A5019588921- Microbial Natural Products and Biosynthesis
- Signaling Pathways in Disease
- Cancer therapeutics and mechanisms
- Carbohydrate Chemistry and Synthesis
- Biochemical and Molecular Research
- Chemical Synthesis and Analysis
- Hepatitis C virus research
- Genomics and Phylogenetic Studies
- Biochemical and Structural Characterization
- Peptidase Inhibition and Analysis
- Computational Drug Discovery Methods
- Heat shock proteins research
- Plant biochemistry and biosynthesis
- Liver Disease Diagnosis and Treatment
- Plant-Microbe Interactions and Immunity
- Synthesis and Biological Evaluation
- PI3K/AKT/mTOR signaling in cancer
- Synthesis and biological activity
- Plant Disease Resistance and Genetics
- Toxin Mechanisms and Immunotoxins
- Click Chemistry and Applications
- 14-3-3 protein interactions
- Synthetic Organic Chemistry Methods
- Bioactive Compounds and Antitumor Agents
- Hepatitis B Virus Studies
Isomerase Therapeutics (United Kingdom)
2013-2024
Oregon State University
2017
Hope College
2013-2016
Institute of Cancer Research
2008
St. Jude Children's Research Hospital
2006
National Institute for Occupational Safety and Health
2004
American Conference of Governmental Industrial Hygienists
2004
Bureau of Land Management
2004
Colorado Department of Public Health and Environment
2004
Johns Hopkins University
2004
ABSTRACT Despite extensive similarities between the genomes of Streptomyces temperate phages φC31 and φBT1, attP-int loci are poorly conserved. Here we demonstrate that φBT1 integrates into a different attachment site than φC31. attB lies within SCO4848 encoding 79-amino-acid putative integral membrane protein. Integration vectors based on integrase were shown to have broad host range fully compatible with those locus.
The macrocyclic polyketides FK506, FK520, and rapamycin are potent immunosuppressants that prevent T-cell proliferation through initial binding to the immunophilin FKBP12. Analogs of these molecules considerable interest as therapeutics in both metastatic inflammatory disease. For starter unit for chain assembly is (4 R ,5 )-4,5-dihydroxycyclohex-1-enecarboxylic acid derived from shikimate pathway. We show here first committed step its formation hydrolysis chorismate form...
Abstract Erythromycin, avermectin and rapamycin are clinically useful polyketide natural products produced on modular synthase multienzymes by an assembly-line process in which each module of enzymes turn specifies attachment a particular chemical unit. Although encoding genes have been successfully engineered to produce novel analogues, the can be relatively slow, inefficient, frequently low-yielding. We now describe method for rapidly recombining gene clusters replace, add or remove...
The fate of live forest biomass is largely controlled by growth and disturbance processes, both natural anthropogenic. Thus, monitoring strategies must characterize the forests at a given point in time dynamic processes that change it. Here, we describe test an empirical system designed to meet those needs. Our uses mix field data, statistical modeling, remotely-sensed time-series imagery, small-footprint lidar data build evaluate maps biomass. It ascribes specific agents, attempts capture...
The surprising discovery has been made that the gene product RapK is required for production of starter unit in rapamycin polyketide cluster. It shown a deletion mutant (Streptomyces hygroscopicus MG2–10) provides clean background mutasynthesis pre-rapamycin (the precursor to rapamycin, see structure) when fed with novel units. Supporting information this article available on WWW under http://www.wiley-vch.de/contents/jc_2002/2005/z462784_s.pdf or from author. Please note: publisher not...
ABSTRACT Rapamycin is an important macrocyclic polyketide produced by Streptomyces hygroscopicus and showing immunosuppressive, antifungal, antitumor activities as well displaying anti-inflammatory neuroregenerative properties. The immense pharmacological potential of rapamycin has led to the production array analogues, including through genetic engineering biosynthetic gene cluster. This cluster contains several putative regulatory genes. Based on DNA sequence analysis, products genes rapH...
A biosynthetic medicinal chemistry approach was applied to the optimization of natural product Hsp90 inhibitor macbecin. By genetic engineering, mutants have been created produce novel macbecin analogues including a nonquinone compound (5) that has significantly improved binding affinity (Kd 3 nM vs 240 for macbecin) and reduced toxicity (MTD > or = 250 mg/kg). Structural flexibility may contribute preorganization 5 exist in solution Hsp90-bound conformation.
The completed genome sequence of the temperate Streptomyces phage φC31 is reported. contains genes that are related by similarities to several other dsDNA phages infecting many diverse bacterial hosts, including Escherichia, Arthrobacter, Mycobacterium, Rhodobacter, Staphylococcus, Bacillus, Streptococcus, Lactobacillus and Lactococcus. These observations provide further evidence from hosts have had access a common genetic pool. Analysis late was particularly informative. sequences head...
