Carbonic Anhydrase Inhibition with Sulfonamides Incorporating Pyrazole- and Pyridazinecarboxamide Moieties Provides Examples of Isoform-Selective Inhibitors

A series of benzenesulfonamides incorporating pyrazole- and pyridazinecarboxamides decorated with several bulky moieties has been obtained by original procedures. The new derivatives were investigated for the inhibition of four physiologically crucial human carbonic anhydrase (hCA, EC 4.2.2.1.1) isoforms, hCA I and II (cytosolic enzymes) as well as hCA IX and XII (transmembrane, tumor-associated isoforms). Examples of isoform-selective inhibitors were obtained for all four enzymes investigated here, and a computational approach was employed for explaining the observed selectivity, which may be useful in drug design approaches for obtaining inhibitors with pharmacological applications useful as antiglaucoma, diuretic, antitumor or anti-cerebral ischemia drugs.

Diagnostic algorithm for comorbidity of babesiosis and dirofilariasis in dogs, taking into account the correlation of redox homeostasis and morphofunctional disorders of the hepatorenal and cardiopulmonary systems

Activation of lipid peroxidation due to a disorder of redox homeostasis in dogs with comorbidity of babesiosis and dirofilariasis causes the involvement of not only the components of the hepatorenal system, but also the cardiopulmonary system in the pathological process against the background of the development of intoxication and hypoxic phenomena in hepatocytes and cardiomyocytes. As a result of the conducted biochemical studies of the blood of sick animals, it was found that the degree of redox homeostasis disorders directly correlates with the nature of morphofunctional disorders of the hepatorenal and cardiopulmonary systems, and the degree of these changes in the systems has an inverse correlation and is determined by the release of cytosolic enzymes into the blood. The involvement of the components of the hepatobiliary system in the pathological process is accompanied by a disorder of protein, carbohydrate, lipid and pigment metabolism.

Hydrogen sulphide synthesis (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Hydrogen sulfide is a gasotransmitter, with similarities to nitric oxide and carbon monoxide. Although the enzymes indicated below have multiple enzymatic activities, the focus here is the generation of hydrogen sulphide (H2S) and the enzymatic characteristics are described accordingly. Cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) are pyridoxal phosphate (PLP)-dependent enzymes. 3-mercaptopyruvate sulfurtransferase (3-MPST) functions to generate H2S; only CAT is PLP-dependent, while 3-MPST is not. Thus, this third pathway is sometimes referred to as PLP-independent. CBS and CSE are predominantly cytosolic enzymes, while 3-MPST is found both in the cytosol and the mitochondria. For an authoritative review on the pharmacological modulation of H2S levels, see Szabo and Papapetropoulos, 2017 [4].

Modification of thiamine pyrophosphate dependent enzyme activity by oxythiamine in Saccharomyces cerevisiae cells

Oxythiamine is an antivitamin derivative of thiamine that after phosphorylation to oxythiamine pyro phos phate can bind to the active centres of thiamine-dependent enzymes. In the present study, the effect of oxythiamine on the viability of Saccharomyces cerevisiae and the activity of thiamine pyrophosphate dependent enzymes in yeast cells has been investigated. We observed a decrease in pyruvate decarboxylase specific activity on both a control and an oxythiamine medium after the first 6 h of culture. The cytosolic enzymes transketolase and pyruvate decarboxylase decreased their specific activity in the presence of oxythiamine but only during the beginning of the cultivation. However, after 12 h of cultivation, oxythiamine-treated cells showed higher specific activity of cytosolic enzymes. More over, it was established by SDS–PAGE that the high specific activity of pyruvate decarboxylase was followed by an increase in the amount of the enzyme protein. In contrast, the mitochondrial enzymes, pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes, were inhibited by oxythiamine during the entire experiment. Our results suggest that the observed strong decrease in growth rate and viability of yeast on medium with oxythiamine may be due to stronger in hibition of mitochondrial pyruvate dehydrogenase than of cytosolic enzymes.Key words: pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase, transketolase, pyruvate decarboxylase, activity, oxythiamine, inhibition.