A5070404702- Enzyme function and inhibition
- Synthesis and Catalytic Reactions
- Chemical Reactions and Mechanisms
- Phenothiazines and Benzothiazines Synthesis and Activities
- Cholinesterase and Neurodegenerative Diseases
- Virology and Viral Diseases
- Enzyme Structure and Function
- Viral Infections and Vectors
- Virus-based gene therapy research
- Hemoglobin structure and function
- Chemical Reactions and Isotopes
- Crystallization and Solubility Studies
- Chemical Reaction Mechanisms
- MicroRNA in disease regulation
- Phosphodiesterase function and regulation
- RNA Interference and Gene Delivery
- Respiratory viral infections research
- HIV Research and Treatment
- Amino Acid Enzymes and Metabolism
- Biochemical and Molecular Research
- Metal-Catalyzed Oxygenation Mechanisms
- Electrochemical sensors and biosensors
- Recommender Systems and Techniques
- Freezing and Crystallization Processes
- Cloud Computing and Resource Management
Sawai ManSingh Medical College and Hospital
2022
Guru Gobind Singh Indraprastha University
2022
Oak Ridge National Laboratory
2014-2018
University of Florida
2011-2016
Florida College
2012-2016
North Carolina Biotechnology Center
2010
University of Florence
2010
Claflin University
2008-2009
A series of dithiocarbamates were prepared by reaction primary/secondary amines with carbon disulfide in the presence bases. These compounds tested for inhibition four human (h) isoforms zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX, and XII, involved pathologies such as glaucoma (CA II XII) or cancer IX). Several low nanomolar inhibitors targeting these CAs detected. The X-ray crystal structure adduct morpholine dithiocarbamate evidenced mechanism compounds, which...
4-Substituted-ureido benzenesulfonamides showing inhibitory activity against carbonic anhydrase (CA, EC 4.2.1.1) II between 3.3–226 nM were crystallized in complex with the enzyme. Hydrophobic interactions scaffold of inhibitors different hydrophobic pockets enzyme observed, explaining diverse range these derivatives.
The zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) is inhibited by several classes of zinc-binders (sulfonamides, sulfamates, and sulfamides) as well compounds which do not interact with the metal ion (phenols, polyamines coumarins). Here we report a new class potent CA inhibitors bind ion: dithiocarbamates (DTCs). They coordinate to from active site in monodentate manner establish many favorable interactions amino acid residues nearby. Several low nanomolar I, II IX were detected.
Carbonic anhydrases (CAs) catalyze the hydration of CO(2) forming HCO(3)(-) and a proton, an important reaction for many physiological processes including respiration, fluid secretion, pH regulation. As such, CA isoforms are prominent clinical targets treating various diseases. The clinically used acetazolamide (AZM) is sulfonamide that binds with high affinity to human isoform II (HCA II). There several X-ray structures available AZM bound isoforms, but these complexes do not show charged...
Aromatic amides comprising branched aliphatic carboxylic acids and 4-aminobenzenesulfonamide were evaluated for their inhibition of carbonic anhydrase (CA) isoforms. Of the most anticonvulsant-active compounds (2, 4, 13, 16, 17), only 17 potent inhibitors CAs VII XIV. Compounds 9, 14, 19 inhibited CA II, while 10 12 all Structural studies suggest that differences in active sites' hydrophobicity modulate affinity inhibitors.
Rapid exchange of metabolites between different cell types is crucial for energy homeostasis the brain. Besides glucose, lactate a major metabolite in brain and primarily produced astrocytes. In present study, we report that carbonic anhydrase 2 (CAII) enhances both influx efflux mouse cerebellar The augmentation transport independent enzyme's catalytic activity, but requires direct binding CAII to C-terminal monocarboxylate transporter MCT1, one lactate/proton cotransporters astrocytes most...
A series of novel benzene- and 2,3,5,6-tetrafluorobenzenesulfonamide was synthesized by using a click chemistry approach starting from azido-substituted sulfonamides alkynes, incorporating aryl, alkyl, cycloalkyl, amino-/hydroxy-/halogenoalkyl moieties. The new compounds were medium potency inhibitors the cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isoforms I II low nanomolar/subnanomolar tumor-associated hCA IX XII isoforms. X-ray crystal structure two such in adduct with allowed us to...
Carbonic anhydrases (CAs) are ubiquitous enzymes that catalyze the reversible hydration/dehydration of carbon dioxide/bicarbonate. As such, there is enormous industrial interest in using CA as a bio-catalyst for sequestration and biofuel production. However, to ensure cost-effective use enzyme under harsh conditions, studies were initiated produce variants with enhanced thermostability while retaining high solubility catalytic activity. Kinetic structural conducted determine functional...
