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polyketide synthase

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https://www.readbyqxmd.com/read/28213537/ketoacylsynthase-domains-of-a-pufa-synthase-in-thraustochytrium-can-effectively-function-as-stand-alone-enzymes-in-escherichia-coli
#1
Xi Xie, Dauenpen Meesapyodsuk, Xiao Qiu
Thraustochytrium sp. 26185 accumulates a high level of docosahexaenoic acid (DHA), a nutritionally important ω-3 very long chain unsaturated fatty acid (VLCPUFA) synthesized primarily by polyunsaturated fatty acid (PUFA) synthase, a Type I polyketide synthase-like mega-enzyme. The PUFA synthase in this species comprises three large subunits each with multiple catalytic domains. It was hypothesized that among these domains, ketoacylsynthase (KS) domains might be critical for catalyzing the condensation of specific unsaturated acyl-ACPs with malonyl-ACP, whereby retaining double bonds in an extended acyl chain...
February 17, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28211202/role-of-modular-polyketide-synthases-in-the-production-of-polyether-ladder-compounds-in-ciguatoxin-producing-gambierdiscus-polynesiensis-and-g-excentricus-dinophyceae
#2
Gurjeet S Kohli, Katrina Campbell, Uwe John, Kirsty F Smith, Santiago Fraga, Lesley L Rhodes, Shauna A Murray
Gambierdiscus, a benthic dinoflagellate, produces ciguatoxins that cause the human illness Ciguatera. Ciguatoxins are polyether ladder compounds that have a polyketide origin, indicating that polyketide synthases (PKS) are involved in their production. We sequenced transcriptomes of G. excentricus and G. polynesiensis and found 264 contigs encoding single domain ketoacyl synthases (KS; G. excentricus: 106, G. polynesiensis: 143) and ketoreductases (KR; G. excentricus: 7, G. polynesiensis: 8) with sequence similarity to type I PKSs, as reported in other dinoflagellates...
February 17, 2017: Journal of Eukaryotic Microbiology
https://www.readbyqxmd.com/read/28203522/mass-spectral-determination-of-phosphopantetheinylation-specificity-for-carrier-proteins-in-mycobacterium-tuberculosis
#3
James Jung, Ghader Bashiri, Jodie M Johnston, Edward N Baker
Phosphopantetheinyl transferases (PPTases) are key elements in the modular syntheses performed by multienzyme systems such as polyketide synthases. PPTases transfer phosphopantetheine derivatives from Coenzyme A to carrier proteins (CPs), thus orchestrating substrate supply. We describe an efficient mass spectrometry-based protocol for determining CP specificity for a particular PPTase in organisms possessing several candidate PPTases. We show that the CPs MbtL and PpsC, both involved in synthesis of essential metabolites in Mycobacterium tuberculosis, are exclusively activated by the type 2 PPTase PptT and not the type 1 AcpS...
December 2016: FEBS Open Bio
https://www.readbyqxmd.com/read/28193896/regulatory-cascade-and-biological-activity-of-beauveria-bassiana-oosporein-that-limits-bacterial-growth-after-host-death
#4
Yanhua Fan, Xi Liu, Nemat O Keyhani, Guirong Tang, Yan Pei, Wenwen Zhang, Sheng Tong
The regulatory network and biological functions of the fungal secondary metabolite oosporein have remained obscure. Beauveria bassiana has evolved the ability to parasitize insects and outcompete microbial challengers for assimilation of host nutrients. A novel zinc finger transcription factor, BbSmr1 (B. bassiana secondary metabolite regulator 1), was identified in a screen for oosporein overproduction. Deletion of Bbsmr1 resulted in up-regulation of the oosporein biosynthetic gene cluster (OpS genes) and constitutive oosporein production...
February 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28187530/structural-and-dynamic-characterization-of-a-freestanding-acyl-carrier-protein-involved-in-the-biosynthesis-of-cyclic-lipopeptide-antibiotics
#5
Subrata Paul, Hiroaki Ishida, Leonard T Nguyen, Zhihong Liu, Hans J Vogel
Friulimicin is a cyclic lipodecapeptide antibiotic that is produced by Actinoplanes friuliensis. Like the related lipopeptide drug daptomycin, the peptide skeleton of friulimicin is synthesized by a large multienzyme Nonribosomal Peptide Synthetase (NRPS) system. The LipD protein plays a major role in the acylation reaction of friulimicin. The attachment of the fatty acid group promotes its antibiotic activity. Phylogenetic analysis reveals that LipD is most closely related to other freestanding Acyl Carrier Proteins (ACPs), for which the genes are located near to NRPS gene clusters...
