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Minghua Chen, Renzhong Wang, Wuli Zhao, Liyan Yu, Conghui Zhang, Shanshan Chang, Yan Li, Tao Zhang, Jianguo Xing, Maoluo Gan, Feng Feng, Shuyi Si
Isocoumarindole A (1), a novel polyketide synthetase-nonribosomal peptide synthetase (PKS-NRPS) hybrid metabolite, was isolated from the endolichenic fungus Aspergillus sp. CPCC 400810. The structure of isocoumarindole A (1) was featured by an unprecedented skeleton containing chlorinated isocoumarin and indole diketopiperazine alkaloid moieties linked by a carbon-carbon bond, which was determined by a combination of spectroscopic analyses, Marfey's method, and calculations of NMR chemical shifts, ECD spectra, and optical rotation values...
February 20, 2019: Organic Letters
Laurence Maschio, Alice E Parnell, Nicholas R Lees, Christine L Willis, Christiane Schaffitzel, James E M Stach, Paul R Race
Polyketides are a structurally and functionally diverse family of bioactive natural products that have proven to be a rich source of pharmaceutical and agrochemical lead compounds. Many polyketides are biosynthesized by large multifunctional megaenzymes termed type I modular polyketide synthases (PKSs). These systems possess a distinctive assembly line-like architecture, comprising a series of linearly arranged, multidomain extension modules, housed in sequence within giant polypeptide chains. Due to their inherently modular structures, PKSs represent attractive targets for reengineering, enabling access to functionally optimized "nonnatural" natural products...
2019: Methods in Enzymology
Zhili Lu, Xiaoting Zhang, Jianlu Dai, Yiguang Wang, Weiqing He
BACKGROUND: Bitespiramycin (BT) is produced by recombinant spiramycin (SP) producing strain Streptomyces spiramyceticus harboring a heterologous 4″-O-isovaleryltransferase gene (ist). Exogenous L-Leucine (L-Leu) could improve the production of BT. The orf2 gene found from the genomic sequence of S. spiramyceticus encodes a leucine-responsive regulatory protein (Lrp) family regulator named as SSP_Lrp. The functions of SSP_Lrp and L-Leu involved in the biosynthesis of spiramycin (SP) and BT were investigated in S...
February 19, 2019: Microbial Cell Factories
Agnieszka J Szwalbe, Katherine Williams, Zhongshu Song, Kate de Mattos-Shipley, Jason L Vincent, Andrew M Bailey, Christine L Willis, Russell J Cox, Thomas J Simpson
Two new dihydroxy-xanthone metabolites, agnestins A and B, were isolated from Paecilomyces variotii along with a number of related benzophenones and xanthones including monodictyphenone. The structures were elucidated by NMR analyses and X-ray crystallography. The agnestin ( agn ) biosynthetic gene cluster was identified and targeted gene disruptions of the PKS, Baeyer-Villiger monooxygenase, and other oxido-reductase genes revealed new details of fungal xanthone biosynthesis. In particular, identification of a reductase responsible for in vivo anthraquinone to anthrol conversion confirms a previously postulated essential step in aromatic deoxygenation of anthraquinones, e...
January 7, 2019: Chemical Science
You Lan, Mao Zhou, Zijuan Jian, Qun Yan, Siyi Wang, Wenen Liu
BACKGROUND: The emerging pks-positive (pks+ ) strains have aroused great public concern recently. Colibactin, encoded by pks gene cluster, has been reported to be involved in DNA damage and increased virulence. Little is known about its prevalence among Klebsiella pneumoniae-induced bloodstream infections (BSIs). Therefore, the aim of this study was to investigate the prevalence of pks gene cluster, and molecular and clinical characteristics of K pneumoniae-induced BSIs. METHODS: A total of 190 non-duplicate K pneumoniae bloodstream isolates were collected at a university hospital in China from March 2016 to March 2018...
