthetic liposomes with encapsulated fluorescent probes. Muscotoxin A permeabilized liposomes composed exclusively of phospholipids, demonstrating that no proteins or carbohydrates present in biomembranes are essential for its activity. Paradoxically, the permeabilization activity of muscotoxin A was mediated by a significant reduction in membrane surface fluidity (stiffening), the opposite of that caused by synthetic detergents and cytolytic lipopeptide puwainaphycin F. At 25 °C, muscotoxin A disrupted liposomes with and without cholesterol/sphingomyelin; however, at 37 °C, it was selective against liposomes with cholesterol/sphingomyelin. It appears that both membrane fluidity and organization can affect the lytic activity of muscotoxin A. Our findings strengthen the evidence that cyanobacterial lipopeptides specifically disrupt mammalian cell membranes and bring new insights into the mechanism of this effect.
authors.forename: Petr
authors.initials: P
authors.lastname: Tomek
authors.forename: Pavel
authors.initials: P
authors.lastname: Hrouzek
authors.forename: Marek
authors.initials: M
authors.lastname: Kuzma
authors.forename: Jan
authors.initials: J
authors.lastname: Sýkora
authors.forename: Radovan
authors.initials: R
authors.lastname: Fiser
authors.forename: Jan
authors.initials: J
authors.lastname: Cerný
authors.forename: Petr
authors.initials: P
authors.lastname: Novák
authors.forename: Simona
authors.initials: S
authors.lastname: Bártová
authors.forename: Petr
authors.initials: P
authors.lastname: Simek
authors.forename: Martin
authors.initials: M
authors.lastname: Hof
authors.forename: Daniel
authors.initials: D
authors.lastname: Kavan
authors.forename: Jirí
authors.initials: J
authors.lastname: Kopecký
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D000458:Cyanobacteria / Q000737:chemistry*; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D055666:Lipopeptides / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity*; D008560:Membrane Fluidity / Q000187:drug effects*; D051379:Mice; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000737:chemistry / Q000302:isolation & purification / Q000633:toxicity*; D010743:Phospholipids / Q000737:chemistry*; D014407:Tumor Cells, Cultured
chemical_list: D055666:Lipopeptides; D010456:Peptides, Cyclic; D010743:Phospholipids; C000611056:muscotoxin A