Tolerance and specificity of polyketide synthases.

Polyketide synthases catalyze the assembly of complex natural products from simple precursors such as propionyl-CoA and methylmalonyl-CoA in a biosynthetic process that closely parallels fatty acid biosynthesis. Like fatty acids, polyketides are assembled by successive decarboxylative condensations of simple precursors. But whereas the intermediates in fatty acid biosynthesis are fully reduced to generate unfunctionalized alkyl chains, the intermediates in polyketide biosynthesis may be only partially processed, giving rise to complex patterns of functional groups. Additional complexity arises from the use of different starter and chain extension substrates, the generation of chiral centers, and further functional group modifications, such as cyclizations. The structural and functional modularity of these multienzyme systems has raised the possibility that polyketide biosynthetic pathways might be rationally reprogrammed by combinatorial manipulation. An essential prerequisite for harnessing this biosynthetic potential is a better understanding of the molecular recognition features of polyketide synthases. Within this decade, a variety of genetic, biochemical, and chemical investigations have yielded insights into the tolerance and specificity of several architecturally different polyketide synthases. The results of these studies, together with their implications for biosynthetic engineering, are summarized in this review.

[1]  P. Leadlay,et al.  Polyketide synthesis in vitro on a modular polyketide synthase. , 1995, Chemistry & biology.

[2]  D. Sherman,et al.  Molecular genetics of polyketides and its comparison to fatty acid biosynthesis. , 1990, Annual review of genetics.

[3]  D. Cane,et al.  Functional orientation of the acyltransferase domain in a module of the erythromycin polyketide synthase. , 1998, Biochemistry.

[4]  C. Khosla,et al.  Engineered Biosynthesis of Novel Polyketides: actVII and actIV Genes Encode Aromatase and Cyclase Enzymes, Respectively , 1994 .

[5]  C R Hutchinson,et al.  Biosynthesis of the ansamycin antibiotic rifamycin: deductions from the molecular analysis of the rif biosynthetic gene cluster of Amycolatopsis mediterranei S699. , 1998, Chemistry & biology.

[6]  C M Kao,et al.  Engineered intermodular and intramodular polyketide synthase fusions. , 1997, Chemistry & biology.

[7]  B. Shen,et al.  The Streptomyces glaucescens tcmKL polyketide synthase and tcmN polyketide cyclase genes govern the size and shape of aromatic polyketides , 1995 .

[8]  C. Kao,et al.  6-deoxyerythronolide B synthase 1 is specifically acylated by a diketide intermediate at the beta-ketoacyl-acyl carrier protein synthase domain of module 2. , 1996, Biochemistry.

[9]  L. Katz,et al.  Identification and characterization of the niddamycin polyketide synthase genes from Streptomyces caelestis , 1997, Journal of bacteriology.

[10]  K. O. Elliston,et al.  Structural organization of a multifunctional polyketide synthase involved in the biosynthesis of the macrolide immunosuppressant FK506. , 1997, European journal of biochemistry.

[11]  D. Cane,et al.  Molecular recognition of diketide substrates by a beta-ketoacyl-acyl carrier protein synthase domain within a bimodular polyketide synthase. , 1997, Chemistry & biology.

[12]  Camilla M. Kao,et al.  GAIN OF FUNCTION MUTAGENESIS OF THE ERYTHROMYCIN POLYKETIDE SYNTHASE. 2. ENGINEERED BIOSYNTHESIS OF AN EIGHT-MEMBERED RING TETRAKETIDE LACTONE , 1997 .

[13]  J. Naggert,et al.  Molecular cloning and sequencing of cDNAs encoding the entire rat fatty acid synthase. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[14]  C M Kao,et al.  Engineered biosynthesis of a complete macrolactone in a heterologous host. , 1994, Science.

[15]  P. Leadlay,et al.  An unusually large multifunctional polypeptide in the erythromycin-producing polyketide synthase of Saccharopolyspora erythraea , 1990, Nature.

[16]  K A Reynolds,et al.  Ethyl-substituted erythromycin derivatives produced by directed metabolic engineering. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Rembert Pieper,et al.  Cell-free synthesis of polyketides by recombinant erythromycin polyketide synthases , 1995, Nature.

[18]  C. Kao,et al.  Evidence for two catalytically independent clusters of active sites in a functional modular polyketide synthase. , 1996, Biochemistry.

[19]  M. Bibb,et al.  Genetic construction and functional analysis of hybrid polyketide synthases containing heterologous acyl carrier proteins , 1993, Journal of bacteriology.

[20]  W. Strohl,et al.  Minimal Streptomyces sp. strain C5 daunorubicin polyketide biosynthesis genes required for aklanonic acid biosynthesis , 1997, Journal of bacteriology.

[21]  P. Leadlay,et al.  Divergent sequence motifs correlated with the substrate specificity of (methyl)malonyl‐CoA:acyl carrier protein transacylase domains in modular polyketide synthases , 1995, FEBS letters.

[22]  James Staunton,et al.  Evidence for a double-helical structure for modular polyketide synthases , 1996, Nature Structural Biology.

