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a sorangium cellulosum (myxobacterium) gene cluster for the biosynthesis of the macrolide antibiotic soraphen a: cloning, characterization, and homology to polyketide synthase genes from actinomycetes.a 40-kb region of dna from sorangium cellulosum so ce26, which contains polyketide synthase (pks) genes for synthesis of the antifungal macrolide antibiotic soraphen a, was cloned. these genes were detected by homology to streptomyces violaceoruber genes encoding components of granaticin pks, thus extending this powerful technique for the identification of bacterial pks genes, which has so far been applied only to actinomycetes, to the gram-negative myxobacteria. functional analysis by gene disr ...19957601830
desoxyepothilone b: an efficacious microtubule-targeted antitumor agent with a promising in vivo profile relative to epothilone b.a new class of 16-membered macrolides, the epothilones (epos), has been synthesized and evaluated for antitumor potential in vitro and in vivo. recent studies in these and other laboratories showed that epothilones and paclitaxel (paclitaxel) share similar mechanisms of action in stabilizing microtubule arrays as indicated by binding-displacement studies, substitution for paclitaxel in paclitaxel-dependent cell growth, and electron microscopic examinations. the present study examined cell growth ...19989689134
the antibody catalysis route to the total synthesis of epothilones.an efficient monoclonal aldolase antibody that proceeds by an enamine mechanism was generated by reactive immunization. here, this catalyst has been used in the total synthesis of epothilones a (1) and c (3). the starting materials for the synthesis of these molecules have been obtained by using antibody-catalyzed aldol and retro-aldol reactions. these precursors were then converted to epothilones a (1) and c (3) to complete the total synthesis.19989843936
mutations that confer resistance to 2-deoxyglucose reduce the specific activity of hexokinase from myxococcus xanthus.the glucose analog 2-deoxyglucose (2dglc) inhibits the growth and multicellular development of myxococcus xanthus. mutants of m. xanthus resistant to 2dglc, designated hex mutants, arise at a low spontaneous frequency. expression of the escherichia coli glk (glucokinase) gene in m. xanthus hex mutants restores 2dglc sensitivity, suggesting that these mutants arise upon the loss of a soluble hexokinase function that phosphorylates 2dglc to form the toxic intermediate, 2-deoxyglucose-6-phosphate. ...199910094702
biosynthesis of polyketides in heterologous hosts.polyketide natural products show great promise as medicinal agents. typically the products of microbial secondary biosynthesis, polyketides are synthesized by an evolutionarily related but architecturally diverse family of multifunctional enzymes called polyketide synthases. a principal limitation for fundamental biochemical studies of these modular megasynthases, as well as for their applications in biotechnology, is the challenge associated with manipulating the natural microorganism that prod ...200111238987
the synthesis, discovery, and development of a highly promising class of microtubule stabilization agents: curative effects of desoxyepothilones b and f against human tumor xenografts in nude mice.we have evaluated two synthetic epothilone analogues lacking the 12,13-epoxide functionality, 12,13-desoxyepothilone b (depob), and 12,13-desoxyepothilone f (depof). the concentrations required for 50% growth inhibition (ic(50)) for a variety of anticancer agents were measured in ccrf-cem/vbl1000 cells (2,048-fold resistance to vinblastine). by using depob, depof, aza-epob, and paclitaxel, the ic(50) values were 0.029, 0.092, 2.99, and 5.17 microm, respectively. these values represent 4-, 33.5-, ...200111438750
in vitro reconstitution of the myxochelin biosynthetic machinery of stigmatella aurantiaca sg a15: biochemical characterization of a reductive release mechanism from nonribosomal peptide synthetases.microorganisms produce iron-chelating compounds to sequester the iron essential for growth from the environment. many of these compounds are biosynthesized by nonribosomal peptide synthetases, some in cooperation with polyketide synthases. myxochelins are produced by the myxobacterium stigmatella aurantiaca sg a15, and the corresponding gene cluster was cloned recently. we have undertaken to express heterologously the myxochelin biosynthetic machinery in escherichia coli. to activate the involve ...200111562468
characterization of indigoidine biosynthetic genes in erwinia chrysanthemi and role of this blue pigment in pathogenicity.in the plant-pathogenic bacterium erwinia chrysanthemi production of pectate lyases, the main virulence determinant, is modulated by a complex network involving several regulatory proteins. one of these regulators, pecs, also controls the synthesis of a blue pigment identified as indigoidine. since production of this pigment is cryptic in the wild-type strain, e. chrysanthemi ind mutants deficient in indigoidine synthesis were isolated by screening a library of tn5-b21 insertions in a pecs mutan ...200211790734
