The structures of type I polyketide synthases.

With the recent structural characterization of each of the component enzymes of type I polyketide synthases, scientists are coming tantalizingly close to elucidating the overall architectures and mechanisms of these enormous molecular factories. This review highlights not only what has been revealed about the structures and activities of each of the domains but also the mysteries that remain to be solved.

[1]  J. Vederas,et al.  Crystal structure and biochemical studies of the trans-acting polyketide enoyl reductase LovC from lovastatin biosynthesis , 2012, Proceedings of the National Academy of Sciences.

[2]  Borries Demeler,et al.  Divergence of multimodular polyketide synthases revealed by a didomain structure , 2012, Nature chemical biology.

[3]  Mark Horsman,et al.  6-Deoxyerythronolide B synthase thioesterase-catalyzed macrocyclization is highly stereoselective. , 2012, Organic letters.

[4]  N. Kelleher,et al.  Interrogation of global active site occupancy of a fungal iterative polyketide synthase reveals strategies for maintaining biosynthetic fidelity. , 2012, Journal of the American Chemical Society.

[5]  Satoshi Yuzawa,et al.  Reprogramming a module of the 6-deoxyerythronolide B synthase for iterative chain elongation , 2012, Proceedings of the National Academy of Sciences.

[6]  P. Güntert,et al.  Characterization of molecular interactions between ACP and halogenase domains in the Curacin A polyketide synthase. , 2012, ACS chemical biology.

[7]  J. Vederas,et al.  A fungal ketoreductase domain that displays substrate-dependent stereospecificity , 2011, Nature chemical biology.

[8]  D. Mohanty,et al.  Modeling holo-ACP:DH and holo-ACP:KR complexes of modular polyketide synthases: a docking and molecular dynamics study , 2012, BMC Structural Biology.

[9]  S. Bruner,et al.  Structural basis for phosphopantetheinyl carrier domain interactions in the terminal module of nonribosomal peptide synthetases. , 2011, Chemistry & biology.

[10]  D. Siegel,et al.  Employing modular polyketide synthase ketoreductases as biocatalysts in the preparative chemoenzymatic syntheses of diketide chiral building blocks. , 2011, Chemistry & biology.

[11]  K. Reynolds,et al.  Acyl-CoA subunit selectivity in the pikromycin polyketide synthase PikAIV: steady-state kinetics and active-site occupancy analysis by FTICR-MS. , 2011, Chemistry & biology.

[12]  Wei Zhang,et al.  Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-γ-linolenic acid , 2011, Proceedings of the National Academy of Sciences.

[13]  D. Cane,et al.  Structure and mechanism of the trans-acting acyltransferase from the disorazole synthase. , 2011, Biochemistry.

[14]  Hau B. Nguyen,et al.  Experimental mapping of soluble protein domains using a hierarchical approach , 2011, Nucleic acids research.

[15]  D. Cane,et al.  Probing the interactions of an acyl carrier protein domain from the 6‐deoxyerythronolide B synthase , 2011, Protein science : a publication of the Protein Society.

[16]  A. Keatinge-Clay,et al.  Structural and functional analysis of C2-type ketoreductases from modular polyketide synthases. , 2011, Journal of molecular biology.

[17]  D. Kwan,et al.  The Stereochemistry of Complex Polyketide Biosynthesis by Modular Polyketide Synthases , 2011, Molecules.

[18]  Kai Blin,et al.  antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences , 2011, Nucleic Acids Res..

[19]  P. Leadlay,et al.  Stereoselectivity of Isolated Dehydratase Domains of the Borrelidin Polyketide Synthase: Implications for cis Double Bond Formation , 2011, ChemBioChem.

[20]  Christophe Corre,et al.  Identification of a bioactive 51-membered macrolide complex by activation of a silent polyketide synthase in Streptomyces ambofaciens , 2011, Proceedings of the National Academy of Sciences.

[21]  P. Leadlay,et al.  Insights into the stereospecificity of ketoreduction in a modular polyketide synthase. , 2011, Organic & biomolecular chemistry.