February 10, 2017: Protein Science: a Publication of the Protein Society
https://www.readbyqxmd.com/read/28179900/production-of-potent-antimicrobial-compounds-from-streptomyces-cyaneofuscatus-associated-with-fresh-water-sediment
#6
Zothanpuia, Ajit K Passari, Preeti Chandra, Vincent V Leo, Vineet K Mishra, Brijesh Kumar, Bhim P Singh
The genus Streptomyces under phylum actinobacteria has been recognized as a prolific source for the production of bioactive secondary metabolites. An actinobacterial strain designated as DST103 isolated from a wetland fresh water sediment of Tamdil Lake, Mizoram, Northeast, India was identified as Streptomyces cyaneofuscatus (KY287599) using 16SrRNA gene sequencing which shares 99.87% sequence similarity with Streptomyces cyaneofuscatus NRRL B-2570 (T) . The strain showed broad spectrum antimicrobial activities against Gram negative bacteria (Escherichia coli MTCC 739 and Pseudomonas aeruginosa MTCC 2453), Gram positive bacteria (Micrococcus luteus NCIM 2170 and Staphylococcus aureus MTCC 96) and yeast pathogen Candida albicans MTCC 3017)...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28165430/towards-precision-engineering-of-canonical-polyketide-synthase-domains-recent-advances-and-future-prospects
#7
REVIEW
Carmen L Bayly, Vikramaditya G Yadav
Modular polyketide synthases (mPKSs) build functionalized polymeric chains, some of which have become blockbuster therapeutics. Organized into repeating clusters (modules) of independently-folding domains, these assembly-line-like megasynthases can be engineered by introducing non-native components. However, poor introduction points and incompatible domain combinations can cause both unintended products and dramatically reduced activity. This limits the engineering and combinatorial potential of mPKSs, precluding access to further potential therapeutics...
February 5, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28157306/mechanism-and-stereochemistry-of-polyketide-chain-elongation-and-methyl-group-epimerization-in-polyether-biosynthesis
#8
Xinqiang Xie, Ashish Garg, Chaitan Khosla, David E Cane
The polyketide synthases responsible for the biosynthesis of the polyether antibiotics nanchangmycin (1) and salinomycin (4) harbor a number of redox-inactive ketoreductase (KR(0)) domains that are implicated in the generation of C2-epimerized (2S)-2-methyl-3-ketoacyl-ACP intermediates. Evidence that the natural substrate for the polyether KR(0) domains is, as predicted, a (2R)-2-methyl-3-ketoacyl-ACP intermediate, came from a newly developed coupled ketosynthase (KS)-ketoreductase (KR) assay that established that the decarboxylative condensation of methylmalonyl-CoA with S-propionyl-N-acetylcysteamine catalyzed by the Nan[KS1][AT1] didomain from module 1 of the nanchangmycin synthase generates exclusively the corresponding (2R)-2-methyl-3-ketopentanoyl-ACP (7a) product...
February 14, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28137838/hydroxyl-regioisomerization-of-anthracycline-catalyzed-by-a-four-enzyme-cascade
#9
Zhuan Zhang, Yu-Kang Gong, Qiang Zhou, Yu Hu, Hong-Min Ma, Yong-Sheng Chen, Yasuhiro Igarashi, Lifeng Pan, Gong-Li Tang
Ranking among the most effective anticancer drugs, anthracyclines represent an important family of aromatic polyketides generated by type II polyketide synthases (PKSs). After formation of polyketide cores, the post-PKS tailoring modifications endow the scaffold with various structural diversities and biological activities. Here we demonstrate an unprecedented four-enzyme-participated hydroxyl regioisomerization process involved in the biosynthesis of kosinostatin. First, KstA15 and KstA16 function together to catalyze a cryptic hydroxylation of the 4-hydroxyl-anthraquinone core, yielding a 1,4-dihydroxyl product, which undergoes a chemically challenging asymmetric reduction-dearomatization subsequently acted by KstA11; then, KstA10 catalyzes a region-specific reduction concomitant with dehydration to afford the 1-hydroxyl anthraquinone...
