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polyketide synthase

Xue Wang, Haibo Zhou, Hanna Chen, Xiaoshu Jing, Wentao Zheng, Ruijuan Li, Tao Sun, Jiaqi Liu, Jun Fu, Liujie Huo, Yue-Zhong Li, Yuemao Shen, Xiaoming Ding, Rolf Müller, Xiaoying Bian, Youming Zhang
Bacterial genomes encode numerous cryptic biosynthetic gene clusters (BGCs) that represent a largely untapped source of drugs or pesticides. Mining of the cryptic products is limited by the unavailability of streamlined genetic tools in native producers. Precise genome engineering using bacteriophage recombinases is particularly useful for genome mining. However, recombinases are usually host-specific. The genome-guided discovery of novel recombinases and their transient expression could boost cryptic BGC mining...
April 16, 2018: Proceedings of the National Academy of Sciences of the United States of America
Lukuan Hou, Huiming Huang, Huayue Li, Shuyao Wang, Jianhua Ju, Wenli Li
BACKGROUND: Type III polyketide synthases (PKSs) are simple homodimer ketosynthases that distribute across plants, fungi, and bacteria, catalyzing formation of pyrone- and resorcinol-types aromatic polyketides with various bioactivities. The broad substrate promiscuity displayed by type III PKSs makes them wonderful candidates for expanding chemical diversity of polyketides. RESULTS: Violapyrone B (VLP B, 10), an α-pyrone compound produced by deepsea-derived Streptomyces somaliensis SCSIO ZH66, is encoded by a type III PKS VioA...
April 12, 2018: Microbial Cell Factories
Chenguang Liu, Meijuan Yuan, Xu Xu, Lei Wang, Adrian T Keatinge-Clay, Zixin Deng, Shuangjun Lin, Jianting Zheng
Ketoreductase (KR) domains of modular polyketide synthases (PKSs) control the stereochemistry of C2 methyl and C3 hydroxyl substituents of polyketide intermediates. To understand the molecular basis of stereocontrol exerted by KRs, the crystal structure of a KR from the second module of the amphotericin PKS (AmpKR2) complexed with NADP+ and 2-methyl-3-oxopentanoyl-pantetheine was solved. This first ternary structure provides direct evidence to the hypothesis that a substrate enters into the active site of an A-type KR from the side opposite the coenzyme to generate an L-hydroxyl substituent...
April 4, 2018: Journal of Structural Biology
Bryan Daniel Ellis, Jacob C Milligan, Alexander R White, Vy Duong, Pilar X Altman, Lina Mohammed, Matthew P Crump, John Crosby, Ray Luo, Christopher D Vanderwal, Shiou-Chuan Tsai
Polyketides are a large class of bioactive natural products with a wide range of structures and functions. Polyketides are biosynthesized by large, multi-domain enzyme complexes termed polyketide synthases (PKSs). One of the primary challenges when studying PKSs is the high reactivity of their poly--ketone substrates. This has hampered structural and mechanistic characterization of PKS-polyketide complexes, and, as a result, little is known about how PKSs position the unstable substrates for proper catalysis while displaying high levels of regio- and stereo-specificity...
April 5, 2018: Journal of the American Chemical Society
Dominik A Herbst, Callie R Huitt-Roehl, Roman P Jakob, Jacob M Kravetz, Philip A Storm, Jamie R Alley, Craig A Townsend, Timm Maier
Polyketide synthases (PKSs) are microbial multienzymes for the biosynthesis of biologically potent secondary metabolites. Polyketide production is initiated by the loading of a starter unit onto an integral acyl carrier protein (ACP) and its subsequent transfer to the ketosynthase (KS). Initial substrate loading is achieved either by multidomain loading modules or by the integration of designated loading domains, such as starter unit acyltransferases (SAT), whose structural integration into PKS remains unresolved...
April 2, 2018: Nature Chemical Biology
Nguyen Huy Thuan, Dipesh Dhakal, Anaya Raj Pokhrel, Luan Luong Chu, Thi Thuy Van Pham, Anil Shrestha, Jae Kyung Sohng
Streptomyces peucetius ATCC 27952 produces two major anthracyclines, doxorubicin (DXR) and daunorubicin (DNR), which are potent chemotherapeutic agents for the treatment of several cancers. In order to gain detailed insight on genetics and biochemistry of the strain, the complete genome was determined and analyzed. The result showed that its complete sequence contains 7187 protein coding genes in a total of 8,023,114 bp, whereas 87% of the genome contributed to the protein coding region. The genomic sequence included 18 rRNA, 66 tRNAs, and 3 non-coding RNAs...
