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new strategies for drug discovery: activation of silent or weakly expressed microbial gene clusters.genome sequencing of streptomyces, myxobacteria, and fungi showed that although each strain contains genes that encode the enzymes to synthesize a plethora of potential secondary metabolites, only a fraction are expressed during fermentation. interest has therefore grown in the activation of these cryptic pathways. we review current progress on this topic, describing concepts for activating silent genes, utilization of "natural" mutant-type rna polymerases and rare earth elements, and the applic ...201223143535
clustermine360: a database of microbial pks/nrps biosynthesis.clustermine360 (http://www.clustermine360.ca/) is a database of microbial polyketide and non-ribosomal peptide gene clusters. it takes advantage of crowd-sourcing by allowing members of the community to make contributions while automation is used to help achieve high data consistency and quality. the database currently has >200 gene clusters from >185 compound families. it also features a unique sequence repository containing >10 000 polyketide synthase/non-ribosomal peptide synthetase domains. ...201223104377
clustermine360: a database of microbial pks/nrps biosynthesis.clustermine360 (http://www.clustermine360.ca/) is a database of microbial polyketide and non-ribosomal peptide gene clusters. it takes advantage of crowd-sourcing by allowing members of the community to make contributions while automation is used to help achieve high data consistency and quality. the database currently has >200 gene clusters from >185 compound families. it also features a unique sequence repository containing >10 000 polyketide synthase/non-ribosomal peptide synthetase domains. ...201223104377
a response regulator interfaces between the frz chemosensory system and the mgla/mglb gtpase/gap module to regulate polarity in myxococcus xanthus.how cells establish and dynamically change polarity are general questions in cell biology. cells of the rod-shaped bacterium myxococcus xanthus move on surfaces with defined leading and lagging cell poles. occasionally, cells undergo reversals, which correspond to an inversion of the leading-lagging pole polarity axis. reversals are induced by the frz chemosensory system and depend on relocalization of motility proteins between the poles. the ras-like gtpase mgla localizes to and defines the lea ...201223028358
myxobacteria: natural pharmaceutical factories.myxobacteria are amongst the top producers of natural products. the diversity and unique structural properties of their secondary metabolites is what make these social microbes highly attractive for drug discovery. screening of products derived from these bacteria has revealed a puzzling amount of hits against infectious and non-infectious human diseases. preying mainly on other bacteria and fungi, why would these ancient hunters manufacture compounds beneficial for us? the answer may be the tar ...201222545867
ppgpp metabolism is involved in heterocyst development in the cyanobacterium anabaena sp. strain pcc 7120.when deprived of a combined-nitrogen source in the growth medium, the filamentous cyanobacterium anabaena sp. pcc 7120 (anabaena) can form heterocysts capable of nitrogen fixation. the process of heterocyst differentiation takes about 20 to 24 h, during which extensive metabolic and morphological changes take place. guanosine tetraphosphate (ppgpp) is the signal of the stringent response that ensures cell survival by adjusting major cellular activities in response to nutrient starvation in bacte ...201323935047
a small predatory core genome in the divergent marine bacteriovorax marinus sj and the terrestrial bdellovibrio bacteriovorus.bacteriovorax marinus sj is a predatory delta-proteobacterium isolated from a marine environment. the genome sequence of this strain provides an interesting contrast to that of the terrestrial predatory bacterium bdellovibrio bacteriovorus hd100. based on their predatory lifestyle, bacteriovorax were originally designated as members of the genus bdellovibrio but subsequently were re-assigned to a new genus and family based on genetic and phenotypic differences. b. marinus attaches to gram-negati ...201222955231
engineering microbial cells for the biosynthesis of natural compounds of pharmaceutical significance.microbes constitute important platforms for the biosynthesis of numerous molecules of pharmaceutical interest such as antitumor, anticancer, antiviral, antihypertensive, antiparasitic, antioxidant, immunological agents, and antibiotics as well as hormones, belonging to various chemical families, for instance, terpenoids, alkaloids, polyphenols, polyketides, amines, and proteins. engineering microbial factories offers rich opportunities for the production of natural products that are too complex ...201323710459
complete genome sequence and comparative genomics of a novel myxobacterium myxococcus hansupus.myxobacteria, a group of gram-negative aerobes, belong to the class δ-proteobacteria and order myxococcales. unlike anaerobic δ-proteobacteria, they exhibit several unusual physiogenomic properties like gliding motility, desiccation-resistant myxospores and large genomes with high coding density. here we report a 9.5 mbp complete genome of myxococcus hansupus that encodes 7,753 proteins. phylogenomic and genome-genome distance based analysis suggest that myxococcus hansupus is a novel member of ...201626900859
natural products: a continuing source of novel drug leads.nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. combinatorial chemistry (late 1980s), shifted the focus of drug discovery efforts from nature to the laboratory bench.201323428572
intra- and interprotein phosphorylation between two-hybrid histidine kinases controls myxococcus xanthus developmental progression.histidine-aspartate phosphorelay signaling systems are used to couple stimuli to cellular responses. a hallmark feature is the highly modular signal transmission modules that can form both simple "two-component" systems and sophisticated multicomponent systems that integrate stimuli over time and space to generate coordinated and fine-tuned responses. the deltaproteobacterium myxococcus xanthus contains a large repertoire of signaling proteins, many of which regulate its multicellular developmen ...201222661709
complete genome sequence of the fruiting myxobacterium corallococcus coralloides dsm 2259.corallococcus coralloides, like most other myxobacteria, undergoes a developmental program culminating in the formation of fruiting bodies. c. coralloides fruiting bodies are morphologically distinct from those of other fruiting myxobacteria for which full-length genome sequences are available. the genome sequence of the 10.0-mb c. coralloides genome is presented herein.201222582372
