Production of octaketide polyenes by the calicheamicin polyketide synthase CalE8: implications for the biosynthesis of enediyne core structures.
Enediyne antibiotics are categorized according to the presence of either a 9- or 10-membered ring within their polyketide-derived core structures. Recent literature reports have favored the notion that biosynthetic divergence of the two structural families is determined by the enediyne polyketide synthases (PKSs) alone. We now disclose the simultaneous in vitro production of three octaketide polyenes by biosynthetic enzymes for the 10-membered enediyne calicheamicin gamma(1)(I), including the elusive beta-keto acid precursor to a previously described C15 methyl hexaenone. Alongside these two polyene products, we have additionally detected a hydrocarbon heptaene previously isolated only from 9-membered enediyne systems. The discovery of the heptaene in the calicheamicin system promotes a more convergent model for the early steps of enediyne biosynthesis. Furthermore, the synthesis of this set of octaketides by the enediyne PKS CalE8 and thioesterase CalE7 suggests, in contrast to recent biosynthetic proposals, that accessory enzymes may be necessary to initiate differentiation to 9- or 10-membered enediyne precursors, either by modulation of enediyne PKS activity or by interception and modification of polyketide chain-extension intermediates.
Belecki
Katherine
K
Department of Chemistry, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
Crawford
Jason M
JM
Townsend
Craig A
CA
D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis* / Q000737:chemistry*; D053281:Enediynes / Q000737:chemistry* / Q000378:metabolism*; D008847:Micromonospora / Q000201:enzymology; D011090:Polyenes / Q000378:metabolism*; D048630:Polyketide Synthases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary
D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D011090:Polyenes; D048630:Polyketide Synthases
Chembiochem. 2008 Mar 3;9(4):585-94
18266306
Biochem J. 1992 Dec 15;288 ( Pt 3):839-46
1471999
J Am Chem Soc. 2008 Sep 3;130(35):11614-6
18693732
Curr Opin Chem Biol. 2001 Oct;5(5):525-34
11578925
Chembiochem. 2008 Apr 14;9(6):826-48
18357594
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):11959-63
14528002
J Biol Chem. 2009 Jun 5;284(23):15739-49
19357082
J Am Chem Soc. 2008 Jul 2;130(26):8142-3
18529057
Science. 2002 Aug 16;297(5584):1173-6
12183629
FEMS Microbiol Lett. 2008 May;282(1):105-14
18328078
Chem Biol. 2005 Mar;12(3):293-302
15797213
Science. 2002 Aug 16;297(5584):1170-3
12183628
J Am Chem Soc. 2007 Oct 31;129(43):13082-94
17918933
Eur J Biochem. 1970 Mar 1;13(1):98-110
4392442
Science. 1999 May 21;284(5418):1368-72
10334994
Chem Biol. 1995 Jan;2(1):33-43
9383401
Nat Biotechnol. 2003 Feb;21(2):187-90
12536216
Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1460-5
18223152