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Tubular Function
Published in Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal, Principles of Physiology for the Anaesthetist, 2020
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal
Intracellular carbonic anhydrase catalyses the reaction between carbon dioxide and water to form carbonic acid. In the proximal tubule, carbonic anhydrase is also present in the luminal cell membrane, where it catalyses the breakdown of carbonic acid to water and carbon dioxide.
Therapeutic Use of Carbonic Anhydrase Inhibitors and Their Multiple Drug Interactions
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Andrea Angeli, Claudiu T. Supuran
The systemic carbonic anhydrase inhibitor, acetazolamide (1), was initially discovered as a diuretic agent (Supuran, 2008; Neri and Supuran, 2011) and introduced in 1954 into ophthalmology as a treatment for glaucoma and, since then, has been widely used for this purpose. At first, its clinical use as diuretic drug is limited to development of metabolic acidosis (Kassamali and Sica, 2011). However, this feature can afford some potential clinical benefit for disease states such as metabolic alkalosis (Faisy et al., 2010; Mazur et al., 1999) nephrolithiasis (Sterrett et al., 2008), rhabdomyolysis (Subbaramaiah et al., 2010; Davidov et al., 2006), contrast-induced nephropathy (CIN) (Pakfetrat et al., 2009), sleep apnea (Nakayama et al., 2002; Angeli and Supuran, 2018), and high-altitude erythropoiesis (Leaf and Goldfarb, 2007; Richalet et al., 2008). In subsequent years the systemic side effects of acetazolamide led to the development of new CAIs such as brinzolamide 3 and dorzolamide 4 (Fig. 3.2) with their high water solubility are administered via the topical route directly into the eye, making them less prone to drug-drug interactions and systemic side effects (Carta et al., 2012; Masini et al., 2013).
Carbonic Anhydrase
Published in Masahiko Mori, Histochemistry of the Salivary Glands, 2019
Carbonic anhydrase (CA) catalyzes the interconversion of carbon dioxide and bicarbonate; the reaction is thought to regulate cellular activity regarding CO2 exchange, secretion of ions, calcification, and pH balances. CA is widely distributed in several mammalian tissues as revealed by biochemical and histochemical studies. The biochemical significances of CA in salivary glands include the membrane transport of CO2 ions into saliva1,2 and the participation in glandular secretions.3–5 The isoenzymes of CA in mammalian cells have been separated and designated CA I, CA II, and CA III. CA I and CA II have molecular weights of about 30,000. CA I has low and CA II has high activity. Fine et al.6 stated that CA I and CA II exhibit no cross activity; however, immunosera against human CA I, human CA II, and bovine CA II showed cross reaction to other mammalian species. The first histochemical detection of CA used the cobalt-bicarbonate technique.7 A modification of the cobalt-bicarbonate method of Häussier8 and Hansson9 uses floating sections; however, these methods occasionally develop artifacts.10 Other immunohistochemical methods for detecting CA and isoenzymes have used immunofluorescein-labeled antibody and peroxidase immunoglobulin methods. Many tissues and organs in mammals including man contain CA isoenzymes with varying intensities.3,5,11,12
Identification of new 4-(6-oxopyridazin-1-yl)benzenesulfonamides as multi-target anti-inflammatory agents targeting carbonic anhydrase, COX-2 and 5-LOX enzymes: synthesis, biological evaluations and modelling insights
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Waleed A. Badawi, Mahmoud Rashed, Alessio Nocentini, Alessandro Bonardi, Mohammad M. Abd-Alhaseeb, Sara T. Al-Rashood, Giri Babu Veerakanellore, Taghreed A. Majrashi, Eslam B. Elkaeed, Bahaa Elgendy, Paola Gratteri, Claudiu T. Supuran, Wagdy M. Eldehna, Mohamed Elagawany
Carbonic anhydrases (EC 4.2.1.1) are metalloenzymes that have a metal ion in their active site.1 CAs were thoroughly studied for decades and were classified as a superfamily of enzymes with eight gene families or classes to date.2 There are basically several cytosolic forms (CA I-III, CA VII), four membrane-bound isozymes (CA IV, CA IX, CA XII, and CA XIV), a mitochondrial form (CA V), and a secreted CA isozyme, CA VI.3 Carbonic anhydrase is involved in diverse physiological and pathological processes including lipogenesis, gluconeogenesis, and tumorigenicity.4 One of the major biochemical reactions involved in proton generation in resting tissues is mediated by carbonic anhydrase (CA) enzymes.5 They are known for their ability to catalyse the reversible hydration of carbon dioxide (CO2 + H2O ⟺ H+ + HCO3−) and have also been extensively demonstrated in a plethora of physiological events at the cellular and tissue levels.6 Numerous CA isoforms have evolved because uncatalyzed transformation is unable to meet the physiological cells' needs.7,8
Carbonic anhydrase inhibitory activity of phthalimide-capped benzene sulphonamide derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Deepak Shilkar, Mohd Usman Mohd Siddique, Silvia Bua, Sabina Yasmin, Mrunali Patil, Ajay Kumar Timiri, Claudiu T. Supuran, Venkatesan Jayaprakash
All CA families catalyse the reversible hydration of carbon dioxide. The active site of α-CAs consists of a zinc ion coordinated to three histidine residues and a water molecule. The water molecule acts as a nucleophile and attacks the carbon dioxide molecule, forming bicarbonate and a proton. The proton is then released into the solvent through a network of hydrogen bonds involving other amino acid residues such as glutamate and asparagine. The active site of carbonic anhydrase is highly conserved among different isoforms and species, indicating its functional importance7. Human carbonic anhydrase II (hCA II), one of the most extensively investigated isoforms, possesses an active site comprising a zinc ion (Zn2+) coordinated to three histidine residues (His94, His96, and His119) and a water molecule or hydroxide ion8. In coordination with these residues, the zinc ion coordinated water/hydroxide serves as a nucleophilic catalyst for enzymatic activity. Apart from zinc-binding histidines, residues in proximity to the active site are involved in substrate/inhibitor orientation. Glu106 establishes a hydrogen-bond network with Thr199 that is crucial for catalysis9–11. Additionally, a hydrophobic pocket encompassing Val121, Leu198, and Val143 influences substrate binding and modulates enzyme function10.
Emerging drugs for the treatment of glaucoma: a review of phase II & III trials
Published in Expert Opinion on Emerging Drugs, 2022
Tyler M. Kaplan, Arthur J. Sit
Carbonic anhydrase inhibitors (CAI) include topical dorzolamide and brinzolamide, and systemic acetazolamide and methazolamide. They inhibit aqueous humor production by reducing the formation of sodium and bicarbonate ions, which subsequently decreases water inflow [63]. Topical CAIs reduce IOP by approximately 15–20% [64] while systemic CAIs reduce IOP by up to 40% [4]. They have an acidic pH (5.5–5.9) thus frequently cause ocular irritation and punctate keratopathy [4]. Systemic CAIs more frequently cause systemic side-effects such as nephrolithiasis, hypokalemia, metabolic acidosis, bitter taste, anorexia, paresthesia, and perioral numbness [65]. Due to their risk of metabolic acidosis, systemic usage should be avoided in patients with sickle cell disease due to the risk of inducing a sickling crisis [11,66].