It is not clear whether the other reactions catalyzed by CAs (Figure 1.1) except for CO2 hydration/bicarbonate dehydration have physiological relevance (Supuran et al. 2003). Thus, at present, only the reaction in Equation 1.1, Figure 1.1, is considered to be the physiological one in which these enzymes are involved.
In prokaryotes, CAs possess two general functions: (1) transport of CO2/bicar-bonate between different tissues of the organism and (2) provide CO2/bicarbonate for enzymatic reactions (Smith and Ferry 2000). In aquatic photosynthetic organisms, an additional role is that of a CO2-concentrating mechanism, which helps overcome CO2 limitation in the environment (Badger and Price 1994; Park et al. 1999). For example, in Chlamydomonas reinhardtii, this CO2-concentrating mechanism is maintained by the pH gradient created across the chloroplast thylakoid membranes by Photosystem II-mediated electron transport processes (Park et al. 1999).
Many nonphotosynthesizing prokaryotes catalyze reactions for which CA are expected to provide CO2/bicarbonate in the vicinity of the active site or to remove such compounds to improve the energetics of the reaction (Smith and Ferry 2000). Smith and Ferry (2000) have reviewed many carboxylation/decarboxylation processes in which prokaryotic CAs might play such an important physiological function.
In higher organisms, including vertebrates, the physiological functions of CAs have been widely investigated over the last 70 years (Maren 1967; Chegwidden and Carter 2000; Supuran et al. 2003). Thus, isozymes I, II and IV are involved in respiration and regulation of the acid/base homeostasis (Maren 1967; Chegwidden and Carter 2000; Supuran et al. 2003). These complex processes involve both the transport of CO2/bicarbonate between metabolizing tissues and excretion sites (lungs, kidneys), facilitated CO2 elimination in capillaries and pulmonary microvas-culature, elimination of H+ ions in the renal tubules and collecting ducts, as well as reabsorption of bicarbonate in the brush border and thick ascending Henle loop in kidneys (Maren 1967; Chegwidden and Carter 2000; Supuran et al. 2003). Usually, isozymes I, II and IV are involved in these processes. By producing the bicarbonate-rich aqueous humor secretion (mediated by ciliary processes isozymes CA II and CA IV) within the eye, CAs are involved in vision, and their misfunctioning leads to high intraocular pressure and glaucoma (Maren 1967; Supuran et al. 2003). CA II is also involved in bone development and function, such as differentiation of osteoclasts or providing acid for bone resorption in osteoclasts (Chegwidden and Carter 2000; Supuran et al. 2003). CAs are involved in the secretion of electrolytes in many other tissues and organs, such as CSF formation, by providing bicarbonate and regulating the pH in the choroid plexus (Maren 1967; Supuran et al. 2003); saliva production in acinar and ductal cells (Parkkila 2000); gastric acid production in the stomach parietal cells (Parkkila 2000; see also Chapter 10); and bile production, pancreatic juice production, intestinal ion transport (Parkkila 2000; Maren 1967; see also Chapter 10). CAs are also involved in gustation and olfaction, protecting the gastrointestinal tract from extreme pH conditions (too acidic or too basic), regulating pH and bicarbonate concentration in the seminal fluid, muscle functions and adapting to cellular stress (Chegwidden and Carter 2000; Parkkila 2000; Supuran et al. 2003). Some isozymes, e.g., CA V, are involved in molecular signaling processes, such as insulin secretion signaling in pancreas P cells (Parkkila 2000). Isozymes II and V are involved in important metabolic processes by providing bicarbonate for gluconeogenesis, fatty acids de novo biosynthesis or pyrimidine base synthesis (Chegwidden et al. 2000). Finally, some isozymes (e.g., CA IX, CA XII, CARP VIII) are highly abundant in tumors, being involved in oncogenesis and tumor progression (Pastorek et al. 1994; Chegwidden et al. 2001; Supuran et al. 2003; see also Chapter 9).
Although the physiological function of some isozymes (CA I, CA III, CARPs) is still unclear, the data presented here helps understand the importance of CAs in a host of physiological processes, both in normal and pathological states. This might explain why inhibitors of these enzymes found a place in clinical medicine by as early as 1954, with acetazolamide (1.1) being the first nonmercurial diuretic agent used clinically (Maren 1967). At present, inhibitors of these enzymes are widely used clinically as antiglaucoma agents, diuretics, antiepileptics, to manage mountain sickness and for gastric and duodenal ulcers, neurological disorders, or osteoporosis. The development of more specific agents is required because of the high number of isozymes present in the human body as well as the isolation of many new representatives of CAs from all kingdoms. This is possible only by understanding in detail the catalytic and inhibition mechanisms of these enzymes. These enzymes and their inhibitors are indeed remarkable — after many years of intense research in this field, they continue to offer interesting opportunities to develop novel drugs and new diagnostic tools or to understanding in greater depth the fundamental processes of the life sciences.
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