A5039530529- Metabolomics and Mass Spectrometry Studies
- Retinal Development and Disorders
- Drug Transport and Resistance Mechanisms
- Metabolism and Genetic Disorders
- Chemical Synthesis and Analysis
- Retinoids in leukemia and cellular processes
- Diet and metabolism studies
- Eicosanoids and Hypertension Pharmacology
- Photochromic and Fluorescence Chemistry
- Retinal Diseases and Treatments
- Liver Disease Diagnosis and Treatment
- Receptor Mechanisms and Signaling
- Antioxidant Activity and Oxidative Stress
- Pharmacogenetics and Drug Metabolism
- Photoreceptor and optogenetics research
- Porphyrin and Phthalocyanine Chemistry
- Analytical Chemistry and Chromatography
- Natural Compounds in Disease Treatment
- Natural product bioactivities and synthesis
- Microbial Natural Products and Biosynthesis
- Protein Interaction Studies and Fluorescence Analysis
- Pediatric Hepatobiliary Diseases and Treatments
- Cholesterol and Lipid Metabolism
- Organophosphorus compounds synthesis
- Autophagy in Disease and Therapy
Case Western Reserve University
2013-2025
Cleveland Eye Clinic
2017
Cleveland Clinic
2010-2017
Louis Stokes Cleveland VA Medical Center
2017
Cleveland Clinic Lerner College of Medicine
2017
Washington University in St. Louis
1998-2015
University School
2011-2013
Case Comprehensive Cancer Center
2012
Harvard University
2004-2005
Harvard Stem Cell Institute
2004
To identify previously unknown small molecules that inhibit cell cycle machinery, we performed a chemical genetic screen in Xenopus extracts. One class of inhibitors, termed ubistatins, blocked progression by inhibiting cyclin B proteolysis and inhibited degradation ubiquitinated Sic1 purified proteasomes. Ubistatins the binding substrates to proteasome targeting ubiquitin-ubiquitin interface Lys 48 -linked chains. The same is recognized ubiquitin-chain receptors proteasome, indicating...
During tumor progression, EphA2 receptor can gain ligand-independent pro-oncogenic functions due to Akt activation and reduced ephrin-A ligand engagement. The effects be reversed by stimulation, which triggers the intrinsic suppressive signaling pathways of including inhibition PI3/Akt Ras/ERK pathways. These observations argue for development small molecule agonists as potential intervention agents. Through virtual screening cell-based assays, we report here identification characterization...
The fatty acid-binding protein FABP5 shuttles ligands from the cytosol to nuclear receptor PPARβ/δ (encoded for by Pparδ), thereby enhancing transcriptional activity of receptor. This FABP5/PPARδ pathway is critical induction proliferation breast carcinoma cells activated epidermal growth factor (EGFR). In this study, we show that highly upregulated in human cancers and provide genetic evidence pathophysiologic significance mammary tumorigenesis. Ectopic expression was found be oncogenic 3T3...
Emixustat is a visual cycle modulator that has entered clinical trials as treatment for age-related macular degeneration (AMD). This molecule been proposed to inhibit the isomerase RPE65, thereby slowing regeneration of 11-cis-retinal and reducing production retinaldehyde condensation byproducts may be involved in AMD pathology. Previously, we reported all-trans-retinal (atRAL) directly cytotoxic certain primary amine compounds transiently sequester atRAL via Schiff base formation ameliorate...
Rhodopsin homeostasis is tightly coupled to rod photoreceptor cell survival and vision. Mutations resulting in the misfolding of rhodopsin can lead autosomal dominant retinitis pigmentosa (adRP), a progressive retinal degeneration that currently untreatable. Using cell-based high-throughput screen (HTS) identify small molecules stabilize P23H-opsin mutant, which causes most cases adRP, we identified novel pharmacological chaperone opsin, YC-001. As non-retinoid molecule, YC-001 demonstrates...
Proteins with multiple binding sites exhibit a complex behavior that depends on the intrinsic affinities for each site and energetic communication between sites. The contributions from affinity cooperativity are difficult to deconvolute using conventional experiments lack information about occupancies of individual Here, we report concerted use NMR isothermal titration calorimetry determine cooperative free energies ligand–protein complex. measurements provided site-specific necessary...
4-Hydroxyacids are products of ubiquitously occurring lipid peroxidation (C9, C6) or drugs abuse (C4, C5). We investigated the catabolism these compounds using a combination metabolomics and mass isotopomer analysis. Livers were perfused with various concentrations unlabeled labeled saturated 4-hydroxyacids (C4 to C11) 4-hydroxynonenal. All tested form new class acyl-CoA esters, 4-hydroxy-4-phosphoacyl-CoAs, characterized by liquid chromatography-tandem spectrometry, accurate 31P-NMR. five...
Propionate, 3-hydroxypropionate (3HP), methylcitrate, related compounds, and ammonium accumulate in body fluids of patients with disorders propionyl-CoA metabolism, such as propionic acidemia. Although liver transplantation alleviates hyperammonemia, high concentrations propionate, 3HP, methylcitrate persist fluids. We hypothesized that conserved metabolic perturbations occurring transplanted result from the simultaneous presence propionate 3HP investigated inter-relations metabolism...
Significance Vertebrate rhodopsin (Rh) has been a model system for many G protein-coupled receptors over decade. However, due to its thus-far limited repertoire of active ligands, use in assisting the development new therapeutic modalities and drugs limited. This study elucidates photocyclic protein activation by Rh bound with six-carbon ring retinal (Rh6mr), thus broadens diversity such signaling modulators. Rh6mr does not release chromophore after light activation, but instead resulting...