ABSTRACT Cyclophilin inhibitors currently in clinical trials for hepatitis C virus (HCV) are all analogues of cyclosporine (CsA). Sanglifehrins a group naturally occurring cyclophilin binding polyketides that structurally distinct from the cyclosporines and produced by microorganism amenable to biosynthetic engineering lead optimization large-scale production fermentation. Preclinical characterization potential utility this class compounds treatment HCV revealed natural sanglifehrins A D...
Macbecin compares favorably to geldanamycin as an Hsp90 inhibitor, being more soluble, stable, potently inhibiting ATPase activity (IC50 = 2 microM) and binding with higher affinity (Kd 0.24 microM). Structural studies reveal significant differences in their characteristics, macbecin-induced tumor cell growth inhibition is accompanied by characteristic degradation of client proteins. significantly reduced rates (minimum T/C: 32%) a DU145 murine xenograft. thus represents attractive lead for...
ABSTRACT Alisporivir is the most advanced host-targeting antiviral cyclophilin (Cyp) inhibitor in phase III studies and has demonstrated a great deal of promise decreasing hepatitis C virus (HCV) viremia infected patients. In an attempt to further elucidate mechanism action alisporivir, HCV replicons resistant drug were selected. Interestingly, mutations constantly arose domain II NS5A. To demonstrate that these are responsible for resistance, they reintroduced into parental genome,...
ABSTRACT The genome sequences of eight Streptomyces phages are presented, four which were isolated for this study. Phages R4, TG1, ϕHau3, and SV1 previously have been exploited as tools understanding genetically manipulating spp. We also extracted five apparently intact prophages from recent projects and, together with six phage genomes in the database, we analyzed all 19 a view to their relationships each other actinophages, particularly mycobacteriophages. Fifteen group into clusters...
The function of gene products involved in the biosynthesis clinically important polyketide rapamycin were elucidated by biotransformation and complementation
It's a rap: A double recombination strategy has been utilized to uncover the biosynthetic route key intermediate in formation of rapamycin. Removal section rapamycin gene cluster from Streptomyces hygroscopicus produced strain that generated no Gene complementation proved, surprisingly, accumulation this previously elusive pre-rapamycin (1) depended on presence rapK. Supporting information for article is available WWW under http://www.wiley-vch.de/contents/jc_2002/2004/z53764_s.pdf or...
Sangamides are amide derivatives of sanglifehrin A, a cyclophilin-binding polyketide natural product which is structurally distinct from cyclosporine A. Cyclosporine A the starting point for synthesis cyclophilin inhibitors such as alisporivir, currently in development treatment HCV infection. We report here initial results optimisation program led to identification sangamides, compounds that exhibit significantly improved potential chronic
Bacteria in the genus Streptomyces and its close relatives are prolific producers of secondary metabolites with antibiotic activity. Genome sequencing these bacteria has revealed a rich source potentially new pathways, whose products have never been observed. Moreover, pathways can provide novel genes that could be used combinatorial biosynthesis approaches to generate unnatural analogues existing antibiotics. We explore here use multiple orthologous integrating plasmid systems, based on...
The polyketide natural product borrelidin 1 is a potent inhibitor of angiogenesis and spontaneous metastasis. Affinity biopanning phage display library colon tumor cell cDNAs identified the tandem WW domains spliceosome-associated protein formin binding 21 (FBP21) as novel molecular target borrelidin, suggesting that may act modulator alternative splicing. In support this idea, 1, its more selective analog 2, bound to purified recombinant FBP21. They also altered ratio vascular endothelial...
Hepatic fibrosis can result as a pathological response to nonalcoholic steatohepatitis (NASH). Cirrhosis, the late stage of fibrosis, has been linked poor survival and an increased risk developing hepatocellular carcinoma, with limited treatment options available. Therefore, there is unmet need for novel effective antifibrotic compounds. Cyclophilins are peptidyl-prolyl cis-trans isomerases that facilitate protein folding conformational changes affecting function targeted proteins. Due their...
A combination of molecular modelling and rational biosynthetic engineering the rapamycin polyketide synthase was used to generate rapalogs lacking O- C-linked methyl groups at positions 16 17 respectively. These displayed enhanced inhibition cancer cell lines were produced titres close those parent strain. By recapitulating these experiments in higher-producing strains, combined with ectopic expression gene products acting late pathway order minimise accumulation intermediates,...
Streptomyces iranensis HM 35 is an alternative rapamycin producer to rapamycinicus Targeted genetic modification of rapamycin-producing actinomycetes a powerful tool for the directed production derivatives, and it has also revealed some key features molecular biology formation in S. rapamycinicus. The approach depends upon efficient conjugational plasmid transfer from Escherichia coli Streptomyces, failure this step frustrated its application 35. Here, by systematically optimizing process...