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Chitin synthase, a fungal glycosyltransferase that is a valuable antifungal target.

During the last 30 past years, more life-threatening fungal infections have appeared due to the increasing frequency of patients with weakened immune systems. Inhibition of fungal enzymes involved in the biosynthesis of sterols is considered to be a safe and effective option for antifungal therapy. However, the intensive use of sterol-biosynthesis inhibitors for years has resulted in resistance development. Consequently, the search for alternative therapeutics must be intensified. In this context, the biosynthesis of chitin, an essential component of the fungal cell wall that is absent in mamm

Metal inhibition of ferrochelatase.

Ferrochelatase activity was examined both in growing MEL cells and in in vitro assays of the purified enzyme to determine what effect a variety of divalent cations would have. Data obtained with the purified enzyme demonstrated that Mn2+ strongly inhibits the activity in a competitive fashion with respect to Fe2+ with a calculated Ki of 15 microM. Cadmium ion is also inhibitory (Ki: 50 microM), as is Hg2+ and arsenite, but Pb2+ is a poor inhibitor. All other metals tested had no effect. When these same metal ions were tested on differentiating MEL cells it was found that their ability to inhib

Least hemolytic, 12.6 kDa, plasmin-like fibrinolytic protease from marine Penicillium steckii KU1.

A novel fibrinolytic enzyme, from the marine fungus Penicillium steckii KU1, was purified to electrophoretic homogeneity. The fibrinolytic protease was purified to 13.56 times with a specific activity of 57.64 U/mg and final yield of 13.93 %. It was found to be a monomeric protein of 12.6 kDa, having optimum activity at 30 °C and pH 8.0. It is a plasmin-like enzyme, showing resemblance to ATP-dependent zinc metalloprotease with isoelectric point (pI) 8.0. Its activity is enhanced by Zn2+, and inhibited by ethylenediaminetetraacetic acid (EDTA), Co2+ and Fe2+. The enzyme interaction with substr

Characterization of two carbonyl reductases from Ogataea polymorpha NBRC 0799.

The enzyme responsible for the enantioselective production of (S)-1,1,1-trifluoro-2-propanol ((S)-TFP) from 1,1,1-trifluoroacetone (TFA) has been identified in Ogataea polymorpha NBRC 0799. We purified two carbonyl reductases, OpCRD-A and OpCRD-B from this strain, and revealed their characteristics. Both enzymes were specific to NADH, but the following characteristics were different: The molecular mass of subunit OpCRD-A was 40 kDa and that of OpCRD-B was 43 kDa. Amino acid sequences of both enzymes were only 21% identical. OpCRD-B contained 4 mol of zinc per mole of enzyme, but OpCRD-A did no

Dissemination of NDM metallo-β-lactamase genes among clinical isolates of Enterobacteriaceae collected during the SMART global surveillance study from 2008 to 2012.

The prevalence of carbapenemase enzymes continues to increase. Among the Ambler class B enzymes is the New Delhi metallo-β-lactamase (NDM). This particular enzyme is capable of hydrolyzing nearly all β-lactam antimicrobial agents and has spread rapidly, becoming a global problem. Therapeutic treatment options for patients infected with isolates which produce this enzyme are difficult to manage, as cross-resistance to other antimicrobial classes is common. The Study for Monitoring Antimicrobial Resistance Trends (SMART) is a global surveillance study evaluating the antimicrobial susceptibilitie

A model of tripeptidyl-peptidase I (CLN2), a ubiquitous and highly conserved member of the sedolisin family of serine-carboxyl peptidases.

BACKGROUND: Tripeptidyl-peptidase I, also known as CLN2, is a member of the family of sedolisins (serine-carboxyl peptidases). In humans, defects in expression of this enzyme lead to a fatal neurodegenerative disease, classical late-infantile neuronal ceroid lipofuscinosis. Similar enzymes have been found in the genomic sequences of several species, but neither systematic analyses of their distribution nor modeling of their structures have been previously attempted. RESULTS: We have analyzed the presence of orthologs of human CLN2 in the genomic sequences of a number of eukaryotic species. En

Clearance by the liver in cirrhosis. I. Relationship between propranolol metabolism in vitro and its extraction by the perfused liver in the rat.

To delineate the factors responsible for impaired clearance in cirrhosis, we examined propranolol disposition in rats with carbon tetrachloride-induced cirrhosis and compared it with that in control animals, rats treated with chlorpromazine (an inhibitor of propranolol metabolism) and rats with acute liver injury. We measured the extraction ratio of propranolol by the isolated perfused liver and related it to estimates of propranolol drug-metabolizing enzyme activity in homogenates of the same livers. In control animals, drug-metabolizing enzyme activity (measured as the ratio Vmax/Km) average

Abnormalities in pancreatic secretory profiles of patients with cancer of the pancreas.