March 30, 2018: Applied Microbiology and Biotechnology
Christopher M Goins, Thanuja D Sudasinghe, Xiaofan Liu, Yanping Wang, George A O'Doherty, Donald R Ronning
Tetrahydrolipstatin (THL) is a covalent inhibitor of many serine esterases. In mycobacteria, THL has been found to covalently react with 261 lipid esterases upon treatment of Mycobacterium bovis cell lysate. However, the covalent adduct is considered unstable in some cases due to the hydrolysis of the enzyme-linked THL adduct resulting in catalytic turnover. In this study, a library of THL stereo-derivatives was tested against three essential Mycobacterium tuberculosis lipid esterases of interest for drug development to assess how the stereochemistry of THL affects respective enzyme inhibition and allows for cross-enzyme inhibition...
March 30, 2018: Biochemistry
Johannes Arp, Sebastian Götze, Ruchira Mukherji, Derek J Mattern, María García-Altares, Martin Klapper, Debra A Brock, Axel A Brakhage, Joan E Strassmann, David C Queller, Bettina Bardl, Karsten Willing, Gundela Peschel, Pierre Stallforth
Investigating microbial interactions from an ecological perspective is a particularly fruitful approach to unveil both new chemistry and bioactivity. Microbial predator-prey interactions in particular rely on natural products as signal or defense molecules. In this context, we identified a grazing-resistant Pseudomonas strain, isolated from the bacterivorous amoeba Dictyostelium discoideum. Genome analysis of this bacterium revealed the presence of two biosynthetic gene clusters that were found adjacent to each other on a contiguous stretch of the bacterial genome...
March 28, 2018: Proceedings of the National Academy of Sciences of the United States of America
He Huang, Ping Gao, Qi Zhao, Hai-Feng Hu
In the present study, we introduced point mutations into Ac_rapA which encodes a polyketide synthase responsible for rapamycin biosynthesis in Actinoplanes sp. N902-109, in order to construct a mutant with an inactivated enoylreductase (ER) domain, which was able to synthesize a new rapamycin analog. Based on the homologous recombination induced by double-strand breaks in chromosome mediated by endonuclease I-SceI, the site-directed mutation in the first ER domain of Ac_rapA was introduced using non-replicating plasmid pLYERIA combined with an I-SceI expression plasmid...
March 2018: Chinese Journal of Natural Medicines
Fernando Guzman-Chavez, Oleksandr Salo, Marta Samol, Marco Ries, Jeroen Kuipers, Roel A L Bovenberg, Rob J Vreeken, Arnold J M Driessen
The Pc21 g14570 gene of Penicillium chrysogenum encodes an ortholog of a class 2 histone deacetylase termed HdaA which may play a role in epigenetic regulation of secondary metabolism. Deletion of the hdaA gene induces a significant pleiotropic effect on the expression of a set of polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS)-encoding genes. The deletion mutant exhibits a decreased conidial pigmentation that is related to a reduced expression of the PKS gene Pc21 g16000 (pks17) responsible for the production of the pigment precursor naphtha-γ-pyrone...
March 24, 2018: MicrobiologyOpen
Xiao-Man Sun, Lu-Jing Ren, Zhi-Qian Bi, Xiao-Jun Ji, Quan-Yu Zhao, Ling Jiang, He Huang
Background: Schizochytrium sp. is a marine microalga with great potential as a promising sustainable source of lipids rich in docosahexaenoic acid (DHA). This organism's lipid accumulation machinery can be induced by various stress conditions, but this stress induction usually comes at the expense of lower biomass in industrial fermentations. Moreover, oxidative damage induced by various environmental stresses can result in the peroxidation of lipids, and especially polyunsaturated fatty acids, which causes unstable DHA production, but is often ignored in fermentation processes...
2018: Biotechnology for Biofuels
Tianzhe Liu, Rabia Mazmouz, Brett A Neilan
Phosphopantetheinyl transferases catalyze the post-translational modification of carrier proteins involved in both primary and secondary metabolism. The functional expression of polyketide synthases and nonribosomal peptide synthetases requires the activation of all carrier protein domains by phosphopantetheinyl transferases. Here we describe the characterization of five bacterial phosphopantetheinyl transferases by their substrate specificity and catalytic efficiency of four cyanobacterial carrier proteins...
March 27, 2018: ACS Synthetic Biology
Francois Dussart, Ryan Douglas, Elisabet Sjökvist, Peter N Hoebe, Steven H Spoel, Graham R D McGrann
Ramularia collo-cygni (Rcc) causes Ramularia leaf spot (RLS) disease of barley. The fungus develops asymptomatically within its host until late in the growing season when necrotic lesions become visible on upper leaves. Fungal secondary metabolites (SMs) have been proposed as important factors in RLS lesion formation, but the biosynthetic pathways involved remain largely unknown. Mining the Rcc genome revealed the presence of ten polyketide synthases (PKSs), ten non-ribosomal peptide synthetases (NRPSs) and three hybrid PKS-NRPS (HPSs) identified within clusters of genes with predicted functions associated with secondary metabolism...