[22]  Peter Wipf,et al.  Terminal Alkene Formation by the Thioesterase of Curacin A Biosynthesis , 2011, The Journal of Biological Chemistry.

[23]  A. Keatinge-Clay,et al.  Enzymatic extender unit generation for in vitro polyketide synthase reactions: structural and functional showcasing of Streptomyces coelicolor MatB. , 2011, Chemistry & biology.

[24]  Patrick Caffrey,et al.  A labile point in mutant amphotericin polyketide synthases , 2011, Biotechnology Letters.

[25]  Chaitan Khosla,et al.  Molecular recognition between ketosynthase and acyl carrier protein domains of the 6-deoxyerythronolide B synthase , 2010, Proceedings of the National Academy of Sciences.

[26]  Chaitan Khosla,et al.  Stereospecificity of the dehydratase domain of the erythromycin polyketide synthase. , 2010, Journal of the American Chemical Society.

[27]  J. Piel.  Biosynthesis of polyketides by trans-AT polyketide synthases. , 2010, Natural product reports.

[28]  T. Steitz,et al.  Revisiting the structures of several antibiotics bound to the bacterial ribosome , 2010, Proceedings of the National Academy of Sciences.

[29]  A. Keatinge-Clay,et al.  Structural and functional analysis of A-type ketoreductases from the amphotericin modular polyketide synthase. , 2010, Structure.

[30]  Janet L. Smith,et al.  Biochemical and structural characterization of the tautomycetin thioesterase: analysis of a stereoselective polyketide hydrolase. , 2010, Angewandte Chemie.

[31]  A. Cavalli,et al.  Insights into protein-protein and enzyme-substrate interactions in modular polyketide synthases. , 2010, Chemistry & biology.

[32]  P. Leadlay,et al.  Mutagenesis of a modular polyketide synthase enoylreductase domain reveals insights into catalysis and stereospecificity. , 2010, ACS chemical biology.

[33]  Gitanjali Yadav,et al.  SBSPKS: structure based sequence analysis of polyketide synthases , 2010, Nucleic Acids Res..

[34]  Y. Chan,et al.  Recognition of (2S)-aminomalonyl-acyl carrier protein (ACP) and (2R)-hydroxymalonyl-ACP by acyltransferases in zwittermicin A biosynthesis. , 2010, Biochemistry.

[35]  Armin Ruf,et al.  Structure of the human fatty acid synthase KS-MAT didomain as a framework for inhibitor design. , 2010, Journal of molecular biology.

[36]  Jason W. Labonte,et al.  Structure and function of an iterative polyketide synthase thioesterase domain catalyzing Claisen cyclization in aflatoxin biosynthesis , 2010, Proceedings of the National Academy of Sciences.

[37]  C. Hertweck,et al.  Functionally Distinct Modules Operate Two Consecutive α,β→β,γ Double‐Bond Shifts in the Rhizoxin Polyketide Assembly Line , 2010 .

[38]  C. Hertweck,et al.  Functionally distinct modules operate two consecutive alpha,beta-->beta,gamma double-bond shifts in the rhizoxin polyketide assembly line. , 2010, Angewandte Chemie.

[39]  Susana P. Gaudêncio,et al.  Sequence-Based Analysis of Secondary-Metabolite Biosynthesis in Marine Actinobacteria , 2010, Applied and Environmental Microbiology.

[40]  David H Sherman,et al.  Crystal structures of dehydratase domains from the curacin polyketide biosynthetic pathway. , 2010, Structure.

[41]  Chaitan Khosla,et al.  The biochemical basis for stereochemical control in polyketide biosynthesis. , 2009, Journal of the American Chemical Society.

[42]  Jason W. Labonte,et al.  Structural basis for biosynthetic programming of fungal aromatic polyketide cyclization , 2009, Nature.

[43]  Kiejung Park,et al.  Development of an analysis program of type I polyketide synthase gene clusters using homology search and profile hidden Markov model. , 2009, Journal of microbiology and biotechnology.

[44]  David H Sherman,et al.  Structural basis for binding specificity between subclasses of modular polyketide synthase docking domains. , 2009, ACS chemical biology.