characterization and description of anaeromyxobacter dehalogenans gen. nov., sp. nov., an aryl-halorespiring facultative anaerobic myxobacterium.five strains were isolated which form a physiologically and phylogenetically coherent group of chlororespiring microorganisms and represent the first taxon in the myxobacteria capable of anaerobic growth. the strains were enriched and isolated from various soils and sediments based on their ability to grow using acetate as an electron donor and 2-chlorophenol (2-cph) as an electron acceptor. they are slender gram-negative rods with a bright red pigmentation that exhibit gliding motility and form ...200211823233
heterologous expression of epothilone biosynthetic genes in myxococcus xanthus.epothilones are potential anticancer drugs that stabilize microtubules in a manner similar to paclitaxel (taxol). epothilones are produced from the myxobacterium sorangium cellulosum, which has a 16-h doubling time and produces only milligram-per-liter amounts of epothilone a and epothilone b. furthermore, genetic manipulation of s. cellulosum is difficult. to produce epothilones in a more genetically amenable and rapidly growing host, we chose the closely related and best-characterized myxobact ...200212183227
characterization of benzoyl coenzyme a biosynthesis genes in the enterocin-producing bacterium "streptomyces maritimus".the novel benzoyl coenzyme a (benzoyl-coa) biosynthesis pathway in "streptomyces maritimus" was investigated through a series of target-directed mutations. genes involved in benzoyl-coa formation were disrupted through single-crossover homologous recombination, and the resulting mutants were analyzed for their ability to biosynthesize the benzoyl-coa-primed polyketide antibiotic enterocin. inactivation of the unique phenylalanine ammonia-lyase-encoding gene encp was previously shown to be absolu ...200312511484
recombinant environmental libraries provide access to microbial diversity for drug discovery from natural products.to further explore possible avenues for accessing microbial biodiversity for drug discovery from natural products, we constructed and screened a 5,000-clone "shotgun" environmental dna library by using an escherichia coli-streptomyces lividans shuttle cosmid vector and dna inserts from microbes derived directly (without cultivation) from soil. the library was analyzed by several means to assess diversity, genetic content, and expression of heterologous genes in both expression hosts. we found th ...200312513976
the stigmatella aurantiaca homolog of myxococcus xanthus high-mobility-group a-type transcription factor card: insights into the functional modules of card and their distribution in bacteria.transcriptional factor card is the only reported prokaryotic analog of eukaryotic high-mobility-group a (hmga) proteins, in that it has contiguous acidic and at hook dna-binding segments and multifunctional roles in myxococcus xanthus carotenogenesis and fruiting body formation. hmga proteins are small, randomly structured, nonhistone, nuclear architectural factors that remodel dna and chromatin structure. here we report on a second at hook protein, card(sa), that is very similar to card and tha ...200312775690
catabolism of arylboronic acids by arthrobacter nicotinovorans strain pba.arthrobacter sp. strain pba metabolized phenylboronic acid to phenol. the oxygen atom in phenol was shown to be derived from the atmosphere using (18)o(2). 1-naphthalene-, 2-naphthalene-, 3-cyanophenyl-, 2,5-fluorophenyl-, and 3-thiophene-boronic acids were also transformed to monooxygenated products. the oxygen atom in the product was bonded to the ring carbon atom originally bearing the boronic acid substituent with all the substrates tested.200312839810
a rhamnogalacturonan lyase in the clostridium cellulolyticum cellulosome.clostridium cellulolyticum secretes large multienzymatic complexes with plant cell wall-degrading activities named cellulosomes. most of the genes encoding cellulosomal components are located in a large gene cluster: cipc-cel48f-cel8c-cel9g-cel9e-orfx-cel9h-cel9j-man5k-cel9m. downstream of the cel9m gene, a new open reading frame was discovered and named rgl11y. amino acid sequence analysis indicates that this gene encodes a multidomain pectinase, rgl11y, containing an n-terminal signal sequence ...200312896991
development of a mariner-based transposon for use in sorangium cellulosum.in order to generate marked insertions in the myxobacterium sorangium cellulosum, a transposon based on the eukaryotic mariner transposon was developed. the transposition frequency was increased with the use of a mutated tnp gene. the transposon randomly inserts into the chromosome, as demonstrated by targeted mutagenesis of the epok gene.200314532095
