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polyketide synthase

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https://www.readbyqxmd.com/read/28106210/multi-step-continuous-flow-synthesis
#1
Joshua Britton, Colin L Raston
Organic chemistry is continually evolving to improve the syntheses of value added and bioactive compounds. Through this progression, a concomitant advancement in laboratory technology has occurred. Many researchers now choose to mediate transformations in continuous-flow systems given the many benefits over round bottom flasks. Furthermore, reaction scale up is often less problematic as this is addressed at the inception of the science. Although single-step transformations in continuous-flow systems are common, multi-step transformations are more valuable...
January 20, 2017: Chemical Society Reviews
https://www.readbyqxmd.com/read/28106181/in-vitro-kinetic-study-of-the-squalestatin-tetraketide-synthase-dehydratase-reveals-the-stereochemical-course-of-a-fungal-highly-reducing-polyketide-synthase
#2
Emma Liddle, Alan Scott, Li-Chen Han, David Ivison, Thomas J Simpson, Christine L Willis, Russell J Cox
Six potential diketide substrates for the squalestatin tetraketide synthase (SQTKS) dehydratase (DH) domain were synthesised as N-acetyl cysteamine thiolesters (SNAC) and tested in kinetic assays as substrates with an isolated DH domain. 3R-3-hydroxybutyryl SNAC 3R-16 was turned over by the enzyme, but its enantiomer was not. Of the four 2-methyl substrates only 2R,3R-2-methyl-3-hydroxybutyryl SNAC 2R,3R-8 was a substrate. Combined with stereochemical information from the isolated SQTKS enoyl reductase (ER) domain, our results provide a near complete stereochemical description of the first cycle of beta-modification reactions of a fungal highly reducing polyketide synthase (HR-PKS)...
January 20, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28103677/inversion-of-extender-unit-selectivity-in-the-erythromycin-polyketide-synthase-by-acyltransferase-domain-engineering
#3
Irina Koryakina, Christian Kasey, John B McArthur, Andrew N Lowell, Joseph A Chemler, Shasha Li, Douglas A Hansen, David H Sherman, Gavin J Williams
Acyltransferase (AT) domains of polyketide synthases (PKSs) select extender units for incorporation into polyketides and dictate large portions of the structures of clinically relevant natural products. Accordingly, there is significant interest in engineering the substrate specificity of PKS ATs in order to site-selectively manipulate polyketide structure. However, previous attempts to engineer ATs have yielded mutant PKSs with relaxed extender unit specificity, rather than an inversion of selectivity from one substrate to another...
January 20, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28102686/one-pot-enzymatic-total-synthesis-of-presteffimycinone-an-early-intermediate-of-the-anthracycline-antibiotic-steffimycin-biosynthesis
#4
Guojun Wang, Jing Chen, Haining Zhu, Jürgen Rohr
Early acting cyclases play critical roles in programming the polyketide biosynthesis toward certain, distinguished scaffolds. Starting from acetyl-CoA and malonyl-CoA, a one-pot enzymatic total synthesis of an anthracyclinone scaffold, presteffimycinone, was achieved by mixing polyketide synthase (PKS) and early post-PKS enzymes from the biosynthetic pathways of three different types of type II-PKS driven anticancer antibiotics, namely, the mithramycin (aureolic acid-type), gilvocarcin (rearranged angucycline-type), and steffimycin (anthracycline) pathways...
January 19, 2017: Organic Letters
https://www.readbyqxmd.com/read/28098952/solving-the-puzzle-of-one-carbon-loss-in-ripostatin-biosynthesis
#5
Chengzhang Fu, David Auerbach, Yanyan Li, Ullrich Scheid, Eva Luxenburger, Ronald Garcia, Herbert Irschik, Rolf Müller
Ripostatin is a promising antibiotic that inhibits RNA polymerase by binding to a novel binding site. In this study, the characterization of the biosynthetic gene cluster of ripostatin, which is a peculiar polyketide synthase (PKS) hybrid cluster encoding cis- and trans-acyltransferase PKS genes, is reported. Moreover, an unprecedented mechanism for phenyl acetic acid formation and loading as a starter unit was discovered. This phenyl-C2 unit is derived from phenylpyruvate (phenyl-C3) and the mechanism described herein explains the mysterious loss of one carbon atom in ripostatin biosynthesis from the phenyl-C3 precursor...