February 8, 2019: Journal of Clinical Laboratory Analysis
Roslyn D Noar, Elizabeth Thomas, Margaret E Daub
Pseudocercospora fijiensis, causal agent of black Sigatoka of banana, produces polyketide synthase (PKS) pathways shown to be important in disease development by related Dothideomycete fungi. Genome analysis of the P. fijiensis PKS8-1 gene identified it as part of a gene cluster including genes encoding two transcription factors, a regulatory protein, a glyoxylase/beta-lactamase-like protein, an MFS transporter, a cytochrome P450, two aldo/keto reductases, a dehydrogenase, and a decarboxylase. Genome analysis of the related pathogens Pseudocercospora musae, Pseudocercospora eumusae, and Pseudocercospora pini-densiflorae, identified orthologous clusters containing a nearly identical combination of genes...
2019: PloS One
Hang Li, Cameron L M Gilchrist, Heather J Lacey, Andrew Crombie, Daniel Vuong, John I Pitt, Ernest Lacey, Yit-Heng Chooi, Andrew M Piggott
The burnettramic acids are a new class of antibiotics from an Australian fungus Aspergillus burnettii. The rare bolaamphiphilic scaffold consists of β-d-mannose linked to a pyrrolizidinedione unit via a 26-carbon chain. The most abundant metabolite displayed potent in vitro antifungal activity. Comparative genomics identified the hybrid PKS-NRPS bua gene cluster, which was verified by heterologous pathway reconstitution in Aspergillus nidulans.
February 8, 2019: Organic Letters
Rodrigo A Olarte, Jon Menke, Ying Zhang, Shawn Sullivan, Jason C Slot, Yinyin Huang, Jonathan P Badalamenti, Alisha C Quandt, Joseph W Spatafora, Kathryn E Bushley
BACKGROUND: Genes involved in production of secondary metabolites (SMs) in fungi are exceptionally diverse. Even strains of the same species may exhibit differences in metabolite production, a finding that has important implications for drug discovery. Unlike in other eukaryotes, genes producing SMs are often clustered and co-expressed in fungal genomes, but the genetic mechanisms involved in the creation and maintenance of these secondary metabolite biosynthetic gene clusters (SMBGCs) remains poorly understood...
February 7, 2019: BMC Genomics
Ramón Gómez-Moreno, María González-Pons, Marievelisse Soto-Salgado, Marcia Cruz-Correa, Abel Baerga-Ortiz
Gut bacterial toxins are thought to contribute to the development of colorectal cancer (CRC). This study examines the presence of specific gut bacterial toxin genes in stool samples from individuals with colorectal neoplasia (adenomas and/or CRC). The presence of bacterial genes encoding genotoxic or pro-inflammatory factors ( pks , tcpC , gelE , cnf-1 , AMmurB , and usp ) was established by PCR of stool samples from individuals from mainland US ( n = 30; controls = 10, adenoma = 10, CRC = 10) and from Puerto Rico (PR) ( n = 33; controls = 13; adenomas = 8; CRC = 12)...
February 1, 2019: Diseases (Basel)
Margarida Costa, Ivo E Sampaio-Dias, Raquel Castelo-Branco, Hugo Scharfenstein, Roberta Rezende de Castro, Artur Silva, Maria Paula C Schneider, Maria João Araújo, Rosário Martins, Valentina F Domingues, Fátima Nogueira, Vera Camões, Vitor M Vasconcelos, Pedro N Leão
Small, single-celled planktonic cyanobacteria are ubiquitous in the world's oceans yet tend not to be perceived as secondary metabolite-rich organisms. Here we report the isolation and structure elucidation of hierridin C, a minor metabolite obtained from the cultured picocyanobacterium Cyanobium sp. LEGE 06113. We describe a simple, straightforward synthetic route to the scarcely produced hierridins that relies on a key regioselective halogenation step. In addition, we show that these compounds originate from a type III PKS pathway and that similar biosynthetic gene clusters are found in a variety of bacterial genomes, most notably those of the globally distributed picocyanobacteria genera Prochlorococcus, Cyanobium and Synechococcus...