Rhodopsin-associated (RHO-associated) retinitis pigmentosa (RP) is a progressive retinal disease that currently has no cure. RHO protein misfolding leads to disturbed proteostasis and the death of rod photoreceptors, resulting in decreased vision. We previously identified nonretinoid chaperones RHO, including YC-001 F5257-0462, by small-molecule high-throughput screening. Here, we profile chaperone activities these molecules toward cell-surface level 27 RP-causing human mutants NIH3T3 cells....
Lipid peroxidation is a complex biochemical process associated with oxidative stress, and its products play crucial roles in cellular signaling the pathophysiology of many diseases. Among diverse array lipid (LPO) products, epoxyketooctadecenoic acids (EKODEs) have emerged as intriguing molecules potential impacts on inflammatory EKODEs arise from linoleic acid reacting reactive oxygen nitrogen species present during inflammation. A hallmark LPO an electrophilic chemical functionality that...
The recognition between proteins and their native ligands is fundamental to biological function. In vivo, human ileal bile acid binding protein (I-BABP) encounters a range of salts that vary in the number position steroidal hydroxyl groups presence type side-chain conjugation. Therefore, it necessary understand how chemical variability ligand affects energetic structural aspects its recognition. Here we report studies site selectivity I-BABP for glycocholic (GCA) glycochenodeoxycholic (GCDA)...
Human ileal bile acid binding protein (I-BABP) is a member of the family intracellular lipid-binding proteins and thought to play role in enterohepatic circulation salts. Our group has previously shown that human I-BABP binds two molecules glycocholate (GCA) with low intrinsic affinity but an extraordinary high degree positive cooperativity. Besides strong cooperativity, exhibits site selectivity its interactions GCA glycochenodeoxycholate (GCDA), major salts humans. In this study, on basis...
Carotenoid cleavage oxygenases (CCOs) are non-heme iron enzymes that catalyze scission of alkene groups in carotenoids and stilbenoids to form biologically important products. CCOs possess a rare four-His center whose resting-state structure interaction with substrates incompletely understood. Here, we address this knowledge gap through comprehensive structural spectroscopic study three phyletically diverse CCOs. The crystal fungal stilbenoid-cleaving CCO, CAO1, reveals strong similarity...
Visual function in vertebrates critically depends on the continuous regeneration of visual pigments rod and cone photoreceptors. RPE65 is a well-established retinoid isomerase pigment epithelium that regenerates rhodopsin during cycle; however, its contribution to remains obscure. In this study, we use potent selective inhibitors rod- cone-dominant animal models discern role enzyme cone-mediated vision. We confirm retinylamine emixustat-family compounds selectively inhibit over DES1,...
The remodeling of a natural product core framework by means diversity-oriented synthesis (DOS) is valuable approach to access diverse/biologically relevant chemical space and overcome the limitations combinatorial-type compounds. Here we provide proof principle thorough conformational analysis for general strategy whereby inherent complexity starting material used define regio- stereochemical outcomes reactions in library construction. This contrast traditional DOS logic employing reaction...
Celastrol is an anti-inflammatory natural triterpenoid, isolated from the herb Tripterygium wilfordii or thunder god vine. Here, we define mechanisms mediating activity of celastrol and demonstrate efficacy a dietary supplement for chemoprevention inflammation-driven carcinogenesis in mice. Dietary (31.25 ppm rodent diet 8 weeks to 25 age) well tolerated protects against LPS-induced acute inflammation C57BL/6 mice, potently suppressing LPS-induction inducible nitric oxide synthase (iNOS),...
Human ileal bile acid binding protein (I-BABP) is a member of the intracellular lipid family. This thought to function in transcellular transport and enterohepatic circulation salts. I-BABP binds two molecules glycocholate, physiologically most abundant salt, with modest intrinsic affinity but remarkably high degree positive cooperativity. Here we report calorimetric analysis for broad panel salts human I-BABP. The interaction nine relevant derivatives cholic acid, chenodeoxycholic...
4-Hydroxyacids are ubiquitous in human physiology. They derived from the drugs of abuse γ-hydroxybutyrate (GHB), γ-hydroxypentanoate(GHP), addition to omnipresent lipid peroxidation product 4-hydroxy-2-(E)-nonenal (4-HNE). Previously we reported that 4-hydroxyacids catabolized through two parallel pathways. In this report detail isotopic tools have allowed dissection catabolic process and illustrate how these can be used quantify relative flux down each pathway. We found 4-hydroxynonanoate...
Modulators of the visual cycle have been developed for treatment various retinal disorders. These agents were designed to inhibit retinoid isomerase [retinal pigment epithelium-specific 65 kDa protein (RPE65)], rate-limiting enzyme cycle, based on idea that attenuation regeneration could reduce formation toxic conjugates. Of these agents, certain ones contain primary amine groups can also reversibly form retinaldehyde Schiff base adducts, which contributes their protective activity. Direct...
Triterpenoids comprise a very diverse family of polycyclic molecules that is well-known to possess myriad medicinal properties. Therefore, triterpenoids constitute an attractive target for chemistry and diversity-oriented synthesis. Photochemical transformations provide promising tool the rapid, green, inexpensive generation skeletal diversity in construction natural product-like libraries. With this mind, we have developed strategy, whereby parent bryonolic acid lanosterol are converted...