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Articles 1 - 8 of 8
Full-Text Articles in Biochemistry, Biophysics, and Structural Biology
The Marine Sponge Metabolite Mycothiazole: A Novel Prototype Mitochondrial Complex I Inhibitor., J Brian Morgan, Fakhri Mahdi, Yang Liu, Veena Coothankandaswamy, Mika B Jekabsons, Tyler A. Johnson, Koneni V Sashidhara, Phillip Crews, Dale G Nagle, Yu-Dong Zhou
The Marine Sponge Metabolite Mycothiazole: A Novel Prototype Mitochondrial Complex I Inhibitor., J Brian Morgan, Fakhri Mahdi, Yang Liu, Veena Coothankandaswamy, Mika B Jekabsons, Tyler A. Johnson, Koneni V Sashidhara, Phillip Crews, Dale G Nagle, Yu-Dong Zhou
Tyler Johnson
A natural product chemistry-based approach was applied to discover small-molecule inhibitors of hypoxia-inducible factor-1 (HIF-1). A Petrosaspongia mycofijiensis marine sponge extract yielded mycothiazole (1), a solid tumor selective compound with no known mechanism for its cell line-dependent cytotoxic activity. Compound 1 inhibited hypoxic HIF-1 signaling in tumor cells (IC(50) 1nM) that correlated with the suppression of hypoxia-stimulated tumor angiogenesis in vitro. However, 1 exhibited pronounced neurotoxicity in vitro. Mechanistic studies revealed that 1 selectively suppresses mitochondrial respiration at complex I (NADH-ubiquinone oxidoreductase). Unlike rotenone, MPP(+), annonaceous acetogenins, piericidin A, and other complex I inhibitors, mycothiazole is a mixed polyketide/peptide-derived compound …
Crosstalk Between Brca-Fanconi Anemia And Mismatch Repair Pathways Prevents Msh2-Dependent Aberrant Dna Damage Responses, Min Peng, Jenny X. Xie, Anna J. Ucher, Janet Stavnezer, Sharon B. Cantor
Crosstalk Between Brca-Fanconi Anemia And Mismatch Repair Pathways Prevents Msh2-Dependent Aberrant Dna Damage Responses, Min Peng, Jenny X. Xie, Anna J. Ucher, Janet Stavnezer, Sharon B. Cantor
Janet M. Stavnezer
Several proteins in the BRCA-Fanconi anemia (FA) pathway, such as FANCJ, BRCA1, and FANCD2, interact with mismatch repair (MMR) pathway factors, but the significance of this link remains unknown. Unlike the BRCA-FA pathway, the MMR pathway is not essential for cells to survive toxic DNA interstrand crosslinks (ICLs), although MMR proteins bind ICLs and other DNA structures that form at stalled replication forks. We hypothesized that MMR proteins corrupt ICL repair in cells that lack crosstalk between BRCA-FA and MMR pathways. Here, we show that ICL sensitivity of cells lacking the interaction between FANCJ and the MMR protein MLH1 is …
Quaking Regulates Hnrnpa1 Expression Through Its 3' Utr In Oligodendrocyte Precursor Cells, Nancy Zearfoss, Carina Clingman, Brian Farley, Lisa Mccoig, Sean Ryder
Quaking Regulates Hnrnpa1 Expression Through Its 3' Utr In Oligodendrocyte Precursor Cells, Nancy Zearfoss, Carina Clingman, Brian Farley, Lisa Mccoig, Sean Ryder
Sean P. Ryder
In mice, Quaking (Qk) is required for myelin formation; in humans, it has been associated with psychiatric disease. QK regulates the stability, subcellular localization, and alternative splicing of several myelin-related transcripts, yet little is known about how QK governs these activities. Here, we show that QK enhances Hnrnpa1 mRNA stability by binding a conserved 3' UTR sequence with high affinity and specificity. A single nucleotide mutation in the binding site eliminates QK-dependent regulation, as does reduction of QK by RNAi. Analysis of exon expression across the transcriptome reveals that QK and hnRNP A1 regulate an overlapping subset of transcripts. Thus, …
Evolution Of The Influenza A Virus Genome During Development Of Oseltamivir Resistance In Vitro, Nicholas Renzette, Daniel Caffrey, Konstantin Zeldovich, Ping Liu, Glen Gallagher, Daniel Aiello, Alyssa Porter, Evelyn Kurt-Jones, Daniel Bolon, Yu-Ping Poh, Jeffrey Jensen, Celia Schiffer, Timothy Kowalik, Robert Finberg, Jennifer Wang
Evolution Of The Influenza A Virus Genome During Development Of Oseltamivir Resistance In Vitro, Nicholas Renzette, Daniel Caffrey, Konstantin Zeldovich, Ping Liu, Glen Gallagher, Daniel Aiello, Alyssa Porter, Evelyn Kurt-Jones, Daniel Bolon, Yu-Ping Poh, Jeffrey Jensen, Celia Schiffer, Timothy Kowalik, Robert Finberg, Jennifer Wang
Glen R. Gallagher
Influenza A virus (IAV) is a major cause of morbidity and mortality throughout the world. Current antiviral therapies include oseltamivir, a neuraminidase inhibitor that prevents the release of nascent viral particles from infected cells. However, the IAV genome can evolve rapidly, and oseltamivir resistance mutations have been detected in numerous clinical samples. Using an in vitro evolution platform and whole-genome population sequencing, we investigated the population genomics of IAV during the development of oseltamivir resistance. Strain A/Brisbane/59/2007 (H1N1) was grown in Madin-Darby canine kidney cells with or without escalating concentrations of oseltamivir over serial passages. Following drug treatment, the H274Y …