Pancreatic secretory profiles for 11 pancreatic enzymes and proteins were established in nine patients with cancer of the pancreas by analysis of minute-to-minute collections of pure pancreatic juice after sequential administration of secretin and cholecystokinin. Aspiration of pancreatic fluid sufficient for this study was successful in less than one quarter of the patients investigated because of ductal obstruction and/or the effect of the disease on pancreatic exocrine function. Flow rates in patients generally were lower than in healthy individuals, and secretion of total protein, trypsin

Oxidative alterations of cyclooxygenase during atherogenesis.

Nitric oxide (*NO) and eicosanoids are critical mediators of physiological and pathophysiological processes. They include inflammation and atherosclerosis. *NO production and eicosanoid synthesis become disrupted during atherosclerosis and thus, it is important to understand the mechanisms that may contribute to this outcome. We, and others, have shown that nitrogen oxide (NO(x)) species modulate cyclooxygenase (COX; also known as prostaglandin H(2) synthase) activity and alter eicosanoid production. We have determined that peroxynitrite (ONOO(-)) has multiple effects on COX activity. ONOO(-)

Covalent alteration of the CYP3A4 active site: evidence for multiple substrate binding domains.

The inhibition of CYP3A4-mediated oxidation of triazolam and testosterone was assessed in the presence of a selection of known CYP3A4 substrates and inhibitors. Under experimental conditions where the Michaelis-Menten model predicts substrate-independent inhibition ([S] = K(m)), results yielded substrate-dependent inhibition. Moreover, when the same experimental design was extended to a group of structurally similar flavonoids it was observed that flavanone, flavone, 3-hydroxyflavone, and 6-hydroxyflavone (10 microM) activated triazolam metabolism, but inhibited testosterone hydroxylation. In

Effects of vitamins and common drugs on reduction of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in rat microsomes.

4-(Methylnitrosamino)-1-(3-pyridyl)-butanone (NNK) is a tobacco-specific nitrosamino that requires metabolic activation by cytochrome P450 enzymes. The activation of NNK by cytochrome P450 enzymes leads to the formation of different metabolites. Detoxification of NNK usually occurs via carbonyl reduction to its hydroxyl product, 4-(methylnitrosamino)-1-(3-pyridyl)-butanol (NNAL). In the present study, the influences of common vitamins and P450 modulators on the reduction of NNK by rat microsomes were studied. The formation of NNAL but not other metabolites was detected by the described HPLC me

Synthesis and antiparasitic and antitumor activity of 2, 4-diamino-6-(arylmethyl)-5,6,7,8-tetrahydroquinazoline analogues of piritrexim.

Nineteen previously undescribed 2,4-diamino-6-(arylmethyl)-5,6,7, 8-tetrahydroquinazolines (5a-m, 10-12) were synthesized as part of a larger effort to assess the therapeutic potential of lipophilic dihydrofolate reductase (DHFR) inhibitors against opportunistic infections of AIDS. Condensation of appropriately substituted (arylmethyl)triphenylphosphoranes with 4, 4-ethylenedioxycyclohexanone, followed by hydrogenation (H2/Pd-C) and acidolysis, yielded the corresponding 4-(arylmethyl)cyclohexanones, which were then condensed with cyanoguanidine to form the tetrahydroquinazolines. Three simple

Inhibitory effects of digoxin and ouabain on aldosterone synthesis in human adrenocortical NCI-H295 cells.

The present study was to investigate the effects and action mechanisms of digoxin and ouabain on steroidogenesis in human adrenocortical NCI-H295 cells. Administration of digoxin or ouabain for 24 h decreased the basal and angiotensin II (Ang II)-stimulated release of aldosterone by NCI-H295 cells. The conversions of corticosterone (substrate of cytochrome P450 aldosterone synthase, P450c11AS) to aldosterone or deoxycortisol (substrate of cytochrome P450 11beta-hydroxylase, P450c11beta) to cortisol were reduced by digoxin or ouabain. The basal and 22-hydroxy-cholesterol (a membrane-permeable c

Inhibitory and inducing effects of denzimol on carbamazepine metabolism in the rat.

In vivo and in vitro alterations in carbamazepine (CBZ) metabolism and the extent of enzyme induction of the hepatic cytochrome P-450 system after chronic oral denzimol to rats were evaluated. No effect on drug-metabolizing enzymes was detected for this new anticonvulsant drug at a dose of 15 mg/kg, which is just above the anticonvulsive dose. At higher doses (60 mg/kg) denzimol significantly raised the hepatic cytochrome P-450 content, enhanced CBZ clearance and tend to shorten its elimination t1/2 and that of its active metabolite. These results, combined with those of a previous study showi

Устранение неврологических расстройств путем борьбы с нейродегенеративными ассоциированными ферментами: естественные и синтетические молекулы.