Variants of human carbonic anhydrase II (HCA II) with amino acid replacements at residues in contact water molecules the active-site cavity have provided insights into proton transfer rates this protein environment. X-ray crystallography and (18)O exchange measured by membrane inlet mass spectrometry been used to investigate structural catalytic properties variants HCA containing Tyr7 Phe (Y7F) Asn67 Gln (N67Q). The rate constants for a from His64 zinc-bound hydroxide during catalysis were 4...
Carbonic anhydrases (CAs; EC 4.2.1.1) catalyze the interconversion of CO 2 and HCO 3 − , their inhibitors have long been used as diuretics a therapeutic treatment for many disorders such glaucoma epilepsy. Acetazolamide (AZM) methazolamide (MZM, methyl derivative AZM) are two classical CA inhibitory drugs that clinically decades. The jointly refined X-ray/neutron structure MZM in complex with human isoform II (hCA II) has determined to resolution 2.2 Å an R cryst ∼16.0%. Presented this...
Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous isozymes involved in crucial physiological and pathological events, representing the targets of inhibitors with several therapeutic applications. In this connection, we report a new class carbonic anhydrase inhibitors, based on thiopyrano-fused pyrazole scaffold to which pendant 4-sulfamoylphenyl moiety was attached. The sulfonamides 3a–e were designed as constrained analogues celecoxib valdecoxib. most interesting feature 3 their...
Human carbonic anhydrases (CAs) are zinc metalloenzymes that catalyze the hydration and dehydration of CO 2 HCO 3 − , respectively. The reaction follows a ping-pong mechanism, in which rate-limiting step is transfer proton from zinc-bound solvent (OH /H O) in/out active site via His64, widely believed to be proton-shuttling residue. decreased catalytic activity (∼20-fold lower with respect wild type) variant CA II His64 replaced Ala (H64A II) can enhanced by exogenous donors/acceptors,...
Carbonic anhydrases (CAs) are enzymes that catalyze the hydration/dehydration of CO2/HCO3– with rates approaching diffusion-controlled limits (kcat/KM ∼ 108 M–1 s–1). This family has evolved disparate protein folds all perform same reaction at near catalytic perfection. Presented here is a structural study β-CA (psCA3) expressed in Pseudomonas aeruginosa, complex CO2, using pressurized cryo-cooled crystallography. The structure been refined to 1.6 Å resolution Rcryst and Rfree values 17.3...
One of the most fascinating discoveries in biology recent years is unquestionably identification family small, noncoding RNAs known as microRNAs (miRNAs). Each miRNA targets multiple mRNA species through recognition complementary sequences, typically located at sites within 3 untranslated region. In animals, single-stranded binds specific messenger RNA (mRNA) by a mechanism that yet to be fully characterized. The bound remains resulting reduced levels corresponding protein; however, if...
Pseudomonas aeruginosa is a Gram-negative facultative anaerobe belonging to the Pseudomonadaceae family. It multidrug-resistant opportunistic human pathogen, common cause of life-threatening nosocomial infections, and key bacterial agent in cystic fibrosis endocarditis. The bacterium exhibits intrinsic resistance most antibacterial agents, including aminoglycosides quinolones. Hence, identification new drug targets for P. ongoing. PsCA3 β-class carbonic anhydrase (β-CA) that catalyzes...
Human carbonic anhydrase (CA; EC 4.2.1.1) isoform IX (CA IX) is an extracellular zinc metalloenzyme that catalyzes the reversible hydration of CO 2 to HCO 3 − , thereby playing a role in pH regulation. The majority normal functioning cells exhibit low-level expression CA IX. However, cancer upregulated as consequence metabolic transition known Warburg effect. upregulation for progression has drawn interest it being potential therapeutic target. transmembrane protein, and its purification,...
Protein X-ray crystallography has seen a progressive shift from data collection at cool/room temperature (277-298 K) to cryotemperature (100 because of its ease crystal preparation and the lessening detrimental effects radiation-induced damage, with 20-25%(v/v) glycerol (GOL) being preferred choice cryoprotectant. Here, case study cryoprotectants on kinetics carbonic anhydrase II (CA II) inhibition by clinically used inhibitor acetazolamide (AZM) is presented. Comparative studies structure,...
Cryoannealing has been demonstrated to improve the diffraction quality and resolution of crystals β-carbonic anhydrase psCA3 concomitant with a change in space group. After initial flash-cooling liquid-nitrogen cryostream an X-ray data set from crystal was indexed group P 2 1 scaled 2.6 Å resolution, but subsequent cryoannealing studies revealed induced protein rearrangements contacts, which transformed I 222, corresponding improvement 0.7 resolution. Although significant, only minor changes...