a comprehensive insight into the lipid composition of myxococcus xanthus by uplc-esi-ms.analysis of whole cell lipid extracts of bacteria by means of ultra-performance (up)lc-ms allows a comprehensive determination of the lipid molecular species present in the respective organism. the data allow conclusions on its metabolic potential as well as the creation of lipid profiles, which visualize the organism's response to changes in internal and external conditions. herein, we describe: i) a fast reversed phase uplc-esi-ms method suitable for detection and determination of individual l ...201425332432
scrutinizing the scaffolds of marine biosynthetics from different source organisms: gram-negative cultured bacterial products enter center stage.compounds from macro marine organisms are presumed to owe their biosynthetic origins to associated microbial symbionts, although few definitive examples exist. an upsurge in the recent literature from 2012 to 2013 has shown that four compounds previously reported from macro marine organisms are in fact biosynthesized by non-photosynthetic gram-negative bacteria (npgnb). structural parallels between compounds isolated from macro marine organisms and npgnb producers form the basis of this review. ...201424571234
ca2+-binding motif of βγ-crystallins.βγ-crystallin-type double clamp (n/d)(n/d)xx(s/t)s motif is an established but sparsely investigated motif for ca(2+) binding. a βγ-crystallin domain is formed of two greek key motifs, accommodating two ca(2+)-binding sites. βγ-crystallins make a separate class of ca(2+)-binding proteins (cabp), apparently a major group of cabp in bacteria. paralleling the diversity in βγ-crystallin domains, these motifs also show great diversity, both in structure and in function. although the expression of som ...201424567326
the phosphopantetheinyl transferases: catalysis of a post-translational modification crucial for life.covering: up to 2013. although holo-acyl carrier protein synthase, acps, a phosphopantetheinyl transferase (pptase), was characterized in the 1960s, it was not until the publication of the landmark paper by lambalot et al. in 1996 that pptases garnered wide-spread attention being classified as a distinct enzyme superfamily. in the past two decades an increasing number of papers have been published on pptases ranging from identification, characterization, structure determination, mutagenesis, inh ...201424292120
characterization of 3'-phosphate rna ligase paralogs rtcb1, rtcb2, and rtcb3 from myxococcus xanthus highlights dna and rna 5'-phosphate capping activity of rtcb3.escherichia coli rtcb exemplifies a family of gtp-dependent rna repair/splicing enzymes that join 3'-po4 ends to 5'-oh ends via stable rtcb-(histidinyl-n)-gmp and transient rna3'pp5'g intermediates. e. coli rtcb also transfers gmp to a dna 3'-po4 end to form a stable "capped" product, dna3'pp5'g. rtcb homologs are found in a multitude of bacterial proteomes, and many bacteria have genes encoding two or more rtcb paralogs; an extreme example is myxococcus xanthus, which has six rtcbs. in this stu ...201526350128
identification and characterization of a putative arginine kinase homolog from myxococcus xanthus required for fruiting body formation and cell differentiation.arginine kinases catalyze the reversible transfer of a high-energy phosphoryl group from atp to l-arginine to form phosphoarginine, which is used as an energy buffer in insects, crustaceans, and some unicellular organisms. it plays an analogous role to that of phosphocreatine in vertebrates. recently, putative arginine kinases were identified in several bacterial species, including the social gram-negative soil bacterium myxococcus xanthus. it is still unclear what role these proteins play in ba ...201222389486
reinvigorating natural product combinatorial biosynthesis with synthetic biology.natural products continue to play a pivotal role in drug-discovery efforts and in the understanding if human health. the ability to extend nature's chemistry through combinatorial biosynthesis--altering functional groups, regiochemistry and scaffold backbones through the manipulation of biosynthetic enzymes--offers unique opportunities to create natural product analogs. incorporating emerging synthetic biology techniques has the potential to further accelerate the refinement of combinatorial bio ...201526284672
allopatric integrations selectively change host transcriptomes, leading to varied expression efficiencies of exotic genes in myxococcus xanthus.exotic genes, especially clustered multiple-genes for a complex pathway, are normally integrated into chromosome for heterologous expression. the influences of insertion sites on heterologous expression and allotropic expressions of exotic genes on host remain mostly unclear.201526194479
pseudomonas putida-a versatile host for the production of natural products.the biosynthesis of natural products by heterologous expression of biosynthetic pathways in amenable production strains enables biotechnological access to a variety of valuable compounds by conversion of renewable resources. pseudomonas putida has emerged as a microbial laboratory work horse, with elaborated techniques for cultivation and genetic manipulation available. beyond that, this bacterium offers several particular advantages with regard to natural product biosynthesis, notably a versati ...201526099332
30s subunit-dependent activation of the sorangium cellulosum so ce56 aminoglycoside resistance-conferring 16s rrna methyltransferase kmr.methylation of bacterial 16s rrna within the ribosomal decoding center confers exceptionally high resistance to aminoglycoside antibiotics. this resistance mechanism is exploited by aminoglycoside producers for self-protection while functionally equivalent methyltransferases have been acquired by human and animal pathogenic bacteria. here, we report structural and functional analyses of the sorangium cellulosum so ce56 aminoglycoside resistance-conferring methyltransferase kmr. our results demon ...201525733511
cell contact-dependent outer membrane exchange in myxobacteria: genetic determinants and mechanism.biofilms are dense microbial communities. although widely distributed and medically important, how biofilm cells interact with one another is poorly understood. recently, we described a novel process whereby myxobacterial biofilm cells exchange their outer membrane (om) lipoproteins. for the first time we report here the identification of two host proteins, traab, required for transfer. these proteins are predicted to localize in the cell envelope; and traa encodes a distant pa14 lectin-like dom ...201222511878
myxobacteria: moving, killing, feeding, and surviving together.myxococcus xanthus, like other myxobacteria, is a social bacterium that moves and feeds cooperatively in predatory groups. on surfaces, rod-shaped vegetative cells move in search of the prey in a coordinated manner, forming dynamic multicellular groups referred to as swarms. within the swarms, cells interact with one another and use two separate locomotion systems. adventurous motility, which drives the movement of individual cells, is associated with the secretion of slime that forms trails at ...201627303375