[45]  Francisco J. Asturias,et al.  Conformational Flexibility of Metazoan Fatty Acid Synthase Enables Catalysis , 2008, Nature Structural &Molecular Biology.

[46]  B. Shen,et al.  Tandem acyl carrier protein domains in polyunsaturated fatty acid synthases. , 2009, Methods in Enzymology.

[47]  B. Shen,et al.  Type I polyketide synthases that require discrete acyltransferases. , 2009, Methods in enzymology.

[48]  Peter Man-Un Ung,et al.  Automated genome mining for natural products , 2009, BMC Bioinformatics.

[49]  Adrian Keatinge-Clay,et al.  Crystal structure of the erythromycin polyketide synthase dehydratase. , 2008, Journal of molecular biology.

[50]  Trygve Brautaset,et al.  Improved antifungal polyene macrolides via engineering of the nystatin biosynthetic genes in Streptomyces noursei. , 2008, Chemistry & biology.

[51]  Frank Schulz,et al.  Prediction and manipulation of the stereochemistry of enoylreduction in modular polyketide synthases. , 2008, Chemistry & biology.

[52]  G. Duester,et al.  Medium- and short-chain dehydrogenase/reductase gene and protein families , 2008, Cellular and Molecular Life Sciences.

[53]  B. Persson,et al.  Medium- and short-chain dehydrogenase/reductase gene and protein families , 2008, Cellular and Molecular Life Sciences.

[54]  B. Persson,et al.  Medium- and short-chain dehydrogenase/reductase gene and protein families , 2008, Cellular and Molecular Life Sciences.

[55]  J. Zucko,et al.  ClustScan: an integrated program package for the semi-automatic annotation of modular biosynthetic gene clusters and in silico prediction of novel chemical structures , 2008, Nucleic acids research.

[56]  Giulio Rastelli,et al.  Molecular modeling and crystal structure of ERK2-hypothemycin complexes. , 2008, Journal of structural biology.

[57]  Timm Maier,et al.  The Crystal Structure of a Mammalian Fatty Acid Synthase , 2008, Science.

[58]  D. Cane,et al.  Stereospecificity of ketoreductase domains 1 and 2 of the tylactone modular polyketide synthase. , 2008, Journal of the American Chemical Society.

[59]  D. Rai,et al.  Engineered synthesis of 7-oxo- and 15-deoxy-15-oxo-amphotericins: insights into structure-activity relationships in polyene antibiotics. , 2008, Chemistry and Biology.

[60]  T. J. Simpson,et al.  A Mammalian Type I Fatty Acid Synthase Acyl Carrier Protein Domain Does Not Sequester Acyl Chains* , 2008, Journal of Biological Chemistry.

[61]  Adrian A Canutescu,et al.  SCWRL and MolIDE: computer programs for side-chain conformation prediction and homology modeling , 2008, Nature Protocols.

[62]  Debasisa Mohanty,et al.  Versatility of polyketide synthases in generating metabolic diversity. , 2007, Current opinion in structural biology.

[63]  Y. Tsybovsky,et al.  10-Formyltetrahydrofolate Dehydrogenase Requires a 4′-Phosphopantetheine Prosthetic Group for Catalysis* , 2007, Journal of Biological Chemistry.

[64]  Chaitan Khosla,et al.  Stereospecificity of ketoreductase domains of the 6-deoxyerythronolide B synthase. , 2007, Journal of the American Chemical Society.

[65]  R. Borriss,et al.  Biosynthesis of the antibiotic bacillaene, the product of a giant polyketide synthase complex of the trans-AT family. , 2007, Angewandte Chemie.

[66]  Rodrigo Lopez,et al.  Clustal W and Clustal X version 2.0 , 2007, Bioinform..

[67]  Chaitan Khosla,et al.  Solution structure and proposed domain–domain recognition interface of an acyl carrier protein domain from a modular polyketide synthase , 2007, Protein science : a publication of the Protein Society.

[68]  Shiou-Chuan Tsai,et al.  The type I fatty acid and polyketide synthases: a tale of two megasynthases. , 2007, Natural product reports.

