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      Engineered polyketides: Synergy between protein and host level engineering

      review-article
      a , 1 , b , 1 , c , d , 1 , d , e , c , d , f , g , h ,
      Synthetic and Systems Biotechnology
      KeAi Publishing
      Polyketide, Polyketide synthase, Natural products, Commodity chemical, Metabolic engineering, Synthetic biology, PK, Polyketide, PKS, Polyketide synthase, FAS, Fatty acid synthases, KS, Ketosynthase, AT, Acyltransferase, ACP, Acyl carrier protein, DH, Dehydratase, KR, Ketoreductase, ER, Enoylreductase, TE, Thioesterase, LM, Loading module, CoL, CoA-Ligase, R, Reductase domain, PDB, Precursor directed biosynthesis, TKL, Triketide lactone, DE, Dimerization element, SNAC, N-acetylcysteamine, DEBS, 6-deoxyerythronolide B synthase, SARP, Streptomyces antibiotic regulatory protein, LTTR, LysR-type transcriptional regulator, PCC, Propionyl-CoA carboxylase

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          Abstract

          Metabolic engineering efforts toward rewiring metabolism of cells to produce new compounds often require the utilization of non-native enzymatic machinery that is capable of producing a broad range of chemical functionalities. Polyketides encompass one of the largest classes of chemically diverse natural products. With thousands of known polyketides, modular polyketide synthases (PKSs) share a particularly attractive biosynthetic logic for generating chemical diversity. The engineering of modular PKSs could open access to the deliberate production of both existing and novel compounds. In this review, we discuss PKS engineering efforts applied at both the protein and cellular level for the generation of a diverse range of chemical structures, and we examine future applications of PKSs in the production of medicines, fuels and other industrially relevant chemicals.

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          antiSMASH 4.0—improvements in chemistry prediction and gene cluster boundary identification

          Abstract Many antibiotics, chemotherapeutics, crop protection agents and food preservatives originate from molecules produced by bacteria, fungi or plants. In recent years, genome mining methodologies have been widely adopted to identify and characterize the biosynthetic gene clusters encoding the production of such compounds. Since 2011, the ‘antibiotics and secondary metabolite analysis shell—antiSMASH’ has assisted researchers in efficiently performing this, both as a web server and a standalone tool. Here, we present the thoroughly updated antiSMASH version 4, which adds several novel features, including prediction of gene cluster boundaries using the ClusterFinder method or the newly integrated CASSIS algorithm, improved substrate specificity prediction for non-ribosomal peptide synthetase adenylation domains based on the new SANDPUMA algorithm, improved predictions for terpene and ribosomally synthesized and post-translationally modified peptides cluster products, reporting of sequence similarity to proteins encoded in experimentally characterized gene clusters on a per-protein basis and a domain-level alignment tool for comparative analysis of trans-AT polyketide synthase assembly line architectures. Additionally, several usability features have been updated and improved. Together, these improvements make antiSMASH up-to-date with the latest developments in natural product research and will further facilitate computational genome mining for the discovery of novel bioactive molecules.
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            Medium- and short-chain dehydrogenase/reductase gene and protein families

            Abstract. Short-chain dehydrogenases/reductases (SDRs) constitute a large family of NAD(P)(H)-dependent oxidoreductases, sharing sequence motifs and displaying similar mechanisms. SDR enzymes have critical roles in lipid, amino acid, carbohydrate, cofactor, hormone and xenobiotic metabolism as well as in redox sensor mechanisms. Sequence identities are low, and the most conserved feature is an α/β folding pattern with a central beta sheet flanked by 2–3 α-helices from each side, thus a classical Rossmannfold motif for nucleotide binding. The conservation of this element and an active site, often with an Asn-Ser-Tyr-Lys tetrad, provides a platform for enzymatic activities encompassing several EC classes, including oxidoreductases, epimerases and lyases. The common mechanism is an underlying hydride and proton transfer involving the nicotinamide and typically an active site tyrosine residue, whereas substrate specificity is determined by a variable C-terminal segment. Relationships exist with bacterial haloalcohol dehalogenases, which lack cofactor binding but have the active site architecture, emphasizing the versatility of the basic fold in also generating hydride transfer-independent lyases. The conserved fold and nucleotide binding emphasize the role of SDRs as scaffolds for an NAD(P)(H) redox sensor system, of importance to control metabolic routes, transcription and signalling.
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              Recent trends in the biochemistry of surfactin.