prokaryote-derived protein inhibitors of peptidases: a sketchy occurrence and mostly unknown function.in metazoan organisms protein inhibitors of peptidases are important factors essential for regulation of proteolytic activity. in vertebrates genes encoding peptidase inhibitors constitute up to 1% of genes reflecting a need for tight and specific control of proteolysis especially in extracellular body fluids. in stark contrast unicellular organisms, both prokaryotic and eukaryotic consistently contain only few, if any, genes coding for putative peptidase inhibitors. this may seem perplexing in ...201020558234
heterologous production of the marine myxobacterial antibiotic haliangicin and its unnatural analogues generated by engineering of the biochemical pathway.despite their fastidious nature, marine myxobacteria have considerable genetic potential to produce novel secondary metabolites. the marine myxobacterium haliangium ochraceum smp-2 produces the antifungal polyketide haliangicin (1), but its productivity is unsatisfactory. the biosynthetic gene cluster hli (47.8 kbp) associated with 1 was identified and heterologously expressed in myxococcus xanthus to permit the production of 1 with high efficiency (tenfold greater amount and threefold faster in ...201626915413
genetic engineering and heterologous expression of the disorazol biosynthetic gene cluster via red/et recombineering.disorazol, a macrocyclic polykitide produced by the myxobacterium sorangium cellulosum so ce12 and it is reported to have potential cytotoxic activity towards several cancer cell lines, including multi-drug resistant cells. the disorazol biosynthetic gene cluster (dis) from sorangium cellulosum (so ce12) was identified by transposon mutagenesis and cloned in a bacterial artificial chromosome (bac) library. the 58-kb dis core gene cluster was reconstituted from bacs via red/et recombineering and ...201626875499
microvirga massiliensis sp. nov., the human commensal with the largest genome.microvirga massiliensis sp. nov. strain jc119(t) is a bacteria isolated in marseille from a stool sample collected in senegal. the 16s rrna (jf824802) of m. massiliensis jc119(t) revealed 95% sequence identity with microvirga lotononidis wsm3557(t) (hm362432). this bacterium is aerobic, gram negative, catalase positive, and oxidase negative. the draft genome of m. massiliensis jc119(t) comprises a 9,207,211-bp-long genome that is the largest bacterial genome of an isolate in humans. the genome e ...201626749561
inter-phylum hgt has shaped the metabolism of many mesophilic and anaerobic bacteria.genome sequencing has revealed that horizontal gene transfer (hgt) is a major evolutionary process in bacteria. although it is generally assumed that closely related organisms engage in genetic exchange more frequently than distantly related ones, the frequency of hgt among distantly related organisms and the effect of ecological relatedness on the frequency has not been rigorously assessed. here, we devised a novel bioinformatic pipeline, which minimized the effect of over-representation of spe ...201425314320
bacterial gras domain proteins throw new light on gibberellic acid response mechanisms.gibberellic acids (gas) are key plant hormones, regulating various aspects of growth and development, which have been at the center of the 'green revolution'. gras family proteins, the primary players in ga signaling pathways, remain poorly understood. using sequence-profile searches, structural comparisons and phylogenetic analysis, we establish that the gras family first emerged in bacteria and belongs to the rossmann fold methyltransferase superfamily. all bacterial and a subset of plant gras ...201222829623
identification of a cyclosporine-specific p450 hydroxylase gene through targeted cytochrome p450 complement (cypome) disruption in sebekia benihana.it was previously proposed that regio-specific hydroxylation of an immunosuppressive cyclosporine (csa) at the 4th n-methyl leucine is mediated by cytochrome p450 hydroxylase (cyp) in the rare actinomycete sebekia benihana. this modification is thought to be the reason for the hair growth-promoting side effect without the immunosuppressive activity of csa. through s. benihana genome sequencing and in silico analysis, we identified the complete cytochrome p450 complement (cypome) of s. benihana, ...201323354713
mining the metabiome: identifying novel natural products from microbial communities.microbial-derived natural products provide the foundation for most of the chemotherapeutic arsenal available to contemporary medicine. in the face of a dwindling pipeline of new lead structures identified by traditional culturing techniques and an increasing need for new therapeutics, surveys of microbial biosynthetic diversity across environmental metabiomes have revealed enormous reservoirs of as yet untapped natural products chemistry. in this review, we touch on the historical context of mic ...201425237864
discovering new bioactive molecules from microbial sources.there is an increased need for new drug leads to treat diseases in humans, animals and plants. a dramatic example is represented by the need for novel and more effective antibiotics to combat multidrug-resistant microbial pathogens. natural products represent a major source of approved drugs and still play an important role in supplying chemical diversity, despite a decreased interest by large pharmaceutical companies. novel approaches must be implemented to decrease the chances of rediscovering ...201424661414
amym, a novel maltohexaose-forming α-amylase from corallococcus sp. strain egb.a novel α-amylase, amym, was purified from the culture supernatant of corallococcus sp. strain egb. amym is a maltohexaose-forming exoamylase with an apparent molecular mass of 43 kda. based on the results of matrix-assisted laser desorption ionization-time of flight mass spectrometry and peptide mass fingerprinting of amym and by comparison to the genome sequence of corallococcus coralloides dsm 2259, the amym gene was identified and cloned into escherichia coli. amym encodes a secretory amylas ...201525576603
inter-phylum hgt has shaped the metabolism of many mesophilic and anaerobic bacteria.genome sequencing has revealed that horizontal gene transfer (hgt) is a major evolutionary process in bacteria. although it is generally assumed that closely related organisms engage in genetic exchange more frequently than distantly related ones, the frequency of hgt among distantly related organisms and the effect of ecological relatedness on the frequency has not been rigorously assessed. here, we devised a novel bioinformatic pipeline, which minimized the effect of over-representation of spe ...201425314320
