bryA:: An unusual modular polyketide synthase gene from the uncultivated bacterial symbiont of the marine bryozoan Bugula neritina

被引:104
作者
Hildebrand, M
Waggoner, LE
Liu, HB
Sudek, S
Allen, S
Anderson, C
Sherman, DH
Haygood, M [1 ]
机构
[1] Univ Calif San Diego, Ctr Marine Biotechnol & Biomed, Scripps Inst Oceanog, Div Marine Biol Res, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Ctr Canc, La Jolla, CA 92093 USA
[3] Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA
[4] Inst Life Sci, Dept Med Chem, Ann Arbor, MI 48109 USA
来源
CHEMISTRY & BIOLOGY | 2004年 / 11卷 / 11期
关键词
D O I
10.1016/j.chembiol.2004.08.018
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Candidatus Endobugula sertula, the uncultivated bacterial symbiont of Bugula neritina, is the proposed source of the bryostatin family of anticancer compounds. We cloned a large modular polyketide synthase (PKS) gene complex from "Candidatus Endobugula sertula" and characterized one gene, bryA, which we propose is responsible for the initial steps of bryostatin biosynthesis. Typical PKS domains are present. However, acyltransferase domains are lacking in bryA, and beta-ketoacyl synthase domains of bryA cluster with those of PKSs with discrete, rather than integral, acyltransferases. We propose a model for biosynthesis of the bryostatin D-lactate starter unit by the bryA loading module, utilizing atypical domains homologous to FkbH, KR, and DH. The bryA gene product is proposed to synthesize a portion of the pharmacologically active part of bryostatin and may be useful in semisynthesis of clinically useful bryostatin analogs.
引用
收藏
页码:1543 / 1552
页数:10
相关论文
共 54 条
  • [1] BASIC LOCAL ALIGNMENT SEARCH TOOL
    ALTSCHUL, SF
    GISH, W
    MILLER, W
    MYERS, EW
    LIPMAN, DJ
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 1990, 215 (03) : 403 - 410
  • [2] Ex vivo expansion of tumor-draining lymph node cells using compounds which activate intracellular signal transduction .1. Characterization and in vivo anti-tumor activity of glioma-sensitized lymphocytes
    Baldwin, NG
    Rice, CD
    Tuttle, TM
    Bear, HD
    Hirsch, JI
    Merchant, RE
    [J]. JOURNAL OF NEURO-ONCOLOGY, 1997, 32 (01) : 19 - 28
  • [3] ABSOLUTE MESSENGER-RNA QUANTIFICATION USING THE POLYMERASE CHAIN-REACTION (PCR) - A NOVEL-APPROACH BY A PCR AIDED TRANSCRIPT TITRATION ASSAY (PATTY)
    BECKERANDRE, M
    HAHLBROCK, K
    [J]. NUCLEIC ACIDS RESEARCH, 1989, 17 (22) : 9437 - 9446
  • [4] 6-DEOXYERYTHRONOLIDE-B SYNTHASE-2 FROM SACCHAROPOLYSPORA-ERYTHRAEA - CLONING OF THE STRUCTURAL GENE, SEQUENCE-ANALYSIS AND INFERRED DOMAIN-STRUCTURE OF THE MULTIFUNCTIONAL ENZYME
    BEVITT, DJ
    CORTES, J
    HAYDOCK, SF
    LEADLAY, PF
    [J]. EUROPEAN JOURNAL OF BIOCHEMISTRY, 1992, 204 (01): : 39 - 49
  • [5] A phase II trial of bryostatin 1 in patients with non-Hodgkin's lymphoma
    Blackhall, FH
    Ranson, M
    Radford, JA
    Hancock, BW
    Soukop, M
    McGown, AT
    Robbins, A
    Halbert, G
    Jayson, GC
    [J]. BRITISH JOURNAL OF CANCER, 2001, 84 (04) : 465 - 469
  • [6] Conserved amino acid residues correlating with ketoreductase stereospecificity in modular polyketicle synthases
    Caffrey, P
    [J]. CHEMBIOCHEM, 2003, 4 (07) : 654 - 657
  • [7] Identification of a set of genes involved in the formation of the substrate for the incorporation of the unusual "glycolate" chain extension unit in ansamitocin biosynthesis
    Carroll, BJ
    Moss, SJ
    Bai, LQ
    Kato, Y
    Toelzer, S
    Yu, TW
    Floss, HG
    [J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2002, 124 (16) : 4176 - 4177
  • [8] Type I polyketide synthase requiring a discrete acyltransferase for polyketide biosynthesis
    Cheng, YQ
    Tang, GL
    Shen, B
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (06) : 3149 - 3154
  • [9] BRYOSTATIN-1 ENHANCES LYMPHOKINE-ACTIVATED KILLER SENSITIVITY AND MODULATES THE BETA(1) INTEGRIN PROFILE OF CULTURED HUMAN TUMOR-CELLS
    CORREALE, P
    CARAGLIA, M
    FABBROCINI, A
    GUARRASI, R
    PEPE, S
    PATELLA, V
    MARONE, G
    PINTO, A
    BIANCO, AR
    TAGLIAFERRI, P
    [J]. ANTI-CANCER DRUGS, 1995, 6 (02) : 285 - 290
  • [10] Evidence for the biosynthesis of bryostatins by the bacterial symbiont "Candidatus Endobugula sertula" of the bryozoan Bugula neritina
    Davidson, SK
    Allen, SW
    Lim, GE
    Anderson, CM
    Haygood, MG
    [J]. APPLIED AND ENVIRONMENTAL MICROBIOLOGY, 2001, 67 (10) : 4531 - 4537