February 4, 2019: Journal of Natural Products
Varun Garg, Jinshan Shen, Chonghua Li, Sagar Agarwal, Asfiha Gebre, Sarah Robertson, Jiayin Huang, Linda Han, Licong Jiang, Kristin Stephan, Linda T Wang, Julie Lekstrom-Himes
Drug-drug interaction (DDI) studies are described for tezacaftor/ivacaftor, a new cystic fibrosis transmembrane conductance regulator modulator therapy for the treatment of cystic fibrosis. Three phase I DDI studies were conducted in healthy subjects to characterize the DDI profile of tezacaftor/ivacaftor with cytochrome P450 (CYP)3A substrates, CYP3A inhibitors, and a permeability glycoprotein (P-gp) substrate. The effects of steady-state tezacaftor/ivacaftor on the pharmacokinetics (PKs) of digoxin (a P-gp substrate), midazolam, and ethinyl estradiol/norethindrone (CYP3A substrates) were evaluated...
January 29, 2019: Clinical and Translational Science
Maja Klaus, Alicia D'Souza, Aleksandra Nivina, Chaitan Khosla, Martin Grininger
Engineering of assembly line polyketide synthases (PKSs) to produce novel bioactive compounds has been a goal for over twenty years. The apparent modularity of PKSs has inspired many engineering attempts in which entire modules or single domains were exchanged. In recent years, it has become evident that certain domain-domain interactions are evolutionarily optimized, and if disrupted, cause a decrease of the overall turnover rate of the chimeric PKS. In this study, we compared different types of chimeric PKSs in order to define the least invasive interface and to expand the toolbox for PKS engineering...
January 25, 2019: ACS Chemical Biology
Anwesha Gohain, Rupak Kumar Sarma, Rajal Debnath, Juthika Saikia, Bhim Pratap Singh, Rajeev Sarmah, Ratul Saikia
The most diverse and versatile endophytic actinobacteria are relatively unexplored potential sources of bioactive metabolites useful for different medical, agricultural, and other commercial applications. Their diversity in symbiotic association with traditionally utilized medicinal plants of northeast India is scantly available. The present investigation assessed the genetic diversity of endophytic actinobacteria (n = 120) distributed around the root, stem, and leaf tissues of six selected medicinal plants (Emblica officinalis, Terminalia chebula, T...
January 24, 2019: Folia Microbiologica
Hegazy Rezk, Ahmed M Nassef, Abrar Inayat, Enas Taha Sayed, Muhammad Shahbaz, A G Olabi
Fossil fuel depletion and the environmental concerns have been under discussion for energy production for many years and finding new and renewable energy sources became a must. Biomass is considered as a net zero CO2 energy source. Gasification of biomass for H2 and syngas production is an attractive process. The main target of this research is to improve the production of hydrogen and syngas from palm kernel shell (PKS) steam gasification through defining the optimal operating parameters' using a modern optimization algorithm...
March 25, 2019: Science of the Total Environment
Edward Kalkreuter, Jared M CroweTipton, Andrew N Lowell, David H Sherman, Gavin J Williams
There is significant interest in diversifying the structures of polyketides to create new analogues of these bioactive molecules. This has traditionally been done by focusing on engineering the acyltransferase (AT) domains of polyketide synthases (PKSs) responsible for the incorporation of malonyl-CoA extender units. Non-natural extender units have been utilized by engineered PKSs previously; however, most of the work to date has been accomplished with ATs that are either naturally promiscuous and/or located in terminal modules lacking downstream bottlenecks...
