Carbonic Anhydrases

Carbonic anhydrase (CA) is a seemingly ubiquitous enzyme of profound physiological importance, which plays essential roles in respiration, acid-base homeostasis, bone resorption, calcification, photosynthesis, several biosynthetic pathways and a variety of processes involving ion, gas and fluid transfer. This enzyme, which is present in at least three gene families (a, ß, ?), has found favour as a model for the study of evolution of gene families and for site-directed mutagenesis in structure/function relationships, for protein folding and for transgenic and gene target studies. Since the early use of CA inhibitors as diuretics and in treating congestive heart failure, the enzyme has been target of considerable clinical attention. Much of this is now focused on endeavours to produce a new generation of such drugs for the effective treatment of glaucoma and other potential applications. Recent data, suggesting links between CA and various disease processes, including cancer, have stimulated further...

This book offers deep insights into the thermodynamics and molecular structures of the twelve catalytically active isoforms of human carbonic anhydrase (CA) with a particular focus on inhibitor binding for drug design. X-ray crystallographic structures in combination with enzyme kinetic testing provide information on the interaction of CAs and their inhibitors, knowledge which is crucial for rational drug design. CAs are zinc carrying enzymes that catalyse the reversible interconversion of carbon dioxide and bicarbonate and are involved in numerous cellular processes. They are therefore a common target for drugs. The suppression of CA activities through inhibitory compounds has found application for example in diuretics and in glaucoma therapy. In this book methods used to determine binding thermodynamics of inhibitory compounds (Isothermal titration calorimetry, Fluorescent thermal shift assay/differential scanning fluorimetry and others) will be compared in detail. Also types and chemical synthesis of CA inhibitors, the use of antibodies against CAs as well as inhibitor application in animals are discussed.

As we approach the twenty-first century the problems of industrialization are evident: we find there is a greenhouse effect, the ozone layer is being depleted, the rain is acidified, and there is a terrible problem of increasing C0 concentrations in the atmo 2 sphere. The carbonic anhydrases are a unique family of enzymes that solve these problems in the human body: they are responsible for converting C0 (a gas) to 2 HC0-, which is the biggest intracellular buffer, with a concomitant decrease in a 3 hydroxyl ion. Globally, the functions of the carbonic anhydrases in photosynthesis in rain forests and in the algae and plankton that cover our oceans indicate that they are also of utmost importance in the maintenance of the acid-base balance on our planet. Although the whole field of C0 metabolism is enormous and still rapidly 2 expanding, because of the research interests of the editors this book is mainly concerned with mammalian carbonic anhydrases. However, if the interested reader intends to purify carbonic anhydrases from nonmammalian sources, Dr. Cheg widden has provided the necessary information in Chapter 7. The carbonic anhydrases were first discovered in 1933; until1976 there were thought to be only two isozymes. Since then CA ill, IY, V, VI, and Vll have been discovered and well characterized. There is, of course, no reason to believe that we have found them all.

The study of carbonic anhydrase has spanned multiple generations of scientists. Carbonic anhydrase was first discovered in 1932 by Meldrum and Roughton. Inhibition by sulfanilamide was shown in 1940 by Mann and Keilin. Even Hans Krebs contributed to early studies with a paper in 1948 showing the relationship of 25 different sulfonamides to CA inhibition. It was he who pointed out the importance of both the charged and uncharged character of these compounds for physiological experiments. The field of study that focuses on carbonic anhydrase (CA) has exploded in recent years with the identification of new families and isoforms. The CAs are metalloenzymes which are comprised of 5 structurally different families: the alpha, beta, gamma, and delta, and epsilon classes. The alpha class is found primarily in animals with several isoforms associated with human disease. The beta CAs are expressed primarily in plants and are the most divergent. The gamma CAs are the most ancient. These are structurally related to the beta CAs, but have