[69]  Blaz Zupan,et al.  Polyketide synthase genes and the natural products potential of Dictyostelium discoideum , 2007, Bioinform..

[70]  A. Keatinge-Clay,et al.  A tylosin ketoreductase reveals how chirality is determined in polyketides. , 2007, Chemistry & biology.

[71]  R. Cox,et al.  Polyketides, proteins and genes in fungi: programmed nano-machines begin to reveal their secrets. , 2007, Organic & biomolecular chemistry.

[72]  Chaitan Khosla,et al.  Structure and mechanism of the 6-deoxyerythronolide B synthase. , 2007, Annual review of biochemistry.

[73]  C. Boddy,et al.  The thioesterase domain from the pimaricin and erythromycin biosynthetic pathways can catalyze hydrolysis of simple thioester substrates. , 2007, Bioorganic & medicinal chemistry letters.

[74]  D. Rice,et al.  Structural studies of fatty acyl-(acyl carrier protein) thioesters reveal a hydrophobic binding cavity that can expand to fit longer substrates. , 2007, Journal of molecular biology.

[75]  Daniel W. Udwary,et al.  Identification of a starter unit acyl-carrier protein transacylase domain in an iterative type I polyketide synthase , 2006, Proceedings of the National Academy of Sciences.

[76]  M. Fischbach,et al.  Directing Biosynthesis , 2006, Science.

[77]  Janet L. Smith,et al.  Structural basis for macrolactonization by the pikromycin thioesterase , 2006, Nature chemical biology.

[78]  Janet L. Smith,et al.  Clearing the skies over modular polyketide synthases. , 2006, ACS Chemical Biology.

[79]  Thomas Börner,et al.  Natural Biocombinatorics in the Polyketide Synthase Genes of the Actinobacterium Streptomyces avermitilis , 2006, PLoS Comput. Biol..

[80]  Chu-Young Kim,et al.  The 2.7-Å crystal structure of a 194-kDa homodimeric fragment of the 6-deoxyerythronolide B synthase , 2006 .

[81]  C. Rock,et al.  Roles of the Active Site Water, Histidine 303, and Phenylalanine 396 in the Catalytic Mechanism of the Elongation Condensing Enzyme of Streptococcus pneumoniae* , 2006, Journal of Biological Chemistry.

[82]  A. D'arcy,et al.  Mapping the active site of Escherichia coli malonyl-CoA-acyl carrier protein transacylase (FabD) by protein crystallography. , 2006, Acta crystallographica. Section D, Biological crystallography.

[83]  J. Hiltunen,et al.  Crystal structure of yeast peroxisomal multifunctional enzyme: structural basis for substrate specificity of (3R)-hydroxyacyl-CoA dehydrogenase units. , 2006, Journal of molecular biology.

[84]  Jun Wang,et al.  Platensimycin is a selective FabF inhibitor with potent antibiotic properties , 2006, Nature.

[85]  John R Carney,et al.  Activating hybrid modular interfaces in synthetic polyketide synthases by cassette replacement of ketosynthase domains. , 2006, Chemistry & biology.

[86]  Robert M Stroud,et al.  The structure of a ketoreductase determines the organization of the beta-carbon processing enzymes of modular polyketide synthases. , 2006, Structure.

[87]  Chu-Young Kim,et al.  Extender unit and acyl carrier protein specificity of ketosynthase domains of the 6-deoxyerythronolide B synthase. , 2006, Journal of the American Chemical Society.

[88]  Timm Maier,et al.  Architecture of Mammalian Fatty Acid Synthase at 4.5 Å Resolution , 2006, Science.

[89]  P. Leadlay,et al.  Directed mutagenesis alters the stereochemistry of catalysis by isolated ketoreductase domains from the erythromycin polyketide synthase. , 2006, Chemistry & biology.

[90]  H. Oikawa,et al.  An iterative type I polyketide synthase PKSN catalyzes synthesis of the decaketide alternapyrone with regio-specific octa-methylation. , 2005, Chemistry & biology.

[91]  P. Leadlay,et al.  Molecular basis of Celmer's rules: stereochemistry of catalysis by isolated ketoreductase domains from modular polyketide synthases. , 2005, Chemistry & biology.