January 18, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28096394/elucidating-the-mechanism-of-fluorinated-extender-unit-loading-for-improved-production-of-fluorine-containing-polyketides
#6
Omer Ad, Benjamin W Thuronyi, Michelle C Y Chang
Polyketides are a large family of bioactive natural products synthesized by polyketide synthase (PKS) enzyme complexes predominantly from acetate and propionate. Given the structural diversity of compounds produced using these two simple building blocks, there has been longstanding interest in engineering the incorporation of alternative extender units. We have been investigating the mechanism of fluorinated monomer insertion by three of the six different modules of the PKS involved in erythromycin biosynthesis (6-deoxyerythronolide B synthase, DEBS) to begin understanding the contribution of different steps, such as enzyme acylation, transacylation, C-C bond formation, and chain transfer, to the overall selectivity and efficiency of this process...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28095865/engineered-biosynthesis-of-milbemycins-in-the-avermectin-high-producing-strain-streptomyces-avermitilis
#7
Myoun-Su Kim, Wan-Je Cho, Myoung Chong Song, Seong-Whan Park, Kaeun Kim, Eunji Kim, Naryeong Lee, Sang-Jip Nam, Ki-Hoon Oh, Yeo Joon Yoon
BACKGROUND: Milbemycins, produced from Streptomyces hygroscopicus subsp. aureolacrimosus and Streptomyces bingchenggensis, are 16-membered macrolides that share structural similarity with avermectin produced from Streptomyces avermitilis. Milbemycins possess strong acaricidal, insecticidal, and anthelmintic activities but low toxicity. Due to the high commercial value of the milbemycins and increasing resistance to the avermectins and their derivatives, it is imperative to develop an efficient combinatorial biosynthesis system exploiting an overproduction host strain to produce the milbemycins and novel analogs in large quantities...
January 17, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/28093838/fusaric-acid-contributes-to-virulence-of-fusarium-oxysporum-on-plant-and-mammalian-hosts
#8
Cristina López-Díaz, Vahid Rahjoo, Michael Sulyok, Veronica Ghionna, Adela Martín-Vicente, Javier Capilla, Antonio Di Pietro, Manuel S López-Berges
Fusaric acid (FA) is among the oldest identified secondary metabolites produced by Fusarium species, known for a long time to display strong phytotoxicity and moderate toxicity to animal cells; however, the cellular targets of FA as well as its function in fungal pathogenicity remain unknown. Here, we investigated the role of FA in Fusarium oxysporum, a soil-borne cross-kingdom pathogen that causes vascular wilt on more than a hundred plant species and opportunistic infections in humans. Targeted deletion of fub1, encoding a predicted orthologue of the polyketide synthase involved in FA biosynthesis in F...
January 17, 2017: Molecular Plant Pathology
https://www.readbyqxmd.com/read/28089042/molecular-screening-of-xerophilic-aspergillus-strains-producing-mycophenolic-acid
#9
Bello Mouhamadou, Lucile Sage, Sophie Périgon, Virginie Séguin, Valérie Bouchart, Patrick Legendre, Mathilde Caillat, Hayet Yamouni, David Garon
Mycophenolic acid (MPA) is the fungal secondary metabolite displaying several biological properties. Up to now, screening of fungal strains producing MPA has mainly been the result of the search of this molecule in their culture medium by chemical methods. Here we developed a molecular approach by targeting the expression level of the MpaC gene encoding the polyketide synthase, one of the key enzymes involved in the MPA synthesis. Thirty xerophilic Aspergillus strains were identified using the RNA polymerase II subunit and the β-tubulin genes...
February 2017: Fungal Biology
https://www.readbyqxmd.com/read/28076787/impdh2-is-an-intracellular-target-of-the-cyclophilin-a-and-sanglifehrin-a-complex
#10
Khian Hong Pua, Dylan T Stiles, Mathew E Sowa, Gregory L Verdine
Natural products have demonstrated utility in the clinic and can also act as probes to understand complex cellular pathways. Sanglifehrin A (SFA) is a mixed polyketide and non-ribosomal peptide synthase natural product with sub-nano-molar affinity for its receptor cyclophilin A (PPIA). It has been shown to behave in vitro as an immune suppressant. Here, we identify inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) as an intracellular target of the PPIA-SFA binary complex. The formation of this ternary complex does not inhibit the enzymatic activity of IMPDH2...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28074866/-mycobacterium-massilipolynesiensis-sp-nov-a-rapidly-growing-mycobacterium-of-medical-interest-related-to-mycobacterium-phlei
#11
M Phelippeau, S Asmar, D Aboubaker Osman, M Sassi, C Robert, C Michelle, D Musso, M Drancourt
In French Polynesia, respiratory tract clinical isolate M26, displayed unusual phenotype and contradictory phylogenetic affiliations, suggesting a hitherto unidentified rapidly-growing Mycobacterium species. The phenotype of strain M26 was further characterized and its genome sequenced. Strain M26 genome consists in a 5,732,017-bp circular chromosome with a G + C% of 67.54%, comprising 5,500 protein-coding genes and 52 RNA genes (including two copies of the 16 S rRNA gene). One region coding for a putative prophage was also predicted...