subtractive hybridization reveals a type i polyketide synthase locus specific to mycobacterium ulcerans.mycobacterium ulcerans causes buruli ulcer, the third most prevalent mycobacterial infection of immunocompetent humans after tuberculosis and leprosy. recent work has shown that the production by m. ulcerans of mycolactone, a novel polyketide, may partly explain the pathogenesis of buruli ulcer. to search for the genetic basis of virulence in m. ulcerans, we took advantage of the close genetic relationship between m. ulcerans and mycobacterium marinum by performing genomic suppressive subtractiv ...200314617651
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
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
possibility of bacterial recruitment of plant genes associated with the biosynthesis of secondary metabolites. 200312857798
microorganisms and cancer: quest for a therapy. 200312700245
availability of specific reductases controls the temporal activity of the cytochrome p450 complement of streptomyces coelicolor a3(2).the annotated genome of streptomyces coelicolor a3(2) revealed 18 cytosolic cytochromes p450 (cyps) with six ferredoxin (fdx) proteins and two soluble ferredoxin reductases (fpr), their putative electron transport proteins. mrna expression was observed for all 18 cyps throughout growth and secondary metabolism, from 3 h after spore germination, and all cyp proteins examined also were present. expression of members of the fdx complement was detected from the same time point, yet both fpr were det ...200414704268
genetics of zwittermicin a production by bacillus cereus.zwittermicin a represents a new chemical class of antibiotic and has diverse biological activities, including suppression of oomycete diseases of plants and potentiation of the insecticidal activity of bacillus thuringiensis. to identify genes involved in zwittermicin a production, we generated 4,800 transposon mutants of b. cereus uw101c and screened them for zwittermicin a accumulation. nine mutants did not produce detectable zwittermicin a, and one mutant produced eightfold more than the pare ...200414711631
genes coding for hepatotoxic heptapeptides (microcystins) in the cyanobacterium anabaena strain 90.the cluster of microcystin synthetase genes from anabaena strain 90 was sequenced and characterized. the total size of the region is 55.4 kb, and the genes are organized in three putative operons. the first operon (mcya-mcyb-mcyc) is transcribed in the opposite direction from the second operon (mcyg-mcyd-mcyj-mcye-mcyf-mcyi) and the third operon (mcyh). the genes mcya, mcyb, and mcyc encode nonribosomal peptide synthetases (nrps), while mcyd codes for a polyketide synthase (pks), and mcyg and mc ...200414766543
the opportunistic pathogen pseudomonas aeruginosa carries a secretable arachidonate 15-lipoxygenase.in mammals, lipoxygenases play key roles in inflammation by initiating the transformation of arachidonic acid into potent bioactive lipid mediators such as leukotrienes and lipoxins. in general, most bacteria are believed to lack lipoxygenases and their polyunsaturated fatty acid substrates. it is therefore of interest that an orf (pa1169) with high homology to eukaryotic lipoxygenases was discovered by analysis of the whole-genome sequence of the opportunistic bacterial pathogen pseudomonas aer ...200414766977
novel genes that influence development in streptomyces coelicolor.filamentous soil bacteria of the genus streptomyces carry out complex developmental cycles that result in sporulation and production of numerous secondary metabolites with pharmaceutically important activities. to further characterize the molecular basis of these developmental events, we screened for mutants of streptomyces coelicolor that exhibit aberrant morphological differentiation and/or secondary metabolite production. on the basis of this screening analysis and the subsequent complementat ...200415150245
genome organization and localization of the puflm genes of the photosynthesis reaction center in phylogenetically diverse marine alphaproteobacteria.genome organization, plasmid content and localization of the puflm genes of the photosynthesis reaction center were studied by pulsed-field gel electrophoresis (pfge) in marine phototrophic alphaproteobacteria. both anaerobic phototrophs (rhodobacter veldkampii and rhodobacter sphaeroides) and strictly aerobic anoxygenic phototrophs from the roseobacter-sulfitobacter-silicibacter clade (roseivivax halodurans, roseobacter litoralis, staleya guttiformis, roseovarius tolerans, and five new strains ...200415184132