January 24, 2019: Journal of the American Chemical Society
Chuan Li Lee, Paik San H'ng, Md Tahir Paridah, Kit Ling Chin, Umer Rashid, Mariusz Maminski, Wen Ze Go, Raja Ahamd Raja Nazrin, Siti Nurul Asyikin Rosli, Pui San Khoo
In the present study, agricultural biomass-palm kernel shell (PKS) and coconut shell (CS)-was used to produce high porosity bioadsorbent using two-stage continuous physical activation method with different gas carrier (air and N2 ) in each stage. The activation temperature was set constant at 600, 700, 800 or 900°C for both activation stages with the heating rate of 3°C min-1 . Two parameters, the gas carrier and activation temperature, were determined as the significant factors on the adsorption properties of bioadsorbent...
December 2018: Royal Society Open Science
Reham Al-Dhelaan, Paul S Russo, Sean E Padden, Anthony Amaya, Debbie W Dong, Young-Ok You
Non-elongating modules with condensation-incompetent ketosynthase (KS0 ) are frequently found in many trans-acyltransferase polyketide synthases ( trans-AT PKS). KS0 catalyzes translocation of carbon chain without decarboxylative condensation. Unlike typical elongating modules where malonylation of acyl carrier protein (ACP) precedes elongation, the malonylation of ACP downstream of KS0 is assumed to be prevented. In this study, the regulation mechanism(s) of ACP malonylation in a non-elongating module of difficidin biosynthase was investigated...
January 14, 2019: ACS Chemical Biology
Jingrun Ye, Mengmeng Liu, Mingxia He, Ying Ye, Junchao Huang
The marine thraustochytrids are a promising source of docosahexaenoic acid (DHA) and the ketocarotenoid astaxanthin. In this study, the biosynthetic pathways of these two important metabolites in Aurantiochytrium sp. SK4 was illustrated by the analyses of the genome, transcriptome, key enzymes, and pathway products. Two sets of genes were involved in two pathways for the biosynthesis of fatty acids. The absence of Δ-15 desaturase genes and the presence of docosapentaenoic acid (DPA), up to 12% of total fatty acids suggest that Aurantiochytrium sp...
January 10, 2019: Marine Drugs
Qiong Hu, Jinming Kong, Dongxue Han, Yuwei Zhang, Yu Bao, Xueji Zhang, Li Niu
Phosphorylation of proteins catalyzed by protein kinases (PKs) is essential to many biological processes; the sensitive detection of PK activity and the screening of PK inhibitors are thus integral to disease diagnosis and drug discovery. Herein, a highly sensitive biosensor has been fabricated for the electrochemical detection of PK activity by exploiting the electrochemically controlled reversible addition-fragmentation chain transfer (eRAFT) polymerization as a novel amplification strategy. The fabrication of the eRAFT-polymerization-based electrochemical biosensor involves (1) the immobilization of substrate peptides onto a gold electrode by way of gold-sulfur self-assembly, (2) the site-specific phosphorylation of substrate peptides by PKs, (3) the anchoring of carboxyl-group-containing chain transfer agents (CTAs) to the phosphorylated sites, and (4) the eRAFT polymerization under a potentiostatic condition, using ferrocenylmethyl methacrylate (FcMMA) as the monomer...
January 11, 2019: Analytical Chemistry
Taro Ozaki, Ryosuke Sugiyama, Morito Shimomura, Shinichi Nishimura, Shumpei Asamizu, Yohei Katsuyama, Hideaki Kakeya, Hiroyasu Onaka
5-Alkyl-1,2,3,4-tetrahydroquinolines (5aTHQs) and streptoaminals (STAMs) are natural products isolated from the combined-culture of Streptomyces nigrescens HEK616 and Tsukamurella pulmonis TP-B0596. Despite their unique structures, their biosynthetic pathway has yet to be elucidated. In the present study, we conducted a feeding experiment using 13C-labeled acetates and demonstrated that 5aTHQs are likely synthesized by the action of polyketide synthase (PKS). Based on this observation, we identified the biosynthetic gene cluster for 5aTHQs...
January 10, 2019: Organic & Biomolecular Chemistry
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