January 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28074041/transcription-factor-xpp1-is-a-switch-between-primary-and-secondary-fungal-metabolism
#12
Christian Derntl, Bernhard Kluger, Christoph Bueschl, Rainer Schuhmacher, Robert L Mach, Astrid R Mach-Aigner
Fungi can produce a wide range of chemical compounds via secondary metabolism. These compounds are of major interest because of their (potential) application in medicine and biotechnology and as a potential source for new therapeutic agents and drug leads. However, under laboratory conditions, most secondary metabolism genes remain silent. This circumstance is an obstacle for the production of known metabolites and the discovery of new secondary metabolites. In this study, we describe the dual role of the transcription factor Xylanase promoter binding protein 1 (Xpp1) in the regulation of both primary and secondary metabolism of Trichoderma reesei Xpp1 was previously described as a repressor of xylanases...
January 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28066819/growth-on-chitin-impacts-the-transcriptome-and-metabolite-profiles-of-antibiotic-producing-vibrio-coralliilyticus-s2052-and-photobacterium-galatheae-s2753
#13
Sonia Giubergia, Christopher Phippen, Kristian Fog Nielsen, Lone Gram
Members of the Vibrionaceae family are often associated with chitin-containing organisms, and they are thought to play a major role in chitin degradation. The purpose of the present study was to determine how chitin affects the transcriptome and metabolome of two bioactive Vibrionaceae strains, Vibrio coralliilyticus and Photobacterium galatheae. We focused on chitin degradation genes and secondary metabolites based on the assumption that these molecules in nature confer an advantage to the producer. Growth on chitin caused upregulation of genes related to chitin metabolism and of genes potentially involved in host colonization and/or infection...
January 2017: MSystems
https://www.readbyqxmd.com/read/28060484/a-highly-promiscuous-%C3%A3-ketoacyl-acp-synthase-kas-iii-like-protein-is-involved-in-pactamycin-biosynthesis
#14
Mostafa E Abugrain, Corey J Brumsted, Andrew R Osborn, Benjamin Philmus, Taifo Mahmud
β-Ketoacyl-acyl carrier protein (β-Ketoacyl-ACP) synthase (KAS) III catalyzes the first step in fatty acid biosynthesis, involving a Claisen condensation of the acetyl-CoA starter unit with the first extender unit, malonyl-ACP, to form acetoacetyl-ACP. KAS III-like proteins have also been reported to catalyze acyltransferase reactions using coenzyme A esters or discrete ACP-bound substrates. Here, we report the in vivo and in vitro characterizations of a KAS III-like protein (PtmR), which directly transfers a 6-methylsalicylyl moiety from an iterative type I polyketide synthase to an aminocyclopentitol unit in pactamycin biosynthesis...
January 12, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28054175/directed-accumulation-of-less-toxic-pimaricin-derivatives-by-improving-the-efficiency-of-a-polyketide-synthase-dehydratase-domain
#15
Zhen Qi, Yucong Zhou, Qianjin Kang, Chunyan Jiang, Jianting Zheng, Linquan Bai
Pimaricin is an important polyene antifungal antibiotic that binds ergosterol and extracts it from fungal membranes. In previous work, two pimaricin derivatives (1 and 2) with improved pharmacological activities and another derivative (3) that showed no antifungal activity were produced by the mutant strain of Streptomyces chattanoogensis, in which the P450 monooxygenase gene scnG has been inactivated. Furthermore, inactivation of the DH12 dehydratase domain of the pimaricin polyketide synthases (PKSs) resulted in specific accumulation of the undesired metabolite 3, suggesting that improvement of the corresponding dehydratase activity may reduce or eliminate the accumulation of 3...