cloning, sequencing, and functional analysis of an iterative type i polyketide synthase gene cluster for biosynthesis of the antitumor chlorinated polyenone neocarzilin in "streptomyces carzinostaticus".neocarzilins (nczs) are antitumor chlorinated polyenones produced by "streptomyces carzinostaticus" var. f-41. the gene cluster responsible for the biosynthesis of nczs was cloned and characterized. dna sequence analysis of a 33-kb region revealed a cluster of 14 open reading frames (orfs), three of which (orf4, orf5, and orf6) encode type i polyketide synthase (pks), which consists of four modules. unusual features of the modular organization is the lack of an obvious acyltransferase domain on ...200415328113
isolation and characterization of novel marine-derived actinomycete taxa rich in bioactive metabolites.a unique selective enrichment procedure has resulted in the isolation and identification of two new genera of marine-derived actinobacteria. approximately 90% of the microorganisms cultured by using the presented method were from the prospective new genera, a result indicative of its high selectivity. in this study, 102 actinomycetes were isolated from subtidal marine sediments collected from the bismarck sea and the solomon sea off the coast of papua new guinea. a combination of physiological p ...200415574955
molecular identification of a novel deltaproteobacterium as the etiologic agent of epizootic bovine abortion (foothill abortion).epizootic bovine abortion (eba) is endemic in california's coastal range and the foothill regions of the sierra nevada, where it has been the primary diagnosed cause of abortion in beef cattle for >50 years. investigation of these losses has defined a specific fetal syndrome characterized by late-term abortion or birth of weak or dead calves. although the unusual clinical presentation and unique fetal pathology associated with eba have been recognized since the 1950s, the identity of the etiolog ...200515695652
biochemical characterization of a prokaryotic phenylalanine ammonia lyase.the committed biosynthetic reaction to benzoyl-coenzyme a in the marine bacterium "streptomyces maritimus" is carried out by the novel prokaryotic phenylalanine ammonia lyase (pal) encp, which converts the primary amino acid l-phenylalanine to trans-cinnamic acid. recombinant encp is specific for l-phenylalanine and shares many biochemical features with eukaryotic pals, which are substantially larger proteins by approximately 200 amino acid residues.200515937191
distribution and diversity of natural product genes in marine and freshwater cyanobacterial cultures and genomes.natural products are a functionally diverse class of biochemically synthesized compounds, which include antibiotics, toxins, and siderophores. in this paper, we describe both the detection of natural product activities and the sequence identification of gene fragments from two molecular systems that have previously been implicated in natural product production, i.e., nonribosomal peptide synthetases (nrpss) and modular polyketide synthases (pkss), in diverse marine and freshwater cyanobacterial ...200516269782
characterization of the polyene macrolide p450 epoxidase from streptomyces natalensis that converts de-epoxypimaricin into pimaricin.the biosynthesis of the antifungal agent pimaricin by streptomyces natalensis has been proposed to involve a cytochrome p450 encoded by the gene pimd. pimaricin is derived from its immediate precursor de-epoxypimaricin by epoxidation of the c-4-c-5 double bond on the macrolactone ring. we have overproduced pimd with a n-terminal his6 affinity tag in escherichia coli and purified the enzyme for kinetic analysis. the protein showed a reduced co-difference spectrum with a soret maximum at 450 nm, i ...200515228385
structural, functional, and genetic analysis of sorangicin inhibition of bacterial rna polymerase.a combined structural, functional, and genetic approach was used to investigate inhibition of bacterial rna polymerase (rnap) by sorangicin (sor), a macrolide polyether antibiotic. sor lacks chemical and structural similarity to the ansamycin rifampicin (rif), an rnap inhibitor widely used to treat tuberculosis. nevertheless, structural analysis revealed sor binds in the same rnap beta subunit pocket as rif, with almost complete overlap of rnap binding determinants, and functional analysis revea ...200515692574
biological evaluation of tubulysin a: a potential anticancer and antiangiogenic natural product.tubulysin a (tuba) is a natural product isolated from a strain of myxobacteria that has been shown to depolymerize microtubules and induce mitotic arrest. the potential of tuba as an anticancer and antiangiogenic agent is explored in the present study. tuba shows potent antiproliferative activity in a panel of human cancer cell lines irrespective of their multidrug resistance properties. it induces apoptosis in cancer cells but not in normal cells and shows significant potential antiangiogenic p ...200616489930