January 30, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28133950/characterization-of-giant-modular-pkss-provides-insight-into-genetic-mechanism-for-structural-diversification-of-aminopolyol-polyketides
#10
Lihan Zhang, Takuya Hashimoto, Bin Qin, Junko Hashimoto, Ikuko Kozone, Teppei Kawahara, Masahiro Okada, Takayoshi Awakawa, Takuya Ito, Yoshinori Asakawa, Masashi Ueki, Shunji Takahashi, Hiroyuki Osada, Toshiyuki Wakimoto, Haruo Ikeda, Kazuo Shin-Ya, Ikuro Abe
Polyketides form many clinically valuable compounds. However, manipulation of their biosynthesis remains highly challenging. An understanding of gene cluster evolution provides a rationale for reprogramming of the biosynthetic machinery. Herein, we report characterization of giant modular polyketide synthases (PKSs) responsible for the production of aminopolyol polyketides. Heterologous expression of over 150 kbp polyketide gene clusters successfully afforded their products, whose stereochemistry was established by taking advantage of bioinformatic analysis...
February 6, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28128554/discovery-of-c-glycosylpyranonaphthoquinones-in-streptomyces-sp-mbt76-by-a-combined-nmr-based-metabolomics-and-bioinformatics-workflow
#11
Changsheng Wu, Chao Du, Koji Ichinose, Young Hae Choi, Gilles P van Wezel
Mining of microbial genomes has revealed that actinomycetes harbor far more biosynthetic potential for bioactive natural products than anticipated. Activation of (cryptic) biosynthetic gene clusters and identification of the corresponding metabolites has become a focal point for drug discovery. Here, we applied NMR-based metabolomics combined with bioinformatics to identify novel C-glycosylpyranonaphthoquinones in Streptomyces sp. MBT76 and to elucidate the biosynthetic pathway. Following activation of the cryptic qin gene cluster for a type II polyketide synthase (PKS) by constitutive expression of its pathway-specific activator, bioinformatics coupled to NMR profiling facilitated the chromatographic isolation and structural elucidation of qinimycins A-C (1-3)...
January 27, 2017: Journal of Natural Products
https://www.readbyqxmd.com/read/28124037/the-polyketide-backbone-of-thiolactomycin-is-assembled-by-an-unusual-iterative-polyketide-synthase
#12
Marie E Yurkovich, Robert Jenkins, Yuhui Sun, Manuela Tosin, Peter F Leadlay
Following the in vivo investigation of thiotetronate assembly in Lentzea sp. and in S. thiolactonus NRRL 15439 (Havemann et al., Chem. Commun., 2017, DOI: 10.1039/c6cc09933e), the minimal set of genes required for thiolactomycin production was determined through heterologous expression and the mechanism for polyketide assembly was established in vitro through incubation of recombinant TlmB with its substrates in the presence of either nonhydrolysable or hydrolysable chemical probes. The results presented here constitute unequivocal evidence of enzymatic processing by an unusual iterative polyketide synthase...
February 9, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28119973/chemical-probing-of-thiotetronate-bio-assembly
#13
Judith Havemann, Marie E Yurkovich, Robert Jenkins, Sophia Harringer, Weixin Tao, Shishi Wen, Yuhui Sun, Peter F Leadlay, Manuela Tosin
Chemical 'chain termination' probes were utilised for the investigation of thiotetronate antibiotic biosynthesis in the filamentous bacteria Lentzea sp. and Streptomyces thiolactonus NRRL 15439. The use of these tools led to the capture of biosynthetic intermediates involved in the thiotetronate polyketide backbone assembly, providing first insights into substrate specificity and in vivo intermediate processing by unusual iterative synthases.
January 25, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28119518/molecular-beacons-to-identify-gifted-microbes-for-genome-mining
#14
Richard H Baltz
Microbial genome mining is a promising technology that is revitalizing natural product discovery. It is now well documented that many bacteria with large genomes, particularly actinomycetes, encode many more secondary metabolites (SMs) than was previously known from their expressed secondary metabolomes. There are effective bioinformatics tools for counting the numbers and nature of SMs, and determining the total coding capacity from finished microbial genomes. However, these methods do not translate well to draft genomes, particularly for large SM gene clusters that contain nonribosomal peptide synthetase (NRPS) or type I polyketide synthase (PKS-I) mega-genes which are prone to fragmentation and misassembly...
January 25, 2017: Journal of Antibiotics
https://www.readbyqxmd.com/read/28106210/multi-step-continuous-flow-synthesis
#15
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
#16
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
#17
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...
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
#18
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
#19
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
#20
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 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
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