[23]  P. Leadlay,et al.  Identification of DEBS 1, DEBS 2 and DEBS 3, the multienzyme polypeptides of the erythromycin‐producing polyketide synthase from Saccharopolyspora erythraea , 1992, FEBS letters.

[24]  L. Katz,et al.  The loading domain of the erythromycin polyketide synthase is not essential for erythromycin biosynthesis in Saccharopolyspora erythraea. , 1998, Microbiology.

[25]  P. Barr,et al.  Production of a polyketide natural product in nonpolyketide-producing prokaryotic and eukaryotic hosts. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[26]  C. Khosla,et al.  ENGINEERED BIOSYNTHESIS OF NOVEL POLYKETIDES : ANALYSIS OF TCMN FUNCTION IN TETRACENOMYCIN BIOSYNTHESIS , 1995 .

[27]  D. Cane,et al.  Dissecting and exploiting intermodular communication in polyketide synthases. , 1999, Science.

[28]  S. Kuroda,et al.  Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells. , 1999, Annual review of biochemistry.

[29]  D. Cane,et al.  Spontaneous priming of a downstream module in 6-deoxyerythronolide B synthase leads to polyketide biosynthesis. , 1998, Biochemistry.

[30]  C. Khosla,et al.  Domain Analysis of the Molecular Recognition Features of Aromatic Polyketide Synthase Subunits* , 1997, The Journal of Biological Chemistry.

[31]  P. Leadlay,et al.  The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[32]  M. Staver,et al.  Acyltransferase domain substitutions in erythromycin polyketide synthase yield novel erythromycin derivatives , 1997, Journal of bacteriology.

[33]  Camilla M. Kao,et al.  Engineered Biosynthesis of Structurally Diverse Tetraketides by a Trimodular Polyketide Synthase , 1996 .

[34]  P. Leadlay,et al.  A mutant generated by expression of an engineered DEBS 1 protein from the erythromycin-producing polyketide synthase (PKS) in Streptomyces coelicolor produces the triketide as a lactone, but the major product is the nor-analogue derived from acetate as starter acid , 1995 .

[35]  Camilla M. Kao,et al.  Manipulation of macrolide ring size by directed mutagenesis of a modular polyketide synthase , 1995 .

[36]  P. Leadlay,et al.  Engineering of a minimal modular polyketide synthase, and targeted alteration of the stereospecificity of polyketide chain extension. , 1998, Chemistry & biology.

[37]  J R Jacobsen,et al.  Precursor-directed biosynthesis of erythromycin analogs by an engineered polyketide synthase. , 1997, Science.

[38]  S. Ripka,et al.  The multifunctional 6-methylsalicylic acid synthase gene of Penicillium patulum. Its gene structure relative to that of other polyketide synthases. , 1990, European journal of biochemistry.

[39]  T. C. Nesbitt,et al.  Twenty-five coregulated transcripts define a sterigmatocystin gene cluster in Aspergillus nidulans. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[40]  C R Hutchinson,et al.  Characterization of the Streptomyces peucetius ATCC 29050 genes encoding doxorubicin polyketide synthase. , 1994, Gene.

[41]  Chaitan Khosla,et al.  PRIMER UNIT SPECIFICITY IN RIFAMYCIN BIOSYNTHESIS PRINCIPALLY RESIDES IN THE LATER STAGES OF THE BIOSYNTHETIC PATHWAY , 1998 .

[42]  Christopher M. Summa,et al.  De novo design and structural characterization of proteins and metalloproteins. , 1999, Annual review of biochemistry.

[43]  C. Walsh,et al.  Cloning, Overproduction, and Characterization of the Escherichia coli Holo-acyl Carrier Protein Synthase (*) , 1995, The Journal of Biological Chemistry.

[44]  P. Leadlay,et al.  Limited proteolysis and active-site studies of the first multienzyme component of the erythromycin-producing polyketide synthase. , 1994, Journal of Biological Chemistry.

[45]  D. Cane,et al.  Erythromycin Biosynthesis: The β-Ketoreductase Domains Catalyze the Stereospecific Transfer of the 4-pro-S Hydride of NADPH , 1998 .

[46]  S Omura,et al.  Cloning, sequencing and deduced functions of a cluster of Streptomyces genes probably encoding biosynthesis of the polyketide antibiotic frenolicin. , 1994, Gene.

[47]  C. Khosla,et al.  Targeted gene replacements in a Streptomyces polyketide synthase gene cluster: role for the acyl carrier protein , 1992, Molecular microbiology.

[48]  D. Cane,et al.  Mechanism and specificity of the terminal thioesterase domain from the erythromycin polyketide synthase. , 1999, Chemistry & biology.

[49]  C. Khosla,et al.  Engineered biosynthesis of novel polyketides: manipulation and analysis of an aromatic polyketide synthase with unproven catalytic specificities , 1993 .

[50]  D. Cane,et al.  Erythromycin biosynthesis: kinetic studies on a fully active modular polyketide synthase using natural and unnatural substrates. , 1996, Biochemistry.