defined enzyme cocktail from the anaerobic fungus orpinomyces sp. strain c1a effectively releases sugars from pretreated corn stover and switchgrass.the anaerobic fungus orpinomyces strain c1a is capable of growth on various types of lignocellulosic substrates, and harbors an impressive reservoir of carbohydrate active enzymes (cazymes). using a minimum enzyme cocktail strategy, we constituted a four-component lignocellulolytic cocktail derived from highly transcribed c1a, and evaluated its efficacy against pretreated corn stover and switchgrass. hydrolysis yields ranged between 65-77.4%, depending on the lignocellulosic substrate and pretre ...201627381262
multisubstrate isotope labeling and metagenomic analysis of active soil bacterial communities.soil microbial diversity represents the largest global reservoir of novel microorganisms and enzymes. in this study, we coupled functional metagenomics and dna stable-isotope probing (dna-sip) using multiple plant-derived carbon substrates and diverse soils to characterize active soil bacterial communities and their glycoside hydrolase genes, which have value for industrial applications. we incubated samples from three disparate canadian soils (tundra, temperate rainforest, and agricultural) wit ...201425028422
diversity of natural product biosynthetic genes in the microbiome of the deep sea sponges inflatella pellicula, poecillastra compressa, and stelletta normani.three different deep sea sponge species, inflatella pellicula, poecillastra compressa, and stelletta normani comprising seven individual samples, retrieved from depths of 760-2900 m below sea level, were investigated using 454 pyrosequencing for their secondary metabolomic potential targeting adenylation domain and ketosynthase domain sequences. the data obtained suggest a diverse microbial origin of nonribosomal peptide synthetases and polyketide synthase fragments that in part correlates with ...201627446062
phi class of glutathione s-transferase gene superfamily widely exists in nonplant taxonomic groups.glutathione s-transferases (gsts) constitute a superfamily of enzymes involved in detoxification of noxious compounds and protection against oxidative damage. gst class phi (gstf), one of the important classes of plant gsts, has long been considered as plant specific but was recently found in basidiomycete fungi. however, the range of nonplant taxonomic groups containing gstfs remains unknown. in this study, the distribution and phylogenetic relationships of nonplant gstfs were investigated. we ...201626884677
natural products genomics. 200821261848
gendb--an open source genome annotation system for prokaryote genomes.the flood of sequence data resulting from the large number of current genome projects has increased the need for a flexible, open source genome annotation system, which so far has not existed. to account for the individual needs of different projects, such a system should be modular and easily extensible. we present a genome annotation system for prokaryote genomes, which is well tested and readily adaptable to different tasks. the modular system was developed using an object-oriented approach, ...200312682369
myxobacteria, polarity, and multicellular morphogenesis.myxobacteria are renowned for the ability to sporulate within fruiting bodies whose shapes are species-specific. the capacity to build those multicellular structures arises from the ability of m. xanthus to organize high cell-density swarms, in which the cells tend to be aligned with each other while constantly in motion. the intrinsic polarity of rod-shaped cells lays the foundation, and each cell uses two polar engines for gliding on surfaces. it sprouts retractile type iv pili from the leadin ...201020610548
characterization of four type iv pilin homologues in stigmatella aurantiaca dsm17044 by heterologous expression in myxococcus xanthus.as prokaryotic models for multicellular development, stigmatella aurantiaca and myxococcus xanthus share many similarities in terms of social behaviors, such as gliding motility. our current understanding of myxobacterial grouped-cell motilities comes mainly from the research on m. xanthus, which shows that filamentous type iv pili (tfp), composed of type iv pilin (also called pila protein) subunits, are the key apparatus for social motility (s-motility). however, little is known about the pilin ...201324058653
complete genome sequence of myxococcus stipitatus strain dsm 14675, a fruiting myxobacterium.hallmarks of the myxobacteria include the formation of spore-filled fruiting bodies in response to starvation and synthesis of secondary metabolites. myxococcus stipitatus forms morphologically highly distinct fruiting bodies and produces secondary metabolites with antibiotic or cytotoxic activities. here, we present the 10.35-mb genome sequence of m. stipitatus strain dsm 14675.201323516218
evolution and diversity of the ras superfamily of small gtpases in prokaryotes.the ras superfamily of small gtpases are single domain nucleotide-dependent molecular switches that act as highly tuned regulators of complex signal transduction pathways. originally identified in eukaryotes for their roles in fundamental cellular processes including proliferation, motility, polarity, nuclear transport, and vesicle transport, recent studies have revealed that single domain gtpases also control complex functions such as cell polarity, motility, predation, development and antibiot ...201425480683
bacterial transcription as a target for antibacterial drug development.transcription, the first step of gene expression, is carried out by the enzyme rna polymerase (rnap) and is regulated through interaction with a series of protein transcription factors. rnap and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. the determination ...201626764017
evolution and diversity of the ras superfamily of small gtpases in prokaryotes.the ras superfamily of small gtpases are single domain nucleotide-dependent molecular switches that act as highly tuned regulators of complex signal transduction pathways. originally identified in eukaryotes for their roles in fundamental cellular processes including proliferation, motility, polarity, nuclear transport, and vesicle transport, recent studies have revealed that single domain gtpases also control complex functions such as cell polarity, motility, predation, development and antibiot ...201425480683
neutral and phospholipids of the myxococcus xanthus lipodome during fruiting body formation and germination.myxobacteria are well-known for their complex life cycle, including the formation of spore-filled fruiting bodies. the model organism myxococcus xanthus exhibits a highly complex composition of neutral and phospholipids, including triacylglycerols (tags), diacylglycerols (dags), phosphatidylethanolamines (pes), phosphatidylglycerols (pgs), cardiolipins (cls), and sphingolipids, including ceramides (cers) and ceramide phosphoinositols (cer-pis). in addition, ether lipids have been shown to be inv ...201526162876