yersiniabactin production by pseudomonas syringae and escherichia coli, and description of a second yersiniabactin locus evolutionary group.the siderophore and virulence factor yersiniabactin is produced by pseudomonas syringae. yersiniabactin was originally detected by high-pressure liquid chromatography (hplc); commonly used pcr tests proved ineffective. yersiniabactin production in p. syringae correlated with the possession of irp1 located in a predicted yersiniabactin locus. three similarly divergent yersiniabactin locus groups were determined: the yersinia pestis group, the p. syringae group, and the photorhabdus luminescens gr ...200616751485
the structural basis for substrate anchoring, active site selectivity, and product formation by p450 pikc from streptomyces venezuelae.the pikromycin (pik)/methymycin biosynthetic pathway of streptomyces venezuelae represents a valuable system for dissecting the fundamental mechanisms of modular polyketide biosynthesis, aminodeoxysugar assembly, glycosyltransfer, and hydroxylation leading to the production of a series of macrolide antibiotics, including the natural ketolides narbomycin and pikromycin. in this study, we describe four x-ray crystal structures and allied functional studies for pikc, the remarkable p450 monooxygena ...200616825192
reconstitution of the myxothiazol biosynthetic gene cluster by red/et recombination and heterologous expression in myxococcus xanthus.although many secondary metabolites exhibiting important pharmaceutical and agrochemical activities have been isolated from myxobacteria, most of these microorganisms remain difficult to handle genetically. to utilize their metabolic potential, heterologous expression methodologies are currently being developed. here, the red/et recombination technology was used to perform all required gene cluster engineering steps in escherichia coli prior to the transfer into the chromosome of the heterologou ...200616997979
efficacy of ambruticin analogs in a murine model of invasive pulmonary aspergillosis.ambruticins are a family of polyketides. the antifungal activity of an ambruticin, kosn-2079, was tested in the mouse model of invasive aspergillosis. kosn-2079 significantly reduced pulmonary fungal burdens and improved survival over that with the vehicle control. these results support the continued development of ambruticins as antifungal agents.200617005833
structural determinants and modulation of substrate specificity in phenylalanine-tyrosine ammonia-lyases.aromatic amino acid ammonia-lyases catalyze the deamination of l-his, l-phe, and l-tyr, yielding ammonia plus aryl acids bearing an alpha,beta-unsaturated propenoic acid. we report crystallographic analyses of unliganded rhodobacter sphaeroides tyrosine ammonia-lyase (rstal) and rstal bound to p-coumarate and caffeate. his 89 of rstal forms a hydrogen bond with the p-hydroxyl moieties of coumarate and caffeate. his 89 is conserved in tals but replaced in phenylalanine ammonia-lyases (pals) and h ...200617185228
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
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
human mass balance study of the novel anticancer agent ixabepilone using accelerator mass spectrometry.ixabepilone (bms-247550) is a semi-synthetic, microtubule stabilizing epothilone b analogue which is more potent than taxanes and has displayed activity in taxane-resistant patients. the human plasma pharmacokinetics of ixabepilone have been described. however, the excretory pathways and contribution of metabolism to ixabepilone elimination have not been determined. to investigate the elimination pathways of ixabepilone we initiated a mass balance study in cancer patients. due to autoradiolysis, ...200717347871
incorporation of nonmethyl branches by isoprenoid-like logic: multiple beta-alkylation events in the biosynthesis of myxovirescin a1.several polyketide secondary metabolites are predicted to undergo isoprenoid-like beta-alkylations during biosynthesis. one such secondary metabolite is myxovirescin a1, produced by myxococcus xanthus. myxovirescin is of special interest in that it appears to undergo two distinct beta-alkylations. additionally, the myxovirescin biosynthetic gene cluster lacks tandem thiolation domains required in the synthesis of other beta-branched secondary metabolites. to probe the origins of the beta-branche ...200717656320
bioinformatics and experimental analysis of proteins of two-component systems in myxococcus xanthus.proteins of two-component systems (tcs) have essential functions in the sensing of external and self-generated signals in bacteria and in the generation of appropriate output responses. accordingly, in myxococcus xanthus, tcs are important for normal motility and fruiting body formation and sporulation. here we analyzed the m. xanthus genome for the presence and genetic organization of genes encoding tcs. two hundred seventy-two tcs genes were identified, 251 of which are not part of che gene cl ...200817993514
