A5001936516- Alkaline Phosphatase Research Studies
- Biochemical and Molecular Research
- Receptor Mechanisms and Signaling
- Analytical Chemistry and Chromatography
- Neuropeptides and Animal Physiology
- Cellular transport and secretion
- Biochemical Acid Research Studies
- Protein Tyrosine Phosphatases
- Particle accelerators and beam dynamics
- Ubiquitin and proteasome pathways
- Nuclear Physics and Applications
- Various Chemistry Research Topics
- Peptidase Inhibition and Analysis
- Enzyme Structure and Function
- Pharmacological Receptor Mechanisms and Effects
- ATP Synthase and ATPases Research
- Heterotopic Ossification and Related Conditions
- Radiopharmaceutical Chemistry and Applications
- Genomics, phytochemicals, and oxidative stress
- Analytical Chemistry and Sensors
- Microtubule and mitosis dynamics
- Retinal Development and Disorders
- Parathyroid Disorders and Treatments
- Cell death mechanisms and regulation
- Superconducting Materials and Applications
Sanford Burnham Prebys Medical Discovery Institute
2016-2025
Discovery Institute
2016-2025
Institute of Psychology
2021-2023
In-Q-Tel
2015
Maastricht University
2014
University of Birmingham
2014
Joint Center for Structural Genomics
2011
ID Genomics (United States)
2010
Institute for Medical Research
2007-2009
Genomics (United Kingdom)
2009
ABSTRACT Medial vascular calcification (MVC) is a pathological phenomenon that causes stiffening and can lead to heart failure; it common variety of conditions, including aging, chronic kidney disease, diabetes, obesity, rare genetic diseases. These conditions share the feature tissue-nonspecific alkaline phosphatase (TNAP) upregulation in vasculature. To evaluate role TNAP MVC, we developed mouse model overexpresses human smooth muscle cells an X-linked manner. Hemizygous overexpressor male...
Abstract Pharmacological strategies that boost intracellular NAD + are highly coveted for their therapeutic potential. One approach is activation of nicotinamide phosphoribosyltransferase (NAMPT) to increase production mononucleotide (NMN), the predominant precursor in mammalian cells. A high-throughput screen NAMPT activators and hit-to-lead campaign yielded SBI-797812, a compound structurally similar active-site directed inhibitors blocks binding these NAMPT. SBI-797812 shifts reaction...
Ectopic calcification in PXE integrates both local and systemic perturbations of extracellular ATP metabolism can be attenuated with a TNAP inhibitor.
We report the characterization and optimization of drug-like small molecule inhibitors tissue-nonspecific alkaline phosphatase (TNAP), an enzyme critical for regulation extracellular matrix calcification during bone formation growth. High-throughput screening (HTS) a library led to identification arylsulfonamides as potent selective TNAP. Critical structural requirements activity were determined, compounds subsequently profiled in vitro bioavailability parameters including metabolic...
Benzoylformate decarboxylase is a member of the family enzymes that are dependent on cofactor thiamin diphosphate. A structure this enzyme binding (R)-mandelate, competitive inhibitor, suggests at least two hydrogen bonds formed between substrate, benzoylformate, and active site side chains. The first carboxylate group benzoylformate hydroxyl S26, second carbonyl substrate an imidazole nitrogen H70. Steady-state kinetic studies indicate catalytic parameters strongly affected in three...
Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) cholangiocytes lining cysts. Takeda G protein receptor 5 (TGR5), a protein–coupled bile acid receptor, linked to cAMP and expressed cholangiocytes. Therefore, we hypothesized that TGR5 might contribute progression. We examined expression Gα proteins cultured livers animal models humans disease. In vitro , assessed cholangiocyte proliferation, levels, cyst growth...