Неврологические расстройства, включая нейродегенеративные и нейро-воспалительные заболевания, создают значительные проблемы в области здравоохранения и клинических проблем. Недавние исследования показали, что различные ферменты играют ключевую роль в наступлении и развитии этих расстройств. В этом обзоре изучается терапевтический потенциал адресации этих ферментов естественными и синтетическими молекулами. К таким заболеваниям, как болезнь Альцгеймера, болезнь Паркинсона и множественный склероз, причастны основные ферменты, включая ацетилхолинестеразу, оксидазу моноамина, бета-секретазу, тау к

Совпадение в аннотации оригинала
Neurological disorders, encompassing neurodegenerative and neuroinflammatory conditions, present significant public health and clinical chal … nzymes with precision. This review examines the progress in creating small molecules, peptides, and enzyme inhibitors through sophisticated drug design techniques. It evaluates the efficacy, safety, and mechanisms of these synthetic agents, highlighting their potential for clinical application. The review offers a comprehensive overview of recent advancements in en …

Computational approaches for designing viral protease inhibitors.

Viral proteases are critical enzymes that play essential roles in the replication of viruses such as Human Immunodeficiency, Hepatitis C, SARS-CoV-2, Zika, Dengue, West Nile, Yellow Fever, Japanese and Saint Louis Encephalitis, Tick-Born Encephalitis, Chikungunya, and others. Designing potent inhibitors against these proteases has been a major therapeutic strategy to control and treat these viral infections. Computational approaches, including structure-based drug design, ligand-based drug design, machine learning and artificial intelligence-based techniques, have significantly accelerated the

Structure and mechanism basis of β-lactam activity against Mycobacterium tuberculosis: A review of literature.

Tuberculosis (TB), caused by the infectious agent Mycobacterium tuberculosis (Mtb), has resulted in the highest mortality rates, even surpassing HIV/AIDS. The rise of Drug-resistant TB has worsened the health crisis and urgently requires new treatment approaches. The WHO has approved the repurposing of β-lactam in combination with β-lactamase (BlaC) inhibitor for treating MDR/XDR-TB. Numerous targets of β lactams present in the Mtb's cell wall are involved in its structural cytoskeleton, peptidoglycan (PG) biosynthesis. Delving into the mechanistic basis of β-lactam activity against Mtb has be

Enhanced Late INa Induces Intracellular Ion Disturbances and Automatic Activity in the Guinea Pig Pulmonary Vein Cardiomyocytes.

The effects of enhanced late INa, a persistent component of the Na+ channel current, on the intracellular ion dynamics and the automaticity of the pulmonary vein cardiomyocytes were studied with fluorescent microscopy. Anemonia viridis toxin II (ATX- II), an enhancer of late INa, caused increases in the basal Na+ and Ca2+ concentrations, increases in the number of Ca2+ sparks and Ca2+ waves, and the generation of repetitive Ca2+ transients. These phenomena were inhibited by eleclazine, a blocker of the late INa; SEA0400, an inhibitor of the Na+/Ca2+ exchanger (NCX); H89, a protein kinase A (PK

Abrocitinib in atopic dermatitis: review of the current literature and clinical trials.

Atopic dermatitis (AD) is an inflammatory chronic-relapsing skin disease affecting approximately 15% to 20% of children and 10% of adults in industrialized countries. Both loss of epidermal barrier permeability and immune dysregulation seem to be the most important actors in AD pathogenesis. Several studies have demonstrated the role of Janus kinase (JAK) enzymes in AD pathogenesis suggesting oral and topical JAK inhibitors as new emerging therapies for AD. Among the JAK inhibitors, abrocitinib is an oral JAK1-selective inhibitor. The aim of this study is reviewing current literature about the

X-ray crystal structure and specificity of the Toxoplasma gondii ME49 TgAPN2.

Toxoplasmosis is a parasitic disease caused by infection with Toxoplasma gondii that currently has few therapeutic options. The M1 aminopeptidase enzymes have been shown to be attractive targets for anti-parasitic agents and/or vaccine candidates, suggesting potential to re-purpose inhibitors between parasite M1 aminopeptidase targets. The M1 aminopeptidase TgAPN2 has been suggested to be a potential new drug target for toxoplasmosis. Here we investigate the structure and function of TgAPN2, a homologue of the antimalarial drug target PfA-M1, and evaluate the capacity to use inhibitors that ta