A5016016965- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Protein Degradation and Inhibitors
- Glycosylation and Glycoproteins Research
- Cancer-related Molecular Pathways
- Biochemical and Molecular Research
- Multiple Myeloma Research and Treatments
- RNA and protein synthesis mechanisms
- Chemical Reactions and Isotopes
- RNA modifications and cancer
- HIV/AIDS drug development and treatment
- Autophagy in Disease and Therapy
- Histone Deacetylase Inhibitors Research
- Endoplasmic Reticulum Stress and Disease
- Protein Structure and Dynamics
- Toxoplasma gondii Research Studies
- Malaria Research and Control
- interferon and immune responses
- vaccines and immunoinformatics approaches
- Cancer Research and Treatments
- HIV Research and Treatment
- Pancreatic and Hepatic Oncology Research
- Cancer, Hypoxia, and Metabolism
- Cancer-related gene regulation
- Genomics and Chromatin Dynamics
The University of Melbourne
2021-2022
Takeda (United States)
2013-2021
Biotechnology Institute
2021
Millennium Engineering and Integration (United States)
2006-2020
Takeda (Japan)
2014-2016
In-Q-Tel
2016
Allscripts (United States)
1997
The University of Texas Southwestern Medical Center
1988-1994
Harvard University
1994
The University of Texas at Dallas
1988-1991
Human angiotensin-converting enzyme-related carboxypeptidase (ACE2) is a zinc metalloprotease whose closest homolog angiotensin I-converting enzyme. To begin to elucidate the physiological role of ACE2, ACE2 was purified, and its catalytic activity characterized. proteolytic has pH optimum 6.5 enhanced by monovalent anions, which consistent with ACE. increased ∼10-fold Cl− F− but unaffected Br−. screened for hydrolytic against panel 126 biological peptides, using liquid chromatography-mass...
The proteasome was validated as an oncology target following the clinical success of VELCADE (bortezomib) for injection treatment multiple myeloma and recurring mantle cell lymphoma. Consequently, several groups are pursuing development additional small-molecule inhibitors both hematologic solid tumor indications. Here, we describe MLN9708, a selective, orally bioavailable, second-generation inhibitor that is in phase I development. MLN9708 has shorter dissociation half-life improved...
Abstract Artemisinin and its derivatives (collectively referred to as ARTs) rapidly reduce the parasite burden in Plasmodium falciparum infections, antimalarial control is highly dependent on ART combination therapies (ACTs). Decreased sensitivity ARTs emerging, making it critically important understand mechanism of action ARTs. Here we demonstrate that dihydroartemisinin (DHA), clinically relevant ART, kills parasites via a two-pronged mechanism, causing protein damage, compromising...
Lactacystin is a Streptomyces metabolite that inhibits cell cycle progression and induces differentiation in murine neuroblastoma line. The cellular target of lactacystin the 20 S proteasome, also known as multicatalytic proteinase complex, an essential component ubiquitin-proteasome pathway for intracellular protein degradation. In aqueous solution at pH 8, undergoes spontaneous hydrolysis to yield N-acetyl-L-cysteine inactive analog, clasto-lactacystin dihydroxy acid. We have studied...
The natural product lactacystin exerts its cellular antiproliferative effects through a mechanism involving acylation and inhibition of the proteasome, cytosolic proteinase complex that is an essential component ubiquitin-proteasome pathway for intracellular protein degradation. In vitro, does not react with proteasome; rather, it undergoes spontaneous conversion (lactonization) to active proteasome inhibitor, clasto-lactacystin β-lactone. We show here when β-lactone added mammalian cells in...
Cancer cells depend on signals that promote cell cycle progression and prevent programmed death would otherwise result from cumulative, aberrant stress. These activities require the temporally controlled destruction of specific intracellular proteins by ubiquitin-proteasome system (UPS). To a large extent, control points in this process include family E3 ubiquitin ligases called cullin-RING (CRLs). The ligase activity these multicomponent complexes requires modification cullin protein...
The mammalian 26S proteasome is a 2500 kDa multi-catalytic complex involved in intracellular protein degradation. We describe the synthesis and properties of novel series non-covalent di-peptide inhibitors used on capped tri-peptide that was first identified by high-throughput screening library approx. 350000 compounds for ubiquitin–proteasome system cells. show these are entirely selective β5 (chymotrypsin-like) site over β1 (caspase-like) β2 (trypsin-like) sites 20S core particle...
Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I II aaRSs as previously unrecognized targets for adenosine 5'-monophosphate-mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid-sulfamate conjugate through a reaction-hijacking mechanism. We identified 5'-sulfamate broad-specificity compound that hijacks range ML901 specific reagent single aaRS in malaria parasite Plasmodium falciparum,...
Abstract The identification of genes in the class II region MHC that are homologous to encoding subunits proteasome has led intense interest possible role this enzyme proteolytic processing polypeptide Ags. We have tested ability 20S produce peptides can be presented by I molecules as targets for killing OVA-specific and beta-galactosidase-specific CTL clones. Samples intact OVA beta-galactosidase were subjected digestion vitro purified from bovine red cells resulting peptide mixtures...
In this paper, we report kinetic studies for the chymotryptic activity of 20S proteasome. Major observations include following: (1) Reaction progress curves that are recorded at concentrations Suc-Leu-Leu-Val-Tyr-AMC greater than about 40 microM biphasic and characterized by initial velocities decay a first-order process to final, steady-state velocities. (2) Also [Suc-Leu-Leu-Val-Tyr-AMC] > microM, smaller predicted from simple, Michaelis-Menten kinetics. (3) The rate constant approach has...
Summary Mycobacterium tuberculosis (Mtb) has the remarkable ability to resist killing by human macrophages. The 750 kDa proteasome, not available in most eubacteria except Actinomycetes , appears contribute Mtb's resistance. crystal structure of Mtb proteasome at 3.0 Å resolution reveals a substrate‐binding pocket with composite features distinct β1, β2 and β5 substrate binding sites eukaryotic proteasomes, accounting for broad specificity towards oligopeptides described companion article...
Ubiquitin and UBL (ubiquitin-like) modifiers are small proteins that covalently modify other to alter their properties or behaviours. modification (ubiquitylation) targets many substrates, often leading proteasomal degradation. NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8) is the most closely related ubiquitin, its best-studied role activation of CRLs (cullin-RING ubiquitin ligases) by conjugation a conserved C-terminal lysine residue on cullin proteins. The...
Ubiquitin-activating enzyme (UAE or E1) activates ubiquitin via an adenylate intermediate and catalyzes its transfer to a ubiquitin-conjugating (E2). MLN4924 is adenosine sulfamate analogue that was identified as selective, mechanism-based inhibitor of NEDD8-activating (NAE), another E1 enzyme, by forming NEDD8-MLN4924 adduct tightly binds at the active site NAE, novel mechanism termed substrate-assisted inhibition (Brownell, J. E., Sintchak, M. D., Gavin, M., Liao, H., Bruzzese, F. J.,...