Autophagy is an evolutionarily conserved process for catabolizing damaged proteins and organelles in a lysosome-dependent manner. Dysregulation of autophagy may cause various diseases, such as cancer neurodegeneration. However, the relevance to diseases remains controversial because limited availability chemical modulators. Herein, authors developed fluorescence-based assay measuring activity protease, autophagin-1(Atg4B). The employs novel reporter substrate Atg4B composed natural (LC3B)...
Glucose-6-phosphate dehydrogenase (G6PD) is the key enzyme of pentose phosphate pathway, converting glucose-6-phosphate to 6-phosphoglucono-δ-lactone with parallel reduction NADP(+). Several human diseases, including cancer, are associated increased G6PD activity. To date, only a few inhibitors have been available. However, adverse side effects and high IC(50) values hamper their use as therapeutics basic research probes. In this study, we developed high-throughput screening assay identify...
Herein we present the outcome of a high throughput screening (HTS) campaign-based strategy for rapid identification and optimization selective general chemotypes both kappa (κ) opioid receptor (KOR) activation inhibition. In this program, have developed potent antagonists (IC(50) < 120 nM) or agonists binding affinity (K(i) 3 nM). contrast to many important KOR ligands, compounds presented here are highly modular, readily synthesized and, in most cases, achiral. The four new hold promise...
// Paul D. Hanavan 1 , Chad R. Borges 2 Benjamin A. Katchman Douglas O. Faigel 3 Thai H. Ho Chen-Ting Ma 4 Eduard Sergienko Nathalie Meurice Joachim L. Petit F. Lake School of Life Sciences, Mayo Clinic Collaborative Research Building, Arizona State University, Scottsdale, AZ, USA Center for Personalized Diagnostics, Biodesign Institute, Tempe, Arizona, Conrad Prebys Chemical Genomics, Sanford-Burnham Medical La Jolla, CA, Correspondence to: Lake, e-mail: douglas.lake@asu.edu Keywords:...
A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. better understanding the molecular mechanisms leading platelet activation important for development improved therapies. Recently, protein tyrosine phosphatases have emerged as critical regulators function.This first report implicating dual-specificity phosphatase 3 (DUSP3) in signaling and thrombosis. This highly expressed human mouse platelets. Platelets DUSP3-deficient...
Ubiquitin-like (Ubl) post-translational modifications are potential targets for therapeutics. However, the only known mechanism inhibiting a Ubl-activating enzyme is through targeting its ATP-binding site. Here we identify an allosteric inhibitory site in small ubiquitin-like modifier (SUMO)-activating (E1). This was unexpected because both it and analogous sites deeply buried all previously solved structures of E1s modifiers (Ubl). The inhibitor not suppresses SUMO E1 activity, but also...
We report the discovery and validation of a series benzoisothiazolones as potent inhibitors phosphomannose isomerase (PMI), an enzyme that converts mannose-6-phosphate (Man-6-P) into fructose-6-phosphate (Fru-6-P) and, more importantly, competes with phosphomannomutase 2 (PMM2) for Man-6-P, diverting this substrate from critical protein glycosylation events. In congenital disorder type Ia, PMM2 activity is compromised; thus, PMI inhibition potential strategy development therapeutics....
Summary Metabolic syndrome and excessive alcohol consumption result in liver injury fibrosis, which is characterized by increased collagen production activated Hepatic Stellate Cells (HSCs). LARP6, an RNA-binding protein, was shown to facilitate production. However, LARP6 expression functionality as a regulator of fibrosis development disease relevant model remains elusive. By using snRNA-sequencing, we show that upregulated mainly HSCs patients. Moreover, knockdown human suppresses...
Yeast pyruvate decarboxylase (YPDC), in addition to forming its metabolic product acetaldehyde, can also carry out carboligase reactions which the central enamine intermediate reacts with acetaldehyde or (instead of usual proton electrophile), resulting formation acetoin and acetolactate, respectively (typically, 1% total reaction). Due common mechanism shared by acetaldehyde-forming through decarboxylation, a detailed analysis rates stereochemistry products formed E477Q, D28A, D28N active...