January 4, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28044276/antimicrobial-potential-and-taxonomic-investigation-of-piezotolerant-streptomyces-sp-niot-ch-40-isolated-from-deep-sea-sediment
#16
Vishnu Priya Padmanaban, Pankaj Verma, Srividhyalakshmi Venkatabaskaran, Thirupathi Keppayan, Dharani Gopal, Ashok Kumar Sekar, Kirubagaran Ramalingam
Microbial-derived natural products from extreme niches such as deepsea are known to possess structural and functional novelty. With this background, the present study was designed to investigate the bioprospecting potential and systematics of a deep-sea derived piezotolerant bacterial strain NIOT-Ch-40, showing affiliation to the genus Streptomyces based on 16S RNA gene similarity. Preliminary screening for the presence of biosynthetic genes like polyketide synthase I, polyketide synthase II, non ribosomal peptide synthase, 3-amino-5-hydroxybenzoic acid synthase and spiroindimicin followed by antibacterial activity testing confirmed the presence of potent bioactivity...
February 2017: World Journal of Microbiology & Biotechnology
https://www.readbyqxmd.com/read/28018603/draft-genome-sequence-of-a-human-associated-isolate-of-haloferax-alexandrinus-strain-arc-hr-an-extremely-halophilic-archaea
#17
S Khelaifia, A Caputo, F Djossou, D Raoult
We report the draft genome sequence of Haloferax alexandrinus strain Arc-hr (CSUR P798), isolated from the human gut of a 10-year-old Amazonian individual. Its 3 893 626 bp genome exhibits a 66.00% GC content. The genome of the strain Arc-hr contains 37 genes identified as ORFans, seven genes associated to halocin and 11 genes associated with polyketide synthases or nonribosomal peptide synthetases.
January 2017: New Microbes and New Infections
https://www.readbyqxmd.com/read/28010735/several-steps-of-lateral-gene-transfer-followed-by-events-of-birth-and-death-evolution-shaped-a-fungal-sorbicillinoid-biosynthetic-gene-cluster
#18
Irina S Druzhinina, Eva M Kubicek, Christian P Kubicek
BACKGROUND: Sorbicillinoids are a family of complex cyclic polyketides produced by only a small number of distantly related ascomycete fungi such as Trichoderma (Sordariomycetes) and Penicillium (Eurotiomycetes). In T. reesei, they are synthesized by a gene cluster consisting of eight genes including two polyketide synthases (PKS). To reconstruct the evolutionary origin of this gene cluster, we examined the occurrence of these eight genes in ascomycetes. RESULTS: A cluster comprising at least six of them was only found in Hypocreales (Acremonium chrysogenum, Ustilaginoidea virens, Trichoderma species from section Longibrachiatum) and in Penicillium rubens (Eurotiales)...
December 7, 2016: BMC Evolutionary Biology
https://www.readbyqxmd.com/read/28005187/improved-pestalotiollide-b-production-by-deleting-competing-polyketide-synthase-genes-in-pestalotiopsis-microspora
#19
Longfei Chen, Yingying Li, Qian Zhang, Dan Wang, Oren Akhberdi, Dongsheng Wei, Jiao Pan, Xudong Zhu
Pestalotiollide B, an analog of dibenzodioxocinones which are inhibitors of cholesterol ester transfer proteins, is produced by Pestalotiopsis microspora NK17. To increase the production of pestalotiollide B, we attempted to eliminate competing polyketide products by deleting the genes responsible for their biosynthesis. We successfully deleted 41 out of 48 putative polyketide synthases (PKSs) in the genome of NK17. Nine of the 41 PKS deleted strains had significant increased production of pestalotiollide B (P < 0...
December 22, 2016: Journal of Industrial Microbiology & Biotechnology
https://www.readbyqxmd.com/read/28004519/antimicrobial-assay-and-genetic-screening-of-selected-freshwater-cyanobacteria-and-identification-of-a-biomolecule-dihydro-2h-pyran-2-one-derivative
#20
A Srivastava, V K Singh, S Patnaik, J Tripathi, P Singh, G Nath, R K Asthana
AIMS: Explorations of freshwater cyanobacteria as antimicrobial (bacteria, fungi and MRSA strains) drug resource using bioassay, NRPS (non-ribosomal polypeptide synthetase) and PKS (polyketide synthase) genes, as well as in silico approach. METHODS AND RESULTS: We have bioassayed the extracts of Phormidium CCC727, Geitlerinema CCC728, Arthrospira CCC729, Leptolyngbya CCC732, Phormidium CCC730, Phormidium CCC731 against six pathogenic bacteria Gram (+ve): Staphylococcus aureus including seven clinical methicillin-resistant S...
December 22, 2016: Journal of Applied Microbiology
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