Iterative chain elongation by a pikromycin monomodular polyketide synthase

被引:44
作者
Beck, BJ
Aldrich, CC
Fecik, RA
Reynolds, KA
Sherman, DH [1 ]
机构
[1] Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA
[2] Univ Minnesota, Inst Biotechnol, Minneapolis, MN 55455 USA
[3] Univ Minnesota, Dept Med Chem, Minneapolis, MN 55455 USA
[4] Virginia Commonwealth Univ, Dept Med Chem, Richmond, VA 23284 USA
[5] Virginia Commonwealth Univ, Inst Struct Biol & Drug Discovery, Richmond, VA 23284 USA
关键词
D O I
10.1021/ja029974c
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
The unique ability of the pikromycin polyketide synthase (Pik PKS) to generate 12- and 14-membered ring macrolactones presents an opportunity to explore the fundamental processes of polyketide synthesis, specifically, the mechanistic details of the chain extension process. We have overexpressed and purified PikAIII and PikAIV and demonstrated the ability of these proteins to generate triketide lactone products using 14C-methylmalonyl-CoA as the sole substrate. Monomodular PikAIII generates TKL (1) when reacted alone, and synthesizes TKL (2) upon reaction in combination with PikAIV. Product formation remains dependent on the enzymatic decarboxylation of methylmalonyl-CoA and transfer of the acyl chain within the enzyme rather than acylation by propionyl-CoA from spontaneous decarboxylation. We propose that synthesis of TKL (1) by PikAIII involves iterative assembly of the triketide chain within a PikAIII homodimer analogous to the nonmodular type I PKS systems. Copyright © 2003 American Chemical Society.
引用
收藏
页码:4682 / 4683
页数:2
相关论文
共 16 条
  • [1] The calicheamicin gene cluster and its iterative type I enediyne PKS
    Ahlert, J
    Shepard, E
    Lomovskaya, N
    Zazopoulos, E
    Staffa, A
    Bachmann, BO
    Huang, KX
    Fonstein, L
    Czisny, A
    Whitwam, RE
    Farnet, CM
    Thorson, JS
    [J]. SCIENCE, 2002, 297 (5584) : 1173 - 1176
  • [2] Functional orientation of the acyltransferase domain in a module of the erythromycin polyketide synthase
    Gokhale, RS
    Lau, J
    Cane, DE
    Khosla, C
    [J]. BIOCHEMISTRY, 1998, 37 (08) : 2524 - 2528
  • [3] MOLECULAR-GENETICS OF POLYKETIDES AND ITS COMPARISON TO FATTY-ACID BIOSYNTHESIS
    HOPWOOD, DA
    [J]. ANNUAL REVIEW OF GENETICS, 1990, 24 : 37 - 66
  • [4] Aspects of the biosynthesis of non-aromatic fungal polyketides by iterative polyketide synthases
    Hutchinson, CR
    Kennedy, J
    Park, C
    Kendrew, S
    Auclair, K
    Vederas, J
    [J]. ANTONIE VAN LEEUWENHOEK INTERNATIONAL JOURNAL OF GENERAL AND MOLECULAR MICROBIOLOGY, 2000, 78 (3-4): : 287 - 295
  • [5] Spontaneous priming of a downstream module in 6-deoxyerythronolide B synthase leads to polyketide biosynthesis
    Jacobsen, JR
    Cane, DE
    Khosla, C
    [J]. BIOCHEMISTRY, 1998, 37 (14) : 4928 - 4934
  • [6] Evidence for two catalytically independent clusters of active sites in a functional modular polyketide synthase
    Kao, CM
    Pieper, R
    Cane, DE
    Khosla, C
    [J]. BIOCHEMISTRY, 1996, 35 (38) : 12363 - 12368
  • [7] Manipulation of modular polyketide syntheses
    Katz, L
    [J]. CHEMICAL REVIEWS, 1997, 97 (07) : 2557 - 2575
  • [8] A new enzyme superfamily - The phosphopantetheinyl transferases
    Lambalot, RH
    Gehring, AM
    Flugel, RS
    Zuber, P
    LaCelle, M
    Marahiel, MA
    Reid, R
    Khosla, C
    Walsh, CT
    [J]. CHEMISTRY & BIOLOGY, 1996, 3 (11): : 923 - 936
  • [9] Biosynthesis of the enediyne antitumor antibiotic C-1027
    Liu, W
    Christenson, SD
    Standage, S
    Shen, B
    [J]. SCIENCE, 2002, 297 (5584) : 1170 - 1173
  • [10] Evidence for a double-helical structure for modular polyketide synthases
    Staunton, J
    Caffrey, P
    Aparicio, JF
    Roberts, GA
    Bethell, SS
    Leadlay, PF
    [J]. NATURE STRUCTURAL BIOLOGY, 1996, 3 (02): : 188 - 192