metcap: a bioinformatics probe design pipeline for large-scale targeted metagenomics.massive sequencing of genes from different environments has evolved metagenomics as central to enhancing the understanding of the wide diversity of micro-organisms and their roles in driving ecological processes. reduced cost and high throughput sequencing has made large-scale projects achievable to a wider group of researchers, though complete metagenome sequencing is still a daunting task in terms of sequencing as well as the downstream bioinformatics analyses. alternative approaches such as t ...201525880302
isolation and identification of myxobacteria from saline-alkaline soils in xinjiang, china.fifty-eight terrestrial and salt-tolerant myxobacteria were isolated from the saline-alkaline soils collected from xinjiang, china. based on the morphologies and the 16s rrna gene sequences, these isolates were assigned into 6 genera, myxococcus, cystobacter, corallococcus, sorangium, nannocystis and polyangium. all the strains grew better with 1% nacl than without nacl. some myxococcus strains were able to grow at 2% nacl concentration, suggesting that these strains may be particular type of te ...201323936436
extraordinary expansion of a sorangium cellulosum genome from an alkaline milieu.complex environmental conditions can significantly affect bacterial genome size by unknown mechanisms. the so0157-2 strain of sorangium cellulosum is an alkaline-adaptive epothilone producer that grows across a wide ph range. here, we show that the genome of this strain is 14,782,125 base pairs, 1.75-megabases larger than the largest bacterial genome from s. cellulosum reported previously. the total 11,599 coding sequences (cdss) include massive duplications and horizontally transferred genes, r ...201323812535
draft genome of a type 4 pilus defective myxococcus xanthus strain, dzf1.myxococcus xanthus is a member of the myxococcales order within the deltaproteobacterial subdivision. here, we report the whole-genome shotgun sequence of the type iv pilus (t4p) defective strain dzf1, which includes many genes found in strain dz2 but absent from strain dk1622.201323788552
function-oriented synthesis: biological evaluation of laulimalide analogues derived from a last step cross metathesis diversification strategy.laulimalide is a potent microtubule stabilizing agent and a promising anticancer therapeutic lead. the identification of stable, efficacious and accessible analogues is critical to clinically exploiting this novel lead. to determine which structural features of laulimalide are required for beneficial function and thus for accessing superior clinical candidates, a series of side chain analogues were prepared through a last step cross metathesis diversification strategy and their biological activi ...200818662015
a natural love of natural products.recent research on the chemistry of natural products from the author's group that led to the receipt of the acs ernest guenther award in the chemistry of natural products is reviewed. redor nmr and synthetic studies established the t-taxol conformation as the bioactive tubulin-binding conformation, and these results were confirmed by the synthesis of compounds which clearly owed their activity or lack of activity to whether or not they could adopt the t-taxol conformation. similar studies with t ...200818459734
biosynthesis and function of polyacetylenes and allied natural products.polyacetylenic natural products are a substantial class of often unstable compounds containing a unique carbon-carbon triple bond functionality, that are intriguing for their wide variety of biochemical and ecological functions, economic potential, and surprising mode of biosynthesis. isotopic tracer experiments between 1960 and 1990 demonstrated that the majority of these compounds are derived from fatty acid and polyketide precursors. during the past decade, research into the metabolism of pol ...200818387369
pharmaceutical approval update. 200819749985
microbial-based therapy of cancer: current progress and future prospects.the use of bacteria in the regression of certain forms of cancer has been recognized for more than a century. much effort, therefore, has been spent over the years in developing wild-type or modified bacterial strains to treat cancer. however, their use at the dose required for therapeutic efficacy has always been associated with toxicity problems and other deleterious effects. recently, the old idea of using bacteria in the treatment of cancer has attracted considerable interest and new genetic ...200921326924
microbial-based therapy of cancer: current progress and future prospects.the use of bacteria in the regression of certain forms of cancer has been recognized for more than a century. much effort, therefore, has been spent over the years in developing wild-type or modified bacterial strains to treat cancer. however, their use at the dose required for therapeutic efficacy has always been associated with toxicity problems and other deleterious effects. recently, the old idea of using bacteria in the treatment of cancer has attracted considerable interest and new genetic ...200921326924
structures of rna polymerase-antibiotic complexes.inhibition of bacterial rna polymerase (rnap) is an established strategy for antituberculosis therapy and broad-spectrum antibacterial therapy. crystal structures of rnap-inhibitor complexes are available for four classes of antibiotics: rifamycins, sorangicin, streptolydigin, and myxopyronin. the structures define three different targets, and three different mechanisms, for inhibition of bacterial rnap: (1) rifamycins and sorangicin bind near the rnap active center and block extension of rna pr ...200919926275
recombinant organisms for production of industrial products.a revolution in industrial microbiology was sparked by the discoveries of ther double-stranded structure of dna and the development of recombinant dna technology. traditional industrial microbiology was merged with molecular biology to yield improved recombinant processes for the industrial production of primary and secondary metabolites, protein biopharmaceuticals and industrial enzymes. novel genetic techniques such as metabolic engineering, combinatorial biosynthesis and molecular breeding te ...200921326937
recombinant organisms for production of industrial products.a revolution in industrial microbiology was sparked by the discoveries of ther double-stranded structure of dna and the development of recombinant dna technology. traditional industrial microbiology was merged with molecular biology to yield improved recombinant processes for the industrial production of primary and secondary metabolites, protein biopharmaceuticals and industrial enzymes. novel genetic techniques such as metabolic engineering, combinatorial biosynthesis and molecular breeding te ...200921326937
a subset of the diverse cog0523 family of putative metal chaperones is linked to zinc homeostasis in all kingdoms of life.cog0523 proteins are, like the nickel chaperones of the ureg family, part of the g3e family of gtpases linking them to metallocenter biosynthesis. even though the first cog0523-encoding gene, cobw, was identified almost 20 years ago, little is known concerning the function of other members belonging to this ubiquitous family.200919822009