Evolution Of The Influenza A Virus Genome During Development Of Oseltamivir Resistance In Vitro, Nicholas Renzette, Daniel R. Caffrey, Konstantin B. Zeldovich, Ping Liu, Glen R. Gallagher, Daniel Aiello, Alyssa J. Porter, Evelyn A. Kurt-Jones, Daniel N. Bolon, Yu-Ping Poh, Jeffrey D. Jensen, Celia A. Schiffer, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang
Evolution Of The Influenza A Virus Genome During Development Of Oseltamivir Resistance In Vitro, Nicholas Renzette, Daniel R. Caffrey, Konstantin B. Zeldovich, Ping Liu, Glen R. Gallagher, Daniel Aiello, Alyssa J. Porter, Evelyn A. Kurt-Jones, Daniel N. Bolon, Yu-Ping Poh, Jeffrey D. Jensen, Celia A. Schiffer, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang
Celia A. Schiffer
Influenza A virus (IAV) is a major cause of morbidity and mortality throughout the world. Current antiviral therapies include oseltamivir, a neuraminidase inhibitor that prevents the release of nascent viral particles from infected cells. However, the IAV genome can evolve rapidly, and oseltamivir resistance mutations have been detected in numerous clinical samples. Using an in vitro evolution platform and whole-genome population sequencing, we investigated the population genomics of IAV during the development of oseltamivir resistance. Strain A/Brisbane/59/2007 (H1N1) was grown in Madin-Darby canine kidney cells with or without escalating concentrations of oseltamivir over serial passages. Following drug treatment, the H274Y …
A Sensitive Assay Using A Native Protein Substrate For Screening Hiv-1 Maturation Inhibitors Targeting The Protease Cleavage Site Between The Matrix And Capsid, Sook-Kyung Lee, Nancy Cheng, Emily Hull-Ryde, Marc Potempa, Celia Schiffer, William Janzen, Ronald Swanstrom
A Sensitive Assay Using A Native Protein Substrate For Screening Hiv-1 Maturation Inhibitors Targeting The Protease Cleavage Site Between The Matrix And Capsid, Sook-Kyung Lee, Nancy Cheng, Emily Hull-Ryde, Marc Potempa, Celia Schiffer, William Janzen, Ronald Swanstrom
Celia A. Schiffer
The matrix/capsid processing site in the HIV-1 Gag precursor is likely the most sensitive target to inhibit HIV-1 replication. We have previously shown that modest incomplete processing at the site leads to a complete loss of virion infectivity. In the study presented here, a sensitive assay based on fluorescence polarization that can monitor cleavage at the MA/CA site in the context of the folded protein substrate is described. The substrate, an MA/CA fusion protein, was labeled with the fluorescein-based FlAsH (fluorescein arsenical hairpin) reagent that binds to a tetracysteine motif (CCGPCC) that was introduced within the N-terminal domain of CA. …
The Marine Sponge Metabolite Mycothiazole: A Novel Prototype Mitochondrial Complex I Inhibitor., J Brian Morgan, Fakhri Mahdi, Yang Liu, Veena Coothankandaswamy, Mika B. Jekabsons, Tyler A. Johnson, Koneni V. Sashidhara, Phillip Crews, Dale G. Nagle, Yu-Dong Zhou
The Marine Sponge Metabolite Mycothiazole: A Novel Prototype Mitochondrial Complex I Inhibitor., J Brian Morgan, Fakhri Mahdi, Yang Liu, Veena Coothankandaswamy, Mika B. Jekabsons, Tyler A. Johnson, Koneni V. Sashidhara, Phillip Crews, Dale G. Nagle, Yu-Dong Zhou
Natural Sciences and Mathematics | Faculty Scholarship
A natural product chemistry-based approach was applied to discover small-molecule inhibitors of hypoxia-inducible factor-1 (HIF-1). A Petrosaspongia mycofijiensis marine sponge extract yielded mycothiazole (1), a solid tumor selective compound with no known mechanism for its cell line-dependent cytotoxic activity. Compound 1 inhibited hypoxic HIF-1 signaling in tumor cells (IC(50) 1nM) that correlated with the suppression of hypoxia-stimulated tumor angiogenesis in vitro. However, 1 exhibited pronounced neurotoxicity in vitro. Mechanistic studies revealed that 1 selectively suppresses mitochondrial respiration at complex I (NADH-ubiquinone oxidoreductase). Unlike rotenone, MPP(+), annonaceous acetogenins, piericidin A, and other complex I inhibitors, mycothiazole is a mixed polyketide/peptide-derived compound …
Heparin Modulates The 99-Loop Of Factor Ixa: Effects On Reactivity With Isolated Kunitz-Type Inhibitor Domains, Pierre F. Neuenschwander, Stephen R. Williamson, Armen Nalian, Kimberly J. Baker-Deadmond
Heparin Modulates The 99-Loop Of Factor Ixa: Effects On Reactivity With Isolated Kunitz-Type Inhibitor Domains, Pierre F. Neuenschwander, Stephen R. Williamson, Armen Nalian, Kimberly J. Baker-Deadmond
Faculty Publications
Reactivity of factor IXa with basic pancreatic trypsin inhibitor is enhanced by low molecular weight heparin (enoxaparin). Previous studies by us have suggested that this effect involves allosteric modulation of factor IXa. We examined the reactivity of factor IXa with several isolated Kunitz-type inhibitor domains: basic pancreatic trypsin inhibitor, the Kunitz inhibitor domain of protease Nexin-2, and the first two inhibitor domains of tissue factor pathway inhibitor. We find that enhancement of factor IXa reactivity by enoxaparin is greatest for basic pancreatic trypsin inhibitor (>10-fold), followed by the second tissue factor pathway inhibitor domain (1.7-fold) and the Kunitz inhibitor …