[92]  John R Carney,et al.  Combinatorial polyketide biosynthesis by de novo design and rearrangement of modular polyketide synthase genes , 2005, Nature Biotechnology.

[93]  Naohiro Matsugaki,et al.  Allosteric Modulation of the RNA Polymerase Catalytic Reaction Is an Essential Component of Transcription Control by Rifamycins , 2005, Cell.

[94]  Ivan Rayment,et al.  Structural basis of swinholide A binding to actin. , 2005, Chemistry & biology.

[95]  K. Fiebig,et al.  The Structure of (3R)-Hydroxyacyl-Acyl Carrier Protein Dehydratase (FabZ) from Pseudomonas aeruginosa* , 2004, Journal of Biological Chemistry.

[96]  F. Asturias,et al.  Head-to-head coiled arrangement of the subunits of the animal fatty acid synthase. , 2004, Chemistry & biology.

[97]  Chaitan Khosla,et al.  Biochemical analysis of the substrate specificity of the beta-ketoacyl-acyl carrier protein synthase domain of module 2 of the erythromycin polyketide synthase. , 2004, Biochemistry.

[98]  B. Chakravarty,et al.  Human fatty acid synthase: structure and substrate selectivity of the thioesterase domain. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[99]  Hanne Grøn,et al.  Recognition and Accommodation at the Androgen Receptor Coactivator Binding Interface , 2004, PLoS biology.

[100]  Ben Cornett,et al.  The Binding Mode of Epothilone A on α,ß-Tubulin by Electron Crystallography , 2004, Science.

[101]  David H Sherman,et al.  Biosynthetic pathway and gene cluster analysis of curacin A, an antitubulin natural product from the tropical marine cyanobacterium Lyngbya majuscula. , 2004, Journal of natural products.

[102]  Katalin F Medzihradszky,et al.  An antibiotic factory caught in action , 2004, Nature Structural &Molecular Biology.

[103]  William H Gerwick,et al.  Structure and biosynthesis of the jamaicamides, new mixed polyketide-peptide neurotoxins from the marine cyanobacterium Lyngbya majuscula. , 2004, Chemistry & biology.

[104]  C. Rock,et al.  Cofactor-induced conformational rearrangements establish a catalytically competent active site and a proton relay conduit in FabG. , 2004, Structure.

[105]  Sarojini Adusumilli,et al.  Giant plasmid-encoded polyketide synthases produce the macrolide toxin of Mycobacterium ulcerans. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[106]  Kenji Watanabe,et al.  Understanding Substrate Specificity of Polyketide Synthase Modules by Generating Hybrid Multimodular Synthases* , 2003, Journal of Biological Chemistry.

[107]  K. Reynolds,et al.  Enhancement and Selective Production of Phoslactomycin B, a Protein Phosphatase IIa Inhibitor, through Identification and Engineering of the Corresponding Biosynthetic Gene Cluster* , 2003, Journal of Biological Chemistry.

[108]  Patrick Caffrey,et al.  Conserved Amino Acid Residues Correlating With Ketoreductase Stereospecificity in Modular Polyketide Synthases , 2003, Chembiochem : a European journal of chemical biology.

[109]  Gitanjali Yadav,et al.  Computational approach for prediction of domain organization and substrate specificity of modular polyketide synthases. , 2003, Journal of molecular biology.

[110]  Chaitan Khosla,et al.  Catalysis, specificity, and ACP docking site of Streptomyces coelicolor malonyl-CoA:ACP transacylase. , 2003, Structure.

[111]  C Richard Hutchinson,et al.  A model of structure and catalysis for ketoreductase domains in modular polyketide synthases. , 2003, Biochemistry.

[112]  J. Hiltunen,et al.  Binary structure of the two-domain (3R)-hydroxyacyl-CoA dehydrogenase from rat peroxisomal multifunctional enzyme type 2 at 2.38 A resolution. , 2003, Structure.

[113]  Jennifer L. Martin,et al.  SAM (dependent) I AM: the S-adenosylmethionine-dependent methyltransferase fold. , 2002, Current opinion in structural biology.

