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The identification of 8-ethyl-2-phenylamino-8H-pyrido[2, 3-d]pyrimidin-7-one (1) as an inhibitor of Cdk4 led to the initiation of a program to evaluate related pyrido[2, 3-d]pyrimidin-7-ones for inhibition of cyclin-dependent kinases (Cdks). Analysis of more than 60 analogues has identified some clear SAR trends that may be exploited in the design of more(More)
A commonly used strategy by microorganisms to survive multiple stresses involves a signal transduction cascade that increases the expression of stress-responsive genes. Stress signals can be integrated by a multiprotein signaling hub that responds to various signals to effect a single outcome. We obtained a medium-resolution cryo-electron microscopy(More)
Compartmentalized co-localization of enzymes and their substrates represents an attractive approach for multi-enzymatic synthesis in engineered cells and biocatalysis. Sequestration of enzymes and substrates would greatly increase reaction efficiency while also protecting engineered host cells from potentially toxic reaction intermediates. Several bacteria(More)
The secondary metabolome of Basidiomycota represents a largely uncharacterized source of pharmaceutically relevant natural products. Terpenoids are the primary class of bioactive compounds isolated from mushrooms. The Jack O'Lantern mushroom Omphalotus olearius was identified 50 years ago as a prolific producer of anticancer illudin sesquiterpenoids;(More)
Enzymes are increasingly being used in an industrial setting as a cheap and environmentally-friendly alternative to chemical catalysts. In order to produce the ideal biocatalyst, natural enzymes often require optimization to increase their catalytic efficiencies and specificities under a particular range of reaction conditions. A number of enzyme(More)
Fungi (Ascomycota and Basidiomycota) are prolific producers of structurally diverse terpenoid compounds. Classes of terpenoids identified in fungi include the sesqui-, di- and triterpenoids. Biosynthetic pathways and enzymes to terpenoids from each of these classes have been described. These typically involve the scaffold generating terpene synthases and(More)
Bacterial microcompartments (BMCs) are protein-based polyhedral organelles which serve to encapsulate and organize enzymes involved in key metabolic pathways. The sequestration of these pathways not only improves the overall reaction efficiency; it can also harbor toxic or volatile pathway intermediates, which would otherwise be detrimental to the cell.(More)
Compartmentalization of designed metabolic pathways within protein based nanocompartments has the potential to increase reaction efficiency in multi-step biosynthetic reactions. We previously demonstrated proof-of-concept of this aim by targeting a functional enzyme to single cellular protein nanocompartments, which were formed upon recombinant expression(More)
The thermophilic bacterium Moorella thermoacetica possesses an rsb operon that is related to the genetic locus common to many Gram-positive bacteria that regulates the activity of the stress-responsive sigma factor sigma(B). One of the gene products of this operon is RsbS, a single STAS-domain protein that is a component of higher order assemblies in(More)
PURPOSE OF REVIEW Over recent years there has been a growing appreciation that a small but significant proportion of patients experience (sometimes serious) adverse events in the hands of health care workers. Although research in this area is very much in its infancy there has been an increasing move towards applying principles of risk management from(More)