A5011454018- Biotin and Related Studies
- Histone Deacetylase Inhibitors Research
- Photosynthetic Processes and Mechanisms
- Sirtuins and Resveratrol in Medicine
- Tryptophan and brain disorders
- Amino Acid Enzymes and Metabolism
- Autophagy in Disease and Therapy
- Radiopharmaceutical Chemistry and Applications
- Dye analysis and toxicity
- Plant biochemistry and biosynthesis
- Biochemical Acid Research Studies
- Microbial Metabolic Engineering and Bioproduction
- Microbial metabolism and enzyme function
- Nicotinic Acetylcholine Receptors Study
- Botulinum Toxin and Related Neurological Disorders
- Microbial Natural Products and Biosynthesis
- Ion channel regulation and function
- Microbial Metabolism and Applications
- Genetic Neurodegenerative Diseases
- Bacterial Genetics and Biotechnology
- Carbon and Quantum Dots Applications
- Bipolar Disorder and Treatment
- Neuroinflammation and Neurodegeneration Mechanisms
- Synthesis and Biological Evaluation
- Neuroscience and Neuropharmacology Research
California University of Pennsylvania
2023
Boston University
2016-2023
University of Pennsylvania
2022-2023
University of Maryland, Baltimore
2013-2017
Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the kynurenine pathway (KP) of tryptophan degradation, has been suggested to play major role physiological and pathological events involving bioactive KP metabolites. To explore this greater detail, we generated mice with targeted genetic disruption Kmo present here first biochemical neurochemical characterization these mutant animals. Kmo−/− lacked KMO activity but showed no obvious abnormalities four additional enzymes tested. As...
Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with pathogenesis cancer neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report design, synthesis, biological characterization first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools inhibition deacetylation. Using biochemical
Botulinum neurotoxins have remarkable persistence (∼weeks to months in cells), outlasting the small-molecule inhibitors designed target them. To address this disconnect, bearing two pharmacophores-a zinc binding group and a Cys-reactive warhead-were leverage both affinity reactivity. A series of first-generation bifunctional was achieved through structure-based inhibitor design. Through X-ray crystallography, engagement catalytic Zn
The first structure of nicotine oxidoreductase (NicA2) was determined by X-ray crystallography. Pseudomonas putida has evolved nicotine-degrading activity to provide a source carbon and nitrogen. establishes NicA2 as member the monoamine oxidase family. Residues 1–50 are disordered may play role in localization. nicotine-binding site proximal isoalloxazine ring flavin shows an unusual composition classical aromatic cage (W427 N462). active architecture is consistent with proposed binding...
Nicotine oxidoreductase (NicA2) is a bacterial flavoenzyme, which catalyzes the first step of nicotine catabolism by oxidizing S-nicotine into N-methyl-myosmine. It has been proposed as biotherapeutic for addiction because its nanomolar substrate binding affinity. The crystal structure NicA2 reported, establishing member monoamine oxidase (MAO) family. However, specificity and structural determinants and/or catalysis have not explored. Herein, analysis pH–rate profile, single-turnover...
Monoamine oxidases (MAOs) play a key role in the breakdown of primary and secondary amines. In eukaryotic organisms, these enzymes are vital to regulation monoamine neurotransmitters degradation dietary monoamines. MAOs have also been identified prokaryotic species, although their organisms is not well understood. Here, we report biophysical structural properties promiscuous, bacterial MAO from Corynebacterium ammoniagenes (caMAO). caMAO catalyzes oxidation number substrates including...
In Pseudomonas putida, the flavoprotein nicotine oxidoreductase (NicA2) catalyzes oxidation of (S)-nicotine to N-methyl-myosmine, which is nonenzymatically hydrolyzed pseudooxynicotine. Structural analysis reveals a monoamine oxidase (MAO)-like fold with conserved FAD-binding domain and variable substrate-binding domain. The flavoenzyme has unique variation classic aromatic cage flanking residue pair W427/N462. Previous mechanistic studies using O2 as oxidizing substrate show that NicA2 low...
3-Hydroxyanthranilic acid 3,4-dioxygenase (3-HAO) is the enzyme responsible for production of neurotoxic tryptophan metabolite quinolinic (QUIN). Elevated brain levels QUIN are observed in several neurodegenerative diseases, but pharmacological investigation on its role pathogenesis these conditions difficult because only one class substrate-analogue 3-HAO inhibitors, with poor chemical stability, has been reported so far. Here we describe design, synthesis, and biological evaluation a novel...
The fungal species Aspergillus flavus produces an alkaloid terpenoid, flavunoidine, through a hybrid biosynthetic pathway combining both terpene cyclase and nonribosomal peptide synthetase enzymes. Flavunoidine consists of tetracyclic, oxygenated sesquiterpene core decorated with dimethyl cadaverine 5,5-dimethyl-l-pipecolate moieties. Unique to the flavunoidine is FlvF, putative enzyme implicated in stereospecific C-N bond formation as linked generate pre-flavunoidine. Here, we report 2.6 Å...
Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with pathogenesis cancer neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report design, synthesis, biological characterization first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools inhibition deacetylation. Using biochemical in vitro assays cell-based methods target engagement, identified Mz325 (31) a...
Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with pathogenesis cancer neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report design, synthesis, biological characterization first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools inhibition deacetylation. Using biochemical in vitro assays cell-based methods target engagement, identified Mz325 (31) a...
Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with pathogenesis cancer neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report design, synthesis, biological characterization first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools inhibition deacetylation. Using biochemical in vitro assays cell-based methods target engagement, identified Mz325 (33) a...
The glucose biosensor, built upon the redox enzyme oxidase, is most commercially successful and studied enzymatic biosensor. However, lack of available functionally validated enzymes prohibiting development redox-based sensors for other important analytes. Herein, we present assessment an electrochemical nicotine using genomic screening to identify gene a known catabolizing enzyme. resulting biosensor demonstrated specific, sensitive, stable operational profile with limit detection 27 μM...
Natural products generated by biosynthetic enzymes provide complex structural diversity. Several fungal species have evolved to obtain this diversity combining several core in a pathway, including polyketide synthases (PKS), nonribosonal peptides (NRPS), and terpene cyclases (TC) along with accessorizing such as transferases oxidoreductases. Combinations of different hybrid gene clusters affords structurally scaffolds unachievable single enzyme. Recently, the Tang laboratory characterized...