[114]  R. Stroud,et al.  Insights into channel architecture and substrate specificity from crystal structures of two macrocycle-forming thioesterases of modular polyketide synthases. , 2002, Biochemistry.

[115]  A. Witkowski,et al.  Mechanism of the β-Ketoacyl Synthase Reaction Catalyzed by the Animal Fatty Acid Synthase† , 2002 .

[116]  James Staunton,et al.  Engineering specificity of starter unit selection by the erythromycin‐producing polyketide synthase , 2002, Molecular microbiology.

[117]  S. Wakil,et al.  Quaternary structure of human fatty acid synthase by electron cryomicroscopy , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[118]  L. Miercke,et al.  Crystal structure of the macrocycle-forming thioesterase domain of the erythromycin polyketide synthase: Versatility from a unique substrate channel , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[119]  C R Hutchinson,et al.  Alteration of the substrate specificity of a modular polyketide synthase acyltransferase domain through site-specific mutations. , 2001, Biochemistry.

[120]  J. Deisenhofer,et al.  Structural Mechanism for Statin Inhibition of HMG-CoA Reductase , 2001, Science.

[121]  J M Ligon,et al.  The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90. , 2000, Chemistry & biology.

[122]  C R Hutchinson,et al.  A multiplasmid approach to preparing large libraries of polyketides. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[123]  Y. Lindqvist,et al.  Conversion of a beta-ketoacyl synthase to a malonyl decarboxylase by replacement of the active-site cysteine with glutamine. , 1999, Biochemistry.

[124]  B. Moore,et al.  Direct evidence that the rifamycin polyketide synthase assembles polyketide chains processively. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[125]  Alcino J. Silva,et al.  Multiple genetic modifications of the erythromycin polyketide synthase to produce a library of novel ‘ ‘ unnatural ’ ’ natural products , 1999 .

[126]  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.

[127]  P. Leadlay,et al.  The molecular basis of Celmer's rules: the stereochemistry of the condensation step in chain extension on the erythromycin polyketide synthase. , 1997, Biochemistry.

[128]  B. Wilkinson,et al.  Biosynthesis of Erythromycin and Rapamycin. , 1997, Chemical reviews.

[129]  Neal Rosen,et al.  Crystal Structure of an Hsp90–Geldanamycin Complex: Targeting of a Protein Chaperone by an Antitumor Agent , 1997, Cell.

[130]  Stuart L. Schreiber,et al.  Structure of the FKBP12-Rapamycin Complex Interacting with Binding Domain of Human FRAP , 1996, Science.

[131]  P. Luisi,et al.  Enzyme-containing liposomes can endogenously produce membrane-constituting lipids. , 1996, Chemistry & biology.

[132]  J. L. Smith,et al.  Structure of a dehydratase-isomerase from the bacterial pathway for biosynthesis of unsaturated fatty acids: two catalytic activities in one active site. , 1996, Structure.

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

[134]  D. Ollis,et al.  Crystal structure of Escherichia coli QOR quinone oxidoreductase complexed with NADPH. , 1995, Journal of molecular biology.

[135]  Z Dauter,et al.  The Escherichia coli Malonyl-CoA:Acyl Carrier Protein Transacylase at 1.5-Å Resolution. , 1995, The Journal of Biological Chemistry.

[136]  J. Sacchettini,et al.  Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis , 1995, Science.

[137]  Anders Liljas,et al.  Crystal structure of catechol O-methyltransferase , 1994, Nature.

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

[139]  B. Sedgwick,et al.  The biosynthesis of long-chain fatty acids. Stereochemical differentiation in the enzymic incorporation of chiral acetates. , 1977, European journal of biochemistry.

[140]  A. Fersht,et al.  Editing mechanisms in protein synthesis. Rejection of valine by the isoleucyl-tRNA synthetase. , 1977, Biochemistry.

[141]  W. Wooster,et al.  Crystal structure of , 2005 .

[142]  J. Porter,et al.  Synthesis of triacetic acid lactone by the pigeon liver fatty acid synthetase complex. , 1968, The Journal of biological chemistry.