March 21, 2018: Molecular Plant-microbe Interactions: MPMI
Nadège Bossuet-Greif, Julien Vignard, Frédéric Taieb, Gladys Mirey, Damien Dubois, Claude Petit, Eric Oswald, Jean-Philippe Nougayrède
Colibactins are hybrid polyketide-nonribosomal peptides produced by Escherichia coli , Klebsiella pneumoniae , and other Enterobacteriaceae harboring the pks genomic island. These genotoxic metabolites are produced by pks -encoded peptide-polyketide synthases as inactive prodrugs called precolibactins, which are then converted to colibactins by deacylation for DNA-damaging effects. Colibactins are bona fide virulence factors and are suspected of promoting colorectal carcinogenesis when produced by intestinal E...
March 20, 2018: MBio
Vasudevan Bakthavatchalu, Katherine J Wert, Yan Feng, Anthony Mannion, Zhongming Ge, Alexis Garcia, Kathleen E Scott, Tyler J Caron, Carolyn M Madden, Johanne T Jacobsen, Gabriel Victora, Rudolf Jaenisch, James G Fox
Immune-compromised mouse models allow for testing the preclinical efficacy of human cell transplantations and gene therapy strategies before moving forward to clinical trials. However, CRISPR/Cas9 gene editing of the Wsh/Wsh mouse strain to create an immune-compromised model lacking function of Rag2 and Il2rγ led to unexpected morbidity and mortality. This warranted an investigation to ascertain the cause and predisposing factors associated with the outbreak. Postmortem examination was performed on 15 moribund mice...
2018: PloS One
Yuan Li, Wan Zhang, Hui Zhang, Wenya Tian, Lian Wu, Shuwen Wang, Mengmeng Zheng, Jinru Zhang, Chenghai Sun, Zixin Deng, Yuhui Sun, Xudong Qu, Jiahai Zhou
Polyketides are a large family of pharmaceutically important natural products, and the structural modification of their scaffolds is significant for drug development. Herein, we report one apo- and two complex structures (with a pentynylmalonyl and benzylmalonyl, respectively) of the broadly selective acyltransferase (AT) from the splenocin polyketide synthase. These structures revealed the molecular basis of the stereo-selectivity and substrate specificity of SpnD-AT and enabled engineering the industrially important Ery-AT6 to broaden its substrate scope to include three new types of extender units...
March 14, 2018: Angewandte Chemie
Yongjun Wei, Lei Zhang, Zhihua Zhou, Xing Yan
Polyketides (PKs) and nonribosomal peptides (NRPs) are widely applied as drugs in use today, and one potential source for novel PKs and NRPs is the marine sediment microbes. However, the diversities of microbes and their PKs and NRPs biosynthetic genes in the marine sediment are rarely reported. In this study, 16S rRNA gene fragments of the Yellow Sea sediment were analyzed, demonstrating that Proteobacteria and Bacteroidetes accounted for 62% of all the bacterial species and Actinobacteria bacteria which were seen as the typical PKs and NRPs producers only accounted for 0...
2018: Frontiers in Microbiology
Graham A Hudson, Douglas A Mitchell
The threat of antibiotic resistant bacterial infections continues to underscore the need for new treatment options. Historically, small molecule metabolites from microbes have provided a rich source of antibiotic compounds, and as a result, significant effort has been invested in engineering the responsible biosynthetic pathways to generate novel analogs with attractive pharmacological properties. Unfortunately, biosynthetic stringency has limited the capacity of non-ribosomal peptide synthetases and polyketide synthases from producing substantially different analogs in large numbers...
March 10, 2018: Current Opinion in Microbiology
Drew A Vander Wood, Adrian T Keatinge-Clay
Here, the term "module" is redefined for trans-acyltransferase (trans-AT) assembly lines to agree with how its domains cooperate and evolutionarily co-migrate. The key domain in both the polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) modules of assembly lines is the acyl carrier protein (ACP). ACPs not only relay growing acyl chains through the assembly line but also collaborate with enzymes in modules, both in cis and in trans, to add a specific chemical moiety. A ketosynthase (KS) downstream of ACP often plays the role of gatekeeper, ensuring that only a single intermediate generated by the enzymes of a module is passed downstream...
March 10, 2018: Proteins
Jeong Sang Yi, Minsuk Kim, Eun-Jung Kim, Byung-Gee Kim
Branched chain amino acids (BCAA) are catabolized into various acyl-CoA compounds, which are key precursors used in polyketide productions. Because of that, BCAA catabolism needs fine tuning of flux balances for enhancing the production of polyketide antibiotics. To enhance BCAA catabolism for pikromycin production in Streptomyces venezuelae ATCC 15439, three key enzymes of BCAA catabolism, 3-ketoacyl acyl carrier protein synthase III, acyl-CoA dehydrogenase, and branched chain α-keto acid dehydrogenase (BCDH) were manipulated...
March 10, 2018: Journal of Industrial Microbiology & Biotechnology
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