title: Bafilomycin L, a new inhibitor of cholesteryl ester synthesis in mammalian cells, produced by marine-derived Streptomyces sp. OPMA00072.
abstract: Marine-derived Streptomyces sp. OPMA00072 was found to produce inhibitors of the synthesis of neutral lipids in a cell-based assay using Chinese hamster ovary (CHO) cells. A new 16-membered macrolide named bafilomycin L (BFL) (1) was isolated along with the known structurally related bafilomycin C1 (BFC1) (3) from the culture broth of the actinomycete by solvent extraction, octadecylsilyl column chromatography and HPLC. BFL inhibited cholesteryl ester (CE) synthesis in CHO cells with an IC50 value of 0.83 nM and also in mouse peritoneal macrophages with an IC50 of 6.1 nM. In addition, BFL blocked cellular acidification in HeLa cells by interfering with vacuolar H(+)-ATPase (V-ATPase) as well as other bafilomycins. These data strongly suggest that BFL disturbed the lysosome function to block cholesterol metabolism, leading to the inhibition of CE accumulation in mammalian cells.
authors.affiliation: Department of Pharmacy, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Pharmacy, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Fukuda
authors.affiliation: Faculty of Life and Environmental Sciences, University of Tsukuba, Ibaragi, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Usui
authors.affiliation: OP Bio Factory Co., Ltd, No. 58 Uruma Sandpit, Okinawa, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kurihara
authors.affiliation: OP Bio Factory Co., Ltd, No. 58 Uruma Sandpit, Okinawa, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kanamoto
authors.affiliation: Department of Pharmacy, Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomoda
mesh_terms: D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D013302:Streptomyces / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002788:Cholesterol Esters; D018942:Macrolides; C000597313:bafilomycin L; C052502:bafilomycin C1; D002784:Cholesterol; D025262:Vacuolar Proton-Translocating ATPases
references.citation: Histol Histopathol. 2007 Apr;22(4):443-54
references.pmid: 17290355
references.citation: J Biol Chem. 1985 Jan 25;260(2):1090-5
references.pmid: 2857169
references.citation: J Biol Chem. 2005 Dec 9;280(49):40481-8
references.pmid: 16216877
references.citation: J Nat Prod. 2010 Mar 26;73(3):422-7
references.pmid: 20028134
references.citation: Biochemistry. 1993 Apr 20;32(15):3902-6
references.pmid: 8385991
references.citation: J Antibiot (Tokyo). 2012 Jan;65(1):15-9
references.pmid: 22108679
references.citation: J Neurochem. 2010 Aug;114(4):1193-204
references.pmid: 20534000
references.citation: J Biochem. 1999 Feb;125(2):319-27
references.pmid: 9990129
references.citation: J Antibiot (Tokyo). 2012 Jun;65(6):331-4
references.pmid: 22491135
references.citation: J Antibiot (Tokyo). 1981 Oct;34(10):1253-6
references.pmid: 7309621
references.citation: Biosci Biotechnol Biochem. 2006 Jun;70(6):1364-70
references.pmid: 16794315
references.citation: Can J Biochem Physiol. 1959 Aug;37(8):911-7
references.pmid: 13671378
references.citation: J Lipid Res. 2004 Feb;45(2):378-86
references.pmid: 14617738
references.citation: J Antibiot (Tokyo). 2012 May;65(5):255-62
references.pmid: 22415459
references.citation: Am J Pathol. 1980 Jul;100(1):57-80
references.pmid: 6772035
references.citation: Subcell Biochem. 1997;28:235-76
references.pmid: 9090297
references.citation: J Antibiot (Tokyo). 2007 Jan;60(1):43-51
references.pmid: 17390588
references.citation: J Cell Biol. 1979 Sep;82(3):597-613
references.pmid: 229107
references.citation: Cell Mol Life Sci. 2006 Jun;63(12):1355-69
references.pmid: 16649142
references.citation: J Antibiot (Tokyo). 1984 May;37(5):610-3
references.pmid: 6547434
references.citation: J Antibiot (Tokyo). 1988 Feb;41(2):250-2
references.pmid: 3356613
references.citation: J Antibiot (Tokyo). 1984 Nov;37(11):1333-43
references.pmid: 6511660
references.citation: J Biol Chem. 1993 Dec 25;268(36):27345-8
references.pmid: 8262974
references.citation: J Antibiot (Tokyo). 2011 Jul;64(7):489-94
references.pmid: 21559025
references.citation: J Biol Chem. 2004 Aug 6;279(32):33131-8
references.pmid: 15180988
references.citation: J Antibiot (Tokyo). 2010 Oct;63(10):627-9
references.pmid: 20808316
references.citation: J Antibiot (Tokyo). 1984 Feb;37(2):110-7
references.pmid: 6423597
references.citation: Proc Natl Acad Sci U S A. 1979 Jan;76(1):333-7
references.pmid: 218198
references.citation: J Antibiot (Tokyo). 2011 May;64(5):391-3
references.pmid: 21386849
references.citation: Cell. 2011 Apr 29;145(3):341-55
references.pmid: 21529710
references.citation: Proc Natl Acad Sci U S A. 1988 Nov;85(21):7972-6
references.pmid: 2973058
references.citation: Eur J Biochem. 1992 Jul 1;207(1):383-9
references.pmid: 1628660
references.citation: Biochim Biophys Acta. 1992 Jun 5;1126(1):41-8
references.pmid: 1606174
references.citation: Curr Med Chem. 2003 May;10(9):787-96
references.pmid: 12678782
references.citation: Biosci Biotechnol Biochem. 2013;77(9):1964-6
references.pmid: 24018676
references.citation: J Antibiot (Tokyo). 2010 Jul;63(7):359-63
references.pmid: 20551984
references.citation: J Antibiot (Tokyo). 1997 Dec;50(12):1073-7
references.pmid: 9510919
references.citation: J Mol Biol. 1990 Oct 5;215(3):403-10
references.pmid: 2231712