total synthesis of (+)-sorangicin a.the final synthetic challenges associated with (+)-sorangicin a have been overcome, thus leading to the first total synthesis of this complex macrolide antibiotic. highlights of the highly convergent synthesis include two julia-kociénski olefinations to unite three advanced fragments with high e-stereoselectivity. critical to the final-stage success was the use of a carefully defined stille coupling and a mukaiyama macrolactonization as well as lewis and protic acid-promoted deprotections carefu ...200919663510
the 1.5-a structure of xpla-heme, an unusual cytochrome p450 heme domain that catalyzes reductive biotransformation of royal demolition explosive.xpla is a cytochrome p450 of unique structural organization, consisting of a heme-domain that is c-terminally fused to its native flavodoxin redox partner. xpla, along with flavodoxin reductase xplb, has been shown to catalyze the breakdown of the nitramine explosive and pollutant hexahydro-1,3,5-trinitro-1,3,5-triazine (royal demolition explosive) by reductive denitration. the structure of the heme domain of xpla (xpla-heme) has been solved in two crystal forms: as a dimer in space group p2(1) ...200919692330
the epothilone b analogue ixabepilone in patients with advanced hepatobiliary cancers: a trial of the university of chicago phase ii consortium.hepatobiliary cancers respond poorly to cytotoxic chemotherapy. we evaluated the activity and safety of ixabepilone, an epothilone b analogue which stabilizes microtubules, in a phase ii trial in patients with advanced cancers of the gallbladder, bile duct, and liver.200919669700
the epothilone b analogue ixabepilone in patients with advanced hepatobiliary cancers: a trial of the university of chicago phase ii consortium.hepatobiliary cancers respond poorly to cytotoxic chemotherapy. we evaluated the activity and safety of ixabepilone, an epothilone b analogue which stabilizes microtubules, in a phase ii trial in patients with advanced cancers of the gallbladder, bile duct, and liver.200919669700
recent applications of acyclic (diene)iron complexes and (dienyl)iron cations in organic synthesis.complexation of (tricarbonyl)iron to an acyclic diene serves to protect the ligand against oxidation, reduction and cycloaddition reactions while the steric bulk of this adjunct serves to direct the approach reagents to unsaturated groups attached to the diene onto the face opposite to iron. furthermore, the fe(co)(3) moiety can serve to stabilize carbocation centers adjacent to the diene (i.e. pentadienyl-iron cations). recent applications of these reactivities to the synthesis of polyene, cycl ...200921709767
automated genome mining for natural products.discovery of new medicinal agents from natural sources has largely been an adventitious process based on screening of plant and microbial extracts combined with bioassay-guided identification and natural product structure elucidation. increasingly rapid and more cost-effective genome sequencing technologies coupled with advanced computational power have converged to transform this trend toward a more rational and predictive pursuit.200919531248
treatment options for breast cancer resistant to anthracycline and taxane.breast cancer is the most common noncutaneous malignancy among every major ethnic group of women in the united states. anthracyclines and taxanes are the most active and widely used chemotherapeutic agents for breast cancer, but the increased use of these agents at an early stage of disease often renders tumors resistant to these drugs by the time the disease recurs, thereby reducing the number of treatment options for metastatic disease. moreover, even when these agents can be used in the metas ...200919483170
total synthesis and evaluation of 22-(3-azidobenzoyloxy)methyl epothilone c for photoaffinity labeling of beta-tubulin.the total synthesis of 22-(3-azidobenzoyloxy)methyl epothilone c is described as a potential photoaffinity probe to elucidate the beta-tubulin binding site. a sequential suzuki-aldol-yamaguchi macrolactonization strategy was utilized employing a novel derivatized c1-c6 fragment. the c22-functionalized analog exhibited good activity in microtubule assembly assays, but cytotoxicity was significantly reduced. molecular modeling simulations indicated that excessive steric bulk in the c22 position is ...200919428248
genome degeneration affects both extracellular and intracellular bacterial endosymbionts.the obligate intracellular bacterial endosymbionts of insects are a paradigm for reductive genome evolution. a study published recently in bmc biology demonstrates that similar evolutionary forces shaping genome structure may also apply to extracellular endosymbionts.200919435469
draft genome sequence of myxococcus xanthus wild-type strain dz2, a model organism for predation and development.myxococcus xanthus is a member of the myxococcales order within the deltaproteobacteria subdivision. the myxobacteria reside in soil, have relatively large genomes, and display complex life cycles. here, we report the whole-genome shotgun sequence of strain dz2, which includes unique genes not found previously in strain dk1622.201323661486
selection and a 3-year field trial of sorangium cellulosum kyc 3262 against anthracnose in hot pepper.kyc 3262 was selected as a biocontrol agent against anthracnose on hot pepper from 813 extracts of myxobacterial isolates. dual culture with colletotrichum acutatum and 813 myxobacterial extracts was conducted, and 19 extracts were selected that inhibited germination and mycelial growth of c. acutatum. all selections were sorangium cellulosum, which are cellulolytic myxobacteria from soil. with the infection bioassay on detached fruits in airtight containers, kyc 3262, kyc 3512, kyc 3279, and ky ...201425289014
characterization and evolutionary implications of the triad asp-xxx-glu in group ii phosphopantetheinyl transferases.phosphopantetheinyl transferases (pptases), which play an essential role in both primary and secondary metabolism, are magnesium binding enzymes. in this study, we characterized the magnesium binding residues of all known group ii pptases by biochemical and evolutionary analysis. our results suggested that group ii pptases could be classified into two subgroups, two-magnesium-binding-residue-pptases containing the triad asp-xxx-glu and three-magnesium-binding-residue-pptases containing the triad ...201425036863
devi is an evolutionarily young negative regulator of myxococcus xanthus development.during starvation-induced development of myxococcus xanthus, thousands of rod-shaped cells form mounds in which they differentiate into spores. the dev locus includes eight genes followed by clustered regularly interspaced short palindromic repeats (crisprs), comprising a crispr-cas system (cas stands for crispr associated) typically involved in rna interference. mutations in devs or devr of a lab reference strain permit mound formation but impair sporulation. we report that natural isolates of ...201525645563