bioinformatics and experimental analysis of proteins of two-component systems in myxococcus xanthus.proteins of two-component systems (tcs) have essential functions in the sensing of external and self-generated signals in bacteria and in the generation of appropriate output responses. accordingly, in myxococcus xanthus, tcs are important for normal motility and fruiting body formation and sporulation. here we analyzed the m. xanthus genome for the presence and genetic organization of genes encoding tcs. two hundred seventy-two tcs genes were identified, 251 of which are not part of che gene cl ...200817993514
social bacteria and asocial eukaryotes. 200818199122
analysis of the cryptophycin p450 epoxidase reveals substrate tolerance and cooperativity.cryptophycins are potent anticancer agents isolated from nostoc sp. atcc 53789 and nostoc sp. gsv 224. the most potent natural cryptophycin analogues retain a beta-epoxide at the c2'-c3' position of the molecule. a p450 epoxidase encoded by c rpe recently identified from the cryptophycin gene cluster was shown to install this key functional group into cryptophycin-4 (cr-4) to produce cryptophycin-2 (cr-2) in a regio- and stereospecific manner. here we report a detailed characterization of the cr ...200818366166
transfer of the high-gc cyclohexane carboxylate degradation pathway from rhodopseudomonas palustris to escherichia coli for production of biotin.this work demonstrates the transfer of the five-gene cyclohexane carboxylate (chc) degradation pathway from the high-gc alphaproteobacterium rhodopseudomonas palustris to escherichia coli, a gammaproteobacterium. the degradation product of this pathway is pimeloyl-coa, a key metabolite in e. coli's biotin biosynthetic pathway. this pathway is useful for biotin overproduction in e. coli; however, the expression of gc-rich genes is troublesome in this host. when the native r. palustris chc degrada ...200818396082
the mosaic genome of anaeromyxobacter dehalogenans strain 2cp-c suggests an aerobic common ancestor to the delta-proteobacteria.anaeromyxobacter dehalogenans strain 2cp-c is a versaphilic delta-proteobacterium distributed throughout many diverse soil and sediment environments. 16s rrna gene phylogenetic analysis groups a. dehalogenans together with the myxobacteria, which have distinguishing characteristics including strictly aerobic metabolism, sporulation, fruiting body formation, and surface motility. analysis of the 5.01 mb strain 2cp-c genome substantiated that this organism is a myxobacterium but shares genotypic t ...200818461135
origins of replication in sorangium cellulosum and microcystis aeruginosa.the genome of sorangium cellulosum has recently been completely sequenced, and it is the largest bacterial genome sequenced so far. in their report, schneiker et al. (in complete genome sequence of the myxobacterium sorangium cellulosum, nat. biotechnol., 2007, 25, 1281-1289) concluded that 'in the absence of the gc-skew inversion typically seen at the replication origin of bacterial chromosomes, it was not possible to discern the location of oric'. in addition, the complete genome of microcysti ...200818477575
efficient transfer of two large secondary metabolite pathway gene clusters into heterologous hosts by transposition.horizontal gene transfer by transposition has been widely used for transgenesis in prokaryotes. however, conjugation has been preferred for transfer of large transgenes, despite greater restrictions of host range. we examine the possibility that transposons can be used to deliver large transgenes to heterologous hosts. this possibility is particularly relevant to the expression of large secondary metabolite gene clusters in various heterologous hosts. recently, we showed that the engineering of ...200818701643
therapeutic effect against human xenograft tumors in nude mice by the third generation microtubule stabilizing epothilones.the epothilones represent a promising class of natural product-based antitumor drug candidates. although these compounds operate through a microtubule stabilization mechanism similar to that of taxol, the epothilones offer a major potential therapeutic advantage in that they retain their activity against multidrug-resistant cell lines. we have been systematically synthesizing and evaluating synthetic epothilone congeners that are not accessible through modification of the natural product itself. ...200818755900
eukaryotic-like protein kinases in the prokaryotes and the myxobacterial kinome.ser/thr/tyr kinases, which together comprise a major class of regulatory proteins in eukaryotes, were not believed to play an important role in prokaryotes until recently. however, our analysis of 626 prokaryotic genomes reveals that eukaryotic-like protein kinases (elks) are found in nearly two-thirds of the sequenced strains. we have identified 2697 elks, most of which are encoded by multicellular strains of the phyla proteobacteria (myxococcales), actinobacteria, cyanobacteria, and chloroflex ...200818836084