              The name surfactin refers to a bacterial cyclic lipopeptide, primarily renowned for its exceptional surfactant power since it lowers the surface tension of water from 72 mN m-1 to 27 mN m-1 at a concentration as low as 20 microM. Although surfactin was discovered about 30 years ago, there has been a revival of interest in this compound over the past decade, triggered by an increasing demand for effective biosurfactants for difficult contemporary ecological problems. This simple molecule also looks very promising as an antitumoral, antiviral and anti-Mycoplasma agent. Structural characteristics show the presence of a heptapeptide with an LLDLLDL chiral sequence linked, via a lactone bond, to a beta-hydroxy fatty acid with 13-15 C atoms. In solution, the molecule exhibits a characteristic "horse saddle" conformation that accounts for its large spectrum of biological activity, making it very attractive for both industrial applications and academic studies. Surfactin biosynthesis is catalysed non-ribosomally by the action of a large multienzyme complex consisting of four modular building blocks, called the surfactin synthetase. The biosynthetic activity involves the multicarrier thiotemplate mechanism and the enzyme is organized in structural domains that place it in the family of peptide synthetases, a class of enzymes involved in peptidic secondary-metabolite synthesis. The srfA operon, the sfp gene encoding a 4'-phosphopantetheinyltransferase and the comA regulatory gene work together for surfactin biosynthesis, while the gene encoding the acyltransferase remains to be isolated. Concerning surfactin production, there is no indication whether the genetic regulation, involving a quorum-sensing mechanism, overrides other regulation factors promoted by the fermentation conditions. Knowledge of the modular arrangement of the peptide synthetases is of the utmost relevance to combinatorial biosynthetic approaches and has been successfully used at the gene level to modify the surfactin template. Biosynthetic and genetic rationales have been described for building variants. A fine study of the structure/function relationships associated with the three-dimensional structure has led to the recognition of the specific residues required for activity. These studies will assist researchers in the selection of molecules with improved and/or refined properties useful in oil and biomedical industries.
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                Author and article information

                Contributors
                Journal
                Synth Syst Biotechnol
                Synth Syst Biotechnol
                Synthetic and Systems Biotechnology
                KeAi Publishing
                2405-805X
                2405-805X
                07 September 2017
                September 2017
                07 September 2017
                : 2
                : 3
                : 147-166
                Affiliations
                [a ]Department of Energy Agile BioFoundry, Emeryville, CA, USA
                [b ]Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA
                [c ]Joint BioEnergy Institute, Emeryville, CA 94608, USA
                [d ]Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
                [e ]Comparative Biochemistry Graduate Group, University of California, Berkeley, Berkeley, CA 94720, USA
                [f ]QB3 Institute, University of California, Berkeley, Emeryville, CA 94608, USA
                [g ]Department of Chemical & Biomolecular Engineering, Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA
                [h ]Novo Nordisk Foundation Center for Biosustainability, Technical University Denmark, DK2970 Horsholm, Denmark
                Author notes
                []Corresponding author. Joint BioEnergy Institute, Emeryville, CA 94608, USA.Joint BioEnergy InstituteEmeryvilleCA94608USA keasling@ 123456berkeley.edu
                [1]

                Authors contributed equally.

                Article
                S2405-805X(17)30085-6
                10.1016/j.synbio.2017.08.005
                5655351
                29318196
                6bbe3b6e-6eb8-41a2-b98a-40305e7fad56

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 31 July 2017
                : 26 August 2017
                : 26 August 2017
                Categories
                Article

                polyketide,polyketide synthase,natural products,commodity chemical,metabolic engineering,synthetic biology,pk, polyketide,pks, polyketide synthase,fas, fatty acid synthases,ks, ketosynthase,at, acyltransferase,acp, acyl carrier protein,dh, dehydratase,kr, ketoreductase,er, enoylreductase,te, thioesterase,lm, loading module,col, coa-ligase,r, reductase domain,pdb, precursor directed biosynthesis,tkl, triketide lactone,de, dimerization element,snac, n-acetylcysteamine,debs, 6-deoxyerythronolide b synthase,sarp, streptomyces antibiotic regulatory protein,lttr, lysr-type transcriptional regulator,pcc, propionyl-coa carboxylase

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