A5060364164- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- Ubiquitin and proteasome pathways
- Bacterial Genetics and Biotechnology
- Biochemical and Molecular Research
- Biochemical and Structural Characterization
- Enzyme Structure and Function
- Antimicrobial Peptides and Activities
- X-ray Diffraction in Crystallography
- RNA and protein synthesis mechanisms
- Vibrio bacteria research studies
- Protein Structure and Dynamics
- Crystallization and Solubility Studies
- Cell death mechanisms and regulation
- Chemical Synthesis and Analysis
- Antibiotic Resistance in Bacteria
- Peptidase Inhibition and Analysis
- Carbohydrate Chemistry and Synthesis
- Metalloenzymes and iron-sulfur proteins
- Aquaculture disease management and microbiota
- Microbial Metabolic Engineering and Bioproduction
- Machine Learning in Materials Science
- Computational Drug Discovery Methods
- RNA modifications and cancer
- thermodynamics and calorimetric analyses
University of Toronto
2012-2024
Princess Margaret Cancer Centre
2019
University Health Network
2019
The mitochondrial caseinolytic protease P (ClpP) plays a central role in protein quality control by degrading misfolded proteins. Using genetic and chemical approaches, we showed that hyperactivation of the selectively kills cancer cells, independently p53 status, selective degradation its respiratory chain substrates disrupts structure function, while it does not affect non-malignant cells. We identified imipridones as potent activators ClpP. Through biochemical studies crystallography,...
Large-scale proteomic analyses in Escherichia coli have documented the composition and physical relationships of multiprotein complexes, but not their functional organization into biological pathways processes. Conversely, genetic interaction (GI) screens can provide insights role(s) individual gene higher order associations. Combining information from both approaches should elucidate how complexes intersect functionally at a systems level. However, such integrative analysis has been...
The problem of antibiotic resistance has prompted the search for new antibiotics with novel mechanisms action. Analogues A54556 cyclic acyldepsipeptides (ADEPs) represent an attractive class antimicrobial agents that act through dysregulation caseinolytic protease (ClpP). Previous studies have shown ADEPs are active against Gram-positive bacteria (e.g., MRSA, VRE, PRSP (penicillin-resistant Streptococcus pneumoniae)); however, there currently few examining Gram-negative bacteria. In this...
MoxR ATPases are widespread throughout bacteria and archaea. The experimental evidence to date suggests that these proteins have chaperone-like roles in facilitating the maturation of dedicated protein complexes functionally diverse. In Escherichia coli, ATPase RavA its putative cofactor ViaA found exist early stationary-phase cells at 37°C low levels about 350 90 molecules per cell, respectively. Both predominantly localized cytoplasm, but was also unexpectedly localize cell membrane. Whole...
The first total synthesis of all six known A54556 acyldepsipeptide (ADEP) antibiotics from Streptomyces hawaiiensis is reported. This family compounds has a unique mechanism antibacterial action, acting as activators caseinolytic protease (ClpP). Assembly the 16-membered depsipeptide core was accomplished via pentafluorophenyl ester-based macrolactamization strategy. Late stage amine deprotection carried out under neutral conditions by employing mild hydrogenolysis strategy, which avoids...
Evolving antimicrobial resistance has motivated the search for novel targets and alternative therapies. Caseinolytic protease (ClpP) emerged as an enticing new target since its function is conserved essential bacterial fitness, because inhibition or dysregulation leads to cell death. ClpP controls global protein homeostasis is, therefore, crucial maintenance of proteome during growth infection. Previously, acyldepsipeptides (ADEPs) were discovered dysregulate ClpP, leading bactericidal...
A series of arylsulfones and heteroarylsulfones have previously been demonstrated to dysregulate the conserved bacterial ClpP protease, causing unspecific degradation essential cellular housekeeping proteins ultimately resulting in cell death. cocrystal structure a 2-β-sulfonylamide analog, ACP1-06, with Escherichia coli showed that its 2-pyridyl sulfonyl substituent adopts two orientations binding site related through sulfone bond rotation. From this, new bis-aryl phosphine oxide scaffold,...
The vertebrate proglucagon gene encodes three glucagon-like sequences (glucagon, peptide-1 [GLP-1], and peptide 2 [GLP-2]) that have distinct functions in regulating metabolism mammals. In contrast, glucagon GLP-1 similar physiological actions fish, of mammalian glucagon. We identified to receptors for proglucagon-derived peptides from the genomes two fish (pufferfish zebrafish), a frog (Xenopus tropicalis), bird (chicken). Phylogenetic analysis receptor suggested an explanation divergent...
MoxR proteins comprise a family of ATPases Associated with diverse cellular Activities (AAA+). These are widespread and found across the diversity prokaryotic species. Despite their ubiquity, members group remain poorly characterized. Only few examples have been associated roles, where they shown to perform chaperone-like functions. A characteristic feature is association containing von Willebrand factor type (VWA) domain. In an effort understand spread family, evolutionary approach was...
Abstract The mitochondrial ClpP protease is responsible for protein quality control through specific degradation of proteins involved in several metabolic processes. overexpression also required many cancer cells to eliminate ROS-damaged and sustain oncogenesis. Targeting dysregulate its function using small molecule agonists a novel strategy therapy. Here, we synthesized imipridone-derived compounds related chemicals, which characterized biochemical, biophysical, cellular studies. Using...
Abstract ClpP is a mitochondrial protease and major protein quality control mediator that primarily interacts with metabolic enzymes in mitochondria. Here, we demonstrate activation of this results prominent anti-cancer activity, propose as novel therapeutic strategy for cancer hematologic malignancies. We used genetic chemical tools to activate ClpP. In approach, tested the effects by expressing constitutively active mutant. Indeed, induction mutant induced apoptosis vitro inhibited tumor...