interrogating the bioactive pharmacophore of the latrunculin chemotype by investigating the metabolites of two taxonomically unrelated sponges.this study involved a campaign to isolate and study additional latrunculin analogues from two taxonomically unrelated sponges, cacospongia mycofijiensis and negombata magnifica. a total of 13 latrunculin analogues were obtained by four different ways, reisolation (1-4), our repository (5, 6), new derivatives (7-12), and a synthetic analogue (7a). the structures of the new metabolites were elucidated on the basis of a combination of comprehensive 1d and 2d nmr analysis, application of dft calcula ...200818942825
the rna polymerase "switch region" is a target for inhibitors.the alpha-pyrone antibiotic myxopyronin (myx) inhibits bacterial rna polymerase (rnap). here, through a combination of genetic, biochemical, and structural approaches, we show that myx interacts with the rnap "switch region"--the hinge that mediates opening and closing of the rnap active center cleft--to prevent interaction of rnap with promoter dna. we define the contacts between myx and rnap and the effects of myx on rnap conformation and propose that myx functions by interfering with opening ...200818957204
in vivo and in vitro trans-acylation by bryp, the putative bryostatin pathway acyltransferase derived from an uncultured marine symbiont.the putative modular polyketide synthase (pks) that prescribes biosynthesis of the bryostatin natural products from the uncultured bacterial symbiont of the marine bryozoan bugula neritina possesses a discrete open reading frame (orf) (bryp) that encodes a protein containing tandem acyltransferase (at) domains upstream of the pks orfs. bryp is hypothesized to catalyze in trans acylation of the pks modules for polyketide chain elongation. to verify conservation of function, bryp was introduced in ...200819022178
design, synthesis and biological evaluation of bridged epothilone d analogues.six epothilone d analogues with a bridge between the c4-methyl and the c12-methyl carbons were prepared in an attempt to constrain epothilone d to its proposed tubulin-binding conformation. ring-closing metathesis (rcm) was employed as the key step to build the c4-c26 bridge. in antiproliferative assays in the human ovarian cancer (a2780) and prostate cancer (pc3) cell lines, and also in tubulin assembly assay, all these compounds proved to be less active than epothilone d.200819039362
metagenome fragment classification using n-mer frequency profiles.a vast amount of microbial sequencing data is being generated through large-scale projects in ecology, agriculture, and human health. efficient high-throughput methods are needed to analyze the mass amounts of metagenomic data, all dna present in an environmental sample. a major obstacle in metagenomics is the inability to obtain accuracy using technology that yields short reads. we construct the unique n-mer frequency profiles of 635 microbial genomes publicly available as of february 2008. the ...200819956701
genomics of bacteria and archaea: the emerging dynamic view of the prokaryotic world.the first bacterial genome was sequenced in 1995, and the first archaeal genome in 1996. soon after these breakthroughs, an exponential rate of genome sequencing was established, with a doubling time of approximately 20 months for bacteria and approximately 34 months for archaea. comparative analysis of the hundreds of sequenced bacterial and dozens of archaeal genomes leads to several generalizations on the principles of genome organization and evolution. a crucial finding that enables function ...200818948295
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
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
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
unpublished but public microbial genomes with biotechnological relevance. 200821261839
in silico analysis of methyltransferase domains involved in biosynthesis of secondary metabolites.secondary metabolites biosynthesized by polyketide synthase (pks) and nonribosomal peptide synthetase (nrps) family of enzymes constitute several classes of therapeutically important natural products like erythromycin, rapamycin, cyclosporine etc. in view of their relevance for natural product based drug discovery, identification of novel secondary metabolite natural products by genome mining has been an area of active research. a number of different tailoring enzymes catalyze a variety of chemi ...200818950525
