Catalytic Domain

Publication Title: 
Clinical Cancer Research: An Official Journal of the American Association for Cancer Research

PURPOSE: To test ribozymes targeting mouse telomerase RNA (mTER) for suppression of the progression of B16-F10 murine melanoma metastases in vivo. EXPERIMENTAL DESIGN: Hammerhead ribozymes were designed to target mTER. The ribozyme sequences were cloned into a plasmid expression vector containing EBV genomic elements that substantially prolong expression of genes delivered in vivo. The activity of various antitelomerase ribozymes or control constructs was examined after i.v. injection of cationic liposome:DNA complexes containing control or ribozyme constructs.

Author(s): 
Nosrati, Mehdi
Li, Shang
Bagheri, Sepideh
Ginzinger, David
Blackburn, Elizabeth H.
Debs, Robert J.
Kashani-Sabet, Mohammed
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

Telomeres are specialized DNA/protein complexes that comprise the ends of eukaryotic chromosomes. The highly expressed Ku heterodimer, composed of 70 and 80 K(d) subunits (Ku70 and Ku80), is the high-affinity DNA binding component of the DNA-dependent protein kinase. Ku is critical for nonhomologous DNA double-stranded break repair and site-specific recombination of V(D)J gene segments. Ku also plays an important role in telomere maintenance in yeast.

Author(s): 
Hsu, H. L.
Gilley, D.
Blackburn, E. H.
Chen, D. J.
Publication Title: 
Molecular Cell

Telomeres protect chromosome ends from fusing to double-stranded breaks (DSBs). Using a quantitative real-time PCR assay, we show that nonhomologous end joining between a telomere and an inducible DSB was undetectable in wild-type cells, but occurred within a few hours of DSB induction in approximately 1/2000 genomes in telomerase-deficient cells and in >1/1000 genomes in telomerase-deficient cells also lacking the ATM homolog Tel1p. The fused telomeres contained very little telomeric DNA, suggesting that catastrophic telomere shortening preceded fusion.

Author(s): 
Chan, Simon W.-L.
Blackburn, Elizabeth H.
Publication Title: 
Protein Science: A Publication of the Protein Society

Glutathione S-transferase of the malarial parasite Plasmodium falciparum (PfGST) represents a novel class of GST isoenzymes. Since the architecture of the PfGST substrate binding site differs significantly from its human counterparts and there is only this one isoenzyme present in the parasite, PfGST is considered a highly attractive target for antimalarial drug development. Here we report the mechanistic, kinetic, and structural characterization of PfGST as well as its interaction with different ligands.

Author(s): 
Hiller, Nicole
Fritz-Wolf, Karin
Deponte, Marcel
Wende, Wolfgang
Zimmermann, Herbert
Becker, Katja
Publication Title: 
Current Opinion in Biotechnology

Protein engineering of cytochrome P450 monooxygenases (P450s) has been very successful in generating valuable non-natural activities and properties, allowing these powerful catalysts to be used for the synthesis of drug metabolites and in biosynthetic pathways for the production of precursors of artemisinin and paclitaxel. Collected experience indicates that the P450s are highly 'evolvable' - they are particularly robust to mutation in their active sites and readily accept new substrates and exhibit new selectivities.

Author(s): 
Jung, Sang Taek
Lauchli, Ryan
Arnold, Frances H.
Publication Title: 
Molecules (Basel, Switzerland)

The Plasmodium falciparum cysteine protease falcipain-2, one of the most promising targets for antimalarial drug design, plays a key role in parasite survival as a major peptide hydrolase within the hemoglobin degradation pathway. In this work, a series of novel dihydroartemisinin derivatives based on (thio)semicarbazone scaffold were designed and synthesized as potential falcipain-2 inhibitors. The in vitro biological assay indicated that most of the target compounds showed excellent inhibition activity against P. falciparum falcipain-2, with IC(50) values in the 0.29-10.63 ?M range.

Author(s): 
Liu, Yang
Cui, Kunqiang
Lu, Weiqiang
Luo, Wei
Wang, Jian
Huang, Jin
Guo, Chun
Publication Title: 
Cell

A central problem in biology is to identify gene function. One approach is to infer function in large supergenomic networks of interactions and ancestral relationships among genes; however, their analysis can be computationally prohibitive. We show here that these biological networks are compressible. They can be shrunk dramatically by eliminating redundant evolutionary relationships, and this process is efficient because in these networks the number of compressible elements rises linearly rather than exponentially as in other complex networks.

Author(s): 
Lisewski, Andreas Martin
Quiros, Joel P.
Ng, Caroline L.
Adikesavan, Anbu Karani
Miura, Kazutoyo
Putluri, Nagireddy
Eastman, Richard T.
Scanfeld, Daniel
Regenbogen, Sam J.
Altenhofen, Lindsey
Llinás, Manuel
Sreekumar, Arun
Long, Carole
Fidock, David A.
Lichtarge, Olivier
Publication Title: 
PloS One

Diabetes mellitus is recognized as a leading cause of new cases of blindness. The prevalence of diabetic eye disease is expected to continue to increase worldwide as a result of the dramatic increase in the number of people with diabetes. At present, there is no medical treatment to delay or prevent the onset and progression of cataract or retinopathy, the most common causes of vision loss in diabetics. The plant Emblica officinalis (gooseberry) has been used for thousands of years as a traditional Indian Ayurvedic preparation for the treatment of diabetes in humans.

Author(s): 
Puppala, Muthenna
Ponder, Jessica
Suryanarayana, Palla
Reddy, Geereddy Bhanuprakash
Petrash, J. Mark
LaBarbera, Daniel V.
Publication Title: 
Bioorganic & Medicinal Chemistry

Inhibition of intestinal α-glucosidases and pancreatic α-amylases is an approach to controlling blood glucose and serum insulin levels in individuals with Type II diabetes. The two human intestinal glucosidases are maltase-glucoamylase and sucrase-isomaltase. Each incorporates two family 31 glycoside hydrolases responsible for the final step of starch hydrolysis.

Author(s): 
Jones, Kyra
Sim, Lyann
Mohan, Sankar
Kumarasamy, Jayakanthan
Liu, Hui
Avery, Stephen
Naim, Hassan Y.
Quezada-Calvillo, Roberto
Nichols, Buford L.
Pinto, B. Mario
Rose, David R.
Publication Title: 
PloS One

Diabetes mellitus is recognized as a leading cause of new cases of blindness. The prevalence of diabetic eye disease is expected to continue to increase worldwide as a result of the dramatic increase in the number of people with diabetes. At present, there is no medical treatment to delay or prevent the onset and progression of cataract or retinopathy, the most common causes of vision loss in diabetics. The plant Emblica officinalis (gooseberry) has been used for thousands of years as a traditional Indian Ayurvedic preparation for the treatment of diabetes in humans.

Author(s): 
Puppala, Muthenna
Ponder, Jessica
Suryanarayana, Palla
Reddy, Geereddy Bhanuprakash
Petrash, J. Mark
LaBarbera, Daniel V.

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