complete genome of the starch-degrading myxobacteria sandaracinus amylolyticus dsm 53668t.myxobacteria are members of δ-proteobacteria and are typified by large genomes, well-coordinated social behavior, gliding motility, and starvation-induced fruiting body formation. here, we report the 10.33 mb whole genome of a starch-degrading myxobacterium sandaracinus amylolyticus dsm 53668(t) that encodes 8,962 proteins, 56 trna, and two rrna operons. phylogenetic analysis, in silico dna-dna hybridization and average nucleotide identity reveal its divergence from other myxobacterial species a ...201627358428
marine-derived myxobacteria of the suborder nannocystineae: an underexplored source of structurally intriguing and biologically active metabolites.myxobacteria are famous for their ability to produce most intriguing secondary metabolites. till recently, only terrestrial myxobacteria were in the focus of research. in this review, however, we discuss marine-derived myxobacteria, which are particularly interesting due to their relatively recent discovery and due to the fact that their very existence was called into question. the to-date-explored members of these halophilic or halotolerant myxobacteria are all grouped into the suborder nannocy ...201627340488
prediction and analysis of the modular structure of cytochrome p450 monooxygenases.cytochrome p450 monooxygenases (cyps) form a vast and diverse family of highly variable sequences. they catalyze a wide variety of oxidative reactions and are therefore of great relevance in drug development and biotechnological applications. despite their differences in sequence and substrate specificity, the structures of cyps are highly similar. although being in research focus for years, factors mediating selectivity and activity remain vague.201020950472
conformational plasticity and structure/function relationships in cytochromes p450.the cytochrome p450s are a superfamily of enzymes that are found in all kingdoms of living organisms, and typically catalyze the oxidative addition of atomic oxygen to an unactivated c-c or c-h bond. over 8000 nonredundant sequences of putative and confirmed p450 enzymes have been identified, but three-dimensional structures have been determined for only a small fraction of these. while all p450 enzymes for which structures have been determined share a common global fold, the flexibility and mod ...201020446763
endometrial carcinoma: a review of chemotherapy, drug resistance, and the search for new agents.adenocarcinoma of the endometrium represents the most common gynecologic malignancy in developed countries. although early-stage cancers are effectively treated surgically, commonly without adjuvant therapy, the treatment of high-risk and advanced disease is more complex. chemotherapy has evolved into an important modality in high-risk early-stage and advanced-stage disease, and in recurrent endometrial cancer. taxane-based therapy consistently demonstrates the highest response rates in the firs ...201020930101
microtubule-binding agents: a dynamic field of cancer therapeutics.microtubules are dynamic filamentous cytoskeletal proteins composed of tubulin and are an important therapeutic target in tumour cells. agents that bind to microtubules have been part of the pharmacopoeia of anticancer therapy for decades and until the advent of targeted therapy, microtubules were the only alternative to dna as a therapeutic target in cancer. the screening of a range of botanical species and marine organisms has yielded promising new antitubulin agents with novel properties. in ...201020885410
optimizing ixabepilone treatment schedules in patients with advanced or metastatic breast cancer.the epothilone b analog, ixabepilone, demonstrates low susceptibility to drug resistance mechanisms and has demonstrated clinically meaningful efficacy in patients refractory to other chemotherapeutic options. ixabepilone is approved by the fda for treatment of patients with metastatic breast cancer (mbc) progressing after taxanes and anthracyclines, either in combination with capecitabine or as monotherapy if the patient has already progressed on capecitabine. ixabepilone is generally well tole ...201020886213
detecting and understanding the roles of nitric oxide in biology.we are pursuing a dual strategy for investigating the chemistry of nitric oxide as a biological signaling agent. in one approach, metal-based fluorescent sensors for the detection of no in living cells are evaluated, and a sensor based on a copper fluorescein complex has proved to be a valuable lead compound. sensors of this class permit identification of no from both inducible and constitutive forms of nitric oxide synthase and facilitate investigation of different no functions in response to e ...201020666391
read length and repeat resolution: exploring prokaryote genomes using next-generation sequencing technologies.there are a growing number of next-generation sequencing technologies. at present, the most cost-effective options also produce the shortest reads. however, even for prokaryotes, there is uncertainty concerning the utility of these technologies for the de novo assembly of complete genomes. this reflects an expectation that short reads will be unable to resolve small, but presumably abundant, repeats.201020634954
presence of a classical rrm-fold palm domain in thg1-type 3'- 5'nucleic acid polymerases and the origin of the ggdef and crispr polymerase domains.almost all known nucleic acid polymerases catalyze 5'-3' polymerization by mediating the attack on an incoming nucleotide 5' triphosphate by the 3'oh from the growing polynucleotide chain in a template dependent or independent manner. the only known exception to this rule is the thg1 rna polymerase that catalyzes 3'-5' polymerization in vitro and also in vivo as a part of the maturation process of histidinyl trna. while the initial reaction catalyzed by thg1 has been compared to adenylation cata ...201020591188
polyketide genes in the marine sponge plakortis simplex: a new group of mono-modular type i polyketide synthases from sponge symbionts.sponge symbionts are a largely unexplored source of new and unusual metabolic pathways. insights into the distribution and function of metabolic genes of sponge symbionts are crucial to dissect and exploit their biotechnological potential. screening of the metagenome of the marine sponge plakortis simplex led to the discovery of the swf family, a new group of mono-modular type i polyketide synthase/fatty acid synthase (pks/fas) specifically associated with sponge symbionts. two different example ...201324249289
the complete genome sequence and analysis of a plasmid-bearing myxobacterial strain myxococcus fulvus 124b02 (m 206081).myxobacteria, phylogenetically located in the delta division of the proteobacteria, are well known for characterized social behaviors and large genomes of more than 9 mb in size. myxococcus fulvus is a typical species of the genus myxococcus in the family myxococcaceae. m. fulvus 124b02, originally isolated from a soil sample collected in northeast china, is the one and only presently known myxobacterial strain that harbors an endogenous autonomously replicating plasmid, named pmf1. the endogeno ...201626734118
genome increase as a clock for the origin and evolution of life.the size of non-redundant functional genome can be an indicator of biological complexity of living organisms. several positive feedback mechanisms including gene cooperation and duplication with subsequent specialization may result in the exponential growth of biological complexity in macro-evolution.200616768805
a reassignment of (-)-mycothiazole and the isolation of a related diol.a reinvestigation of the thiazole constituents from cacospongia mycofijiensis, collected in vanuatu, yielded known mycothiazole (3) plus a new derivative, mycothiazole-4,19-diol (6). the e stereochemistry at delta14,15 of 3 has been revised to z and the structural features of 6 are elucidated. these compounds, which presumably arise by the action of a polyketide-nonribosomal peptide synthetase (pks/nrps) hybrid, possess cytotoxic properties that need further exploration.200616441088
the treatment of hormone-refractory prostate cancer: docetaxel and beyond.two randomized clinical trials demonstrated a survival benefit of 20% to 24% with docetaxel-based therapy when compared with survival with mitoxantrone and prednisone after failure of androgen ablation therapy. these studies supported the approval of docetaxel-based therapy for the treatment of metastatic hormone-refractory prostate cancer by the us food and drug administration in may 2005. clinical trials in hormone-refractory prostate cancer are now focused on building on the survival improvem ...200617021642
phase i trial and pharmacokinetic study of ixabepilone administered daily for 5 days in children and adolescents with refractory solid tumors.the objectives of this phase i trial were to determine the maximum-tolerated dose (mtd), toxicity profile, dose-limiting toxicities (dlts), pharmacokinetics, and preliminary response rate for ixabepilone, a microtubule-stabilizing agent, administered intravenously daily for 5 days in children and adolescents.200819075272
phase i trial and pharmacokinetic study of ixabepilone administered daily for 5 days in children and adolescents with refractory solid tumors.the objectives of this phase i trial were to determine the maximum-tolerated dose (mtd), toxicity profile, dose-limiting toxicities (dlts), pharmacokinetics, and preliminary response rate for ixabepilone, a microtubule-stabilizing agent, administered intravenously daily for 5 days in children and adolescents.200819075272
genome analysis of the fruiting body-forming myxobacterium chondromyces crocatus reveals high potential for natural product biosynthesis.here, we report the complete genome sequence of the type strain of the myxobacterial genus chondromyces, chondromyces crocatus cm c5. it presents one of the largest prokaryotic genomes featuring a single circular chromosome and no plasmids. analysis revealed an enlarged set of trna genes, along with reduced pressure on preferred codon usage compared to that of other bacterial genomes. the large coding capacity and the plethora of encoded secondary metabolite biosynthetic gene clusters are in lin ...201626773087
pretubulysin: from hypothetical biosynthetic intermediate to potential lead in tumor therapy.pretubulysin is a natural product that is found in strains of myxobacteria in only minute amounts. it represents the first enzyme-free intermediate in the biosynthesis of tubulysins and undergoes post-assembly acylation and oxidation reactions. pretubulysin inhibits the growth of cultured mammalian cells, as do tubulysins, which are already in advanced preclinical development as anticancer and antiangiogenic agents. the mechanism of action of this highly potent compound class involves the depoly ...201222616003
hormone-refractory prostate cancer: new horizons.the eighth session of the 13th international prostate cancer update focused on the mechanisms of androgen-independent cancer growth and on new therapeutic approaches to the treatment of androgen-independent prostate cancer. three possible mechanisms that might account for the development of hormone resistance are reviewed here. these are: changes in antigen receptor expression, changes in androgen receptor structure, and changes in androgen receptor function. therapeutic approaches discussed inc ...200316985978
synthesis of the entire framework of tartrolon b utilizing a silicon-tethered ring-closing metathesis strategy.[structure: see text] a tandem ring-closing metathesis (rcm) of silaketal-tethered dienynes gives rise to bicyclic siloxanes, which upon removal of the silicon tether afford dienediol skeletons with a stereodefined e,z-1,3-diene motif. the implementation of this methodology has led to the construction of the entire c1-c21 linear carbon skeleton of tartrolon b.200617078682
novel microtubule-targeting agents - the epothilones.epothilones are a new class of antimicrotubule agents currently in clinical trials. their chemical structures are distinct from taxanes and are more amenable to synthetic modification. six epothilones have been studied in preclinical and clinical trials: patupilone (epothilone b), ixabepilone (bms247550), bms 310705, sagopilone (zk-epo), kos-862 (epothilone d), and kos-1584. in vitro data have shown increased potency in taxane-sensitive and taxane-resistant cancer cell lines. this enhanced cytot ...200819707459
ixabepilone (ixempra), a therapeutic option for locally advanced or metastatic breast cancer.ixabepilone (ixempra) is a member of a new class of cytotoxic agents, the epothilones. epothilones promote tubulin polymerization in vitro and demonstrate antitumor activity. this article reviews the preclinical and clinical data that have led to the approval of ixabepilone for patients with locally advanced or metastatic breast cancer for whom anthracycline and taxane treatments have failed.200819750031
limits in energy generation and biotechnology of primary and secondary products. 200821261854
novel therapies in genitourinary cancer: an update.in recent years, new treatment for renal cell carcinoma (rcc) has been a spotlight in the field of cancer therapeutics. with several emerging agents branded as 'targeted therapy' now available, both medical oncologists and urologists are progressively more hopeful for better outcomes. the new remedies may provide patients with improved survival and at the same time less toxicity when compared to traditional cytotoxic agents. this article will center on current and emerging treatment strategies f ...200818694493
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