Oxidoreductase Inhibitors

Enzyme-catalyzed redox reactions use various cofactors to accomplish the electron or hydride transfer from the oxidized to the reduced group. The most important cofactors are dinucleotides, such as nicotinamide NAD(P)+ or flavine derivatives and the iron-containing protoporphyrin system in heme enzymes. Nicotinamide is an N-substituted pyridine derivative that either accepts or releases a hydride ion at the 4-position. The cofactor often binds to a conserved Rossmann fold motif. Dihydrofolate reductase is involved in the biosynthesis of thymine. Inhibitors that compete for the binding site of the natural substrate dihydrofolate are potent chemotherapeutic or bacteriostatic agents. HMG-CoA reductase inhibitors (statins) are used to lower blood cholesterol levels in the treatment of coronary heart disease and atherosclerosis. They occupy the cofactor binding site and became the best-selling drugs of all time. Aldose reductase is involved in the polyol pathway by which glucose is metabolized to sorbitol and fructose. The long-term consequences of poorly controlled blood glucose levels in diabetes preferentially affect cells that do not control glucose uptake by insulin. Inhibition of aldose reductase is a viable principle for reducing long-term complications. The enzyme has a highly adaptable binding pocket, allowing the development of inhibitors with very different scaffolds and binding modes. Cortisol is converted to cortisone and vice versa by two isoforms of 11β-hydroxysteroid dehydrogenase. Inhibition of the first enzyme is a promising therapeutic concept for the treatment of metabolic syndrome. Cytochrome P450 enzymes are monooxygenases that carry out biochemical transformations by adding oxygen to a substrate. They are involved in the metabolism of xenobiotics. They are highly adaptable to substrates of varying sizes and can be inhibited by drug molecules containing heteroaromatic rings. Their expression can be induced and upregulated by xenobiotics that activate the PXR transcription factor. The P450 enzyme load varies with genotype and phenotype, resulting in different metabolic behaviors in different individuals, giving rise to slow, extensive, and fast metabolizers. This has implications for the prescription and required dose of drugs metabolized by CYPs. Inhibition and induction of CYPs may affect the level of concomitant medications and require dose adjustments to avoid unwanted and dangerous side effects or unexpected failure of the drug. Monoamine oxidases MAOA and MAOB are FAD-dependent oxidases and metabolize important neurotransmitters. Their inhibition can treat depression, Alzheimer’s disease and Parkinson’s disease. Most current MAO inhibitors bind covalently to the FAD cofactor and alter its redox properties. Membrane associated cyclooxygenases synthesize prostaglandin precursors from arachidonic acid. Prostaglandins are paracrine hormones and serve as inflammatory mediators. COXs contain a heme center that can be inhibited by non-steroidal anti-inflammatory drugs such as acetylsalicylic acid, ibuprofen, indomethacin, or diclofenac. They block access of the natural substrate, arachidonic acid to the reaction channel. Acetylsalicylic acid irreversibly transfers its acetyl group to a channel-exposed Ser residue. Two isoforms exist, COX-1, which is ubiquitously expressed and constitutively present in all tissues, and COX-2, which is induced in inflamed tissues. Because of its multiple involvement in many physiological processes, overdosage of COX-1 inhibitors can cause serious side effects. COX-1 and COX-2 differ in the reaction channel by an exchange of isoleucine for valine. The additional volume in COX-2 led to the development of the extended furcated inhibitors, the coxibs. Their indications range from rheumatism, osteoarthritis, chronic polyarthritis to ankylosing spondylitis, all of which are associated with severe pain. https://sn.pub/x4cyhg