[51]  C. Kao,et al.  Gain-of-Function Mutagenesis of a Modular Polyketide Synthase , 1997 .

[52]  Camilla M. Kao,et al.  ALCOHOL STEREOCHEMISTRY IN POLYKETIDE BACKBONES IS CONTROLLED BY THE BETA -KETOREDUCTASE DOMAINS OF MODULAR POLYKETIDE SYNTHASES , 1998 .

[53]  Chaitan Khosla,et al.  Rational design of aromatic polyketide natural products by recombinant assembly of enzymatic subunits , 1995, Nature.

[54]  G. Schneider,et al.  Crystal structure of β‐ketoacyl‐acyl carrier protein synthase II from E.coli reveals the molecular architecture of condensing enzymes , 1998, The EMBO journal.

[55]  P. Leadlay,et al.  Repositioning of a domain in a modular polyketide synthase to promote specific chain cleavage. , 1995, Science.

[56]  P. Bartel,et al.  Biosynthesis of anthraquinones by interspecies cloning of actinorhodin biosynthesis genes in streptomycetes: clarification of actinorhodin gene functions , 1990, Journal of Bacteriology.

[57]  D. Cane,et al.  Remarkably broad substrate specificity of a modular polyketide synthase in a cell-free system , 1995 .

[58]  P. Leadlay,et al.  Stereospecific acyl transfers on the erythromycin-producing polyketide synthase. , 1994, Science.

[59]  C. Khosla,et al.  Expression of a functional fungal polyketide synthase in the bacterium Streptomyces coelicolor A3(2) , 1995, Journal of bacteriology.

[60]  M. Marahiel,et al.  A new enzyme superfamily - the phosphopantetheinyl transferases. , 1996, Chemistry & biology.

[61]  Arinthip Thamchaipenet,et al.  Biosynthesis of 2-Nor-6-deoxyerythronolide B by Rationally Designed Domain Substitution , 1997 .

[62]  E. Wendt-Pienkowski,et al.  Reconstitution of the iterative type II polyketide synthase for tetracenomycin F2 biosynthesis. , 1998, Biochemistry.

[63]  M. Bibb,et al.  Analysis of the nucleotide sequence of the Streptomyces glaucescens tcmI genes provides key information about the enzymology of polyketide antibiotic biosynthesis. , 1989, The EMBO journal.

[64]  P. Leadlay,et al.  Avermectin biosynthesis. Intact incorporation of a diketide chain-assembly intermediate into the polyketide macrocyclic ring , 1994 .

[65]  J B McAlpine,et al.  An erythromycin analog produced by reprogramming of polyketide synthesis. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[66]  A. Witkowski,et al.  Structural organization of the multifunctional animal fatty-acid synthase. , 1991, European journal of biochemistry.

[67]  J. Turner,et al.  Production of a novel polyketide through the construction of a hybrid polyketide synthase. , 1996, Gene.

[68]  C. Khosla,et al.  Engineered biosynthesis of novel polyketides: influence of a downstream enzyme on the catalytic specificity of a minimal aromatic polyketide synthase. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[69]  Cloning and sequence analysis of the putative rifamycin polyketide synthase gene cluster from Amycolatopsis mediterranei. , 1998, FEMS microbiology letters.

[70]  J. Bu’lock,et al.  Novel avermectins produced by mutational biosynthesis. , 1991, The Journal of antibiotics.

[71]  D. Cane,et al.  Purification and characterization of bimodular and trimodular derivatives of the erythromycin polyketide synthase. , 1997, Biochemistry.

[72]  The Thioesterase of the Erythromycin-Producing Polyketide Synthase: Influence of Acyl Chain Structure on the Mode of Release of Substrate Analogues from the Acyl Enzyme Intermediates. , 1998, Angewandte Chemie.

[73]  B Wilkinson,et al.  Engineering broader specificity into an antibiotic-producing polyketide synthase. , 1998, Science.

[74]  J B McAlpine,et al.  Modular organization of genes required for complex polyketide biosynthesis. , 1991, Science.

[75]  J. Lawrence,et al.  Isolation and sequence analysis of polyketide synthase genes from the daunomycin-producing Streptomyces sp. strain C5 , 1994, Journal of bacteriology.

[76]  P. Leadlay,et al.  A hybrid modular polyketide synthase obtained by domain swapping. , 1996, Chemistry & biology.

[77]  C. Khosla,et al.  Efficient Synthesis of Aromatic Polyketides in Vitro by the Actinorhodin Polyketide Synthase , 1996 .

[78]  D. Hopwood,et al.  Nucleotide sequence and deduced functions of a set of cotranscribed genes of Streptomyces coelicolor A3(2) including the polyketide synthase for the antibiotic actinorhodin. , 1992, The Journal of biological chemistry.

[79]  David E. Cane,et al.  Macrolide biosynthesis. 3. Stereochemistry of the chain-elongation steps of erythromycin biosynthesis , 1986 .

[80]  S. P. Cole,et al.  Mutactin, a novel polyketide from Streptomyces coelicolor. Structure and biosynthetic relationship to actinorhodin , 1990 .