pcr detection of type i polyketide synthase genes in myxobacteria.the diversity of type i modular polyketide synthase (pks) was explored by pcr amplification of dna encoding ketosynthase and acyltransferase domains in myxobacteria. the sequencing of the amplicons revealed that many pks genes were distantly related to the published sequences. thus, myxobacteria may be excellent resources for novel and diverse polyketides.200818606793
total synthesis of epothilones b and d: stannane equivalents for beta-keto ester dianions.studies leading to a total synthesis of epothilones b and d are described. the overall synthetic plan was based on late-stage fragment assembly of two segments representing c(1)-c(9) and c(10)-c(21) of the structure. the c(1)-c(9) fragment was prepared by elaboration of commercially available (2r)-3-hydroxy-2-methylpropanoate at both ends of the three-carbon unit. introduction of carbons 1-4 containing the gem-dimethyl unit was achieved in a convergent manner using a diastereoselective addition ...200818991385
natural products genomics. 200821261848
type i polyketide synthases that require discrete acyltransferases.the diverse structures of polyketide natural products are reflected by the equally diverse polyketide biosynthetic enzymes, namely polyketide synthases (pkss). three major classes of pkss are known-noniterative type i pkss, iterative type ii pkss and acyl carrier protein-independent type iii pkss, each of which consists of additional variants. one such variant is the noniterative type i pks in which each pks module lacks the cognate acyltransferase (at) domain. the essential at activity is inste ...200919362640
p2cs: a two-component system resource for prokaryotic signal transduction research.with the escalation of high throughput prokaryotic genome sequencing, there is an ever-increasing need for databases that characterise, catalogue and present data relating to particular gene sets and genomes/metagenomes. two-component system (tcs) signal transduction pathways are the dominant mechanisms by which micro-organisms sense and respond to external as well as internal environmental changes. these systems respond to a wide range of stimuli by triggering diverse physiological adjustments, ...200919604365
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
an efficient, second-generation synthesis of the signature dioxabicyclo[3.2.1]octane core of (+)-sorangicin a and elaboration of the (z,z,e)-triene acid system.an efficient, second-generation synthesis of the signature dioxabicyclo[3.2.1]octane core of (+)-sorangicin a (1), in conjunction with an effective, stereocontrolled protocol to arrive at the requisite (z,z,e)-triene acid system has been developed. highlights of the core construction entail a three-component union, a khmds-promoted epoxide ring formation-ring opening cascade, a takai olefination, and a chemoselective sharpless dihydroxylation. assembly of the triene acid system was then achieved ...200919182995
tubulin-interactive natural products as anticancer agents.this review provides an overview of the discovery, structures, and biological activities of anticancer natural products that act by inhibiting or promoting the assembly of tubulin to microtubules. the emphasis is on providing recent information on those compounds in clinical use or in advanced clinical trials. the vinca alkaloids, the combretastatins, npi-2358, the halichondrin b analogue eribulin, dolastatin 10, noscapine, hemiasterlin, and rhizoxin are discussed as tubulin polymerization inhib ...200919125622
alterations of chemotherapeutic pharmacokinetic profiles by drug-drug interactions.drug interactions in oncology are common place and largely ignored as we tolerate high thresholds of 'toxic' drug responses in these patients. however, in the era of 'targeted' or seemingly 'less toxic' therapy, these interactions are more commonly flagged and contribute significantly towards poor 'quality of life' and medical fatalities.200919239394
asymmetric total synthesis of soraphen a: a flexible alkyne strategy. 200919554583
biosynthesis of polyketide synthase extender units.this review covers the biosynthesis of extender units that are utilized for the assembly of polyketides by polyketide synthases. the metabolic origins of each of the currently known polyketide synthase extender units are covered.200919374124
management of advanced breast cancer with the epothilone b analog, ixabepilone.despite the activity of standard chemotherapies in advanced breast cancer, disease progression remains inevitable. most patients exposed to anthracyclines and taxanes develop resistance and a significant subset shows primary resistance. the increasing use of these agents as adjuvant therapy may result in more anthracycline- and taxane-resistant patients in the metastatic setting; few treatment options are available for patients with metastatic breast cancer (mbc) resistant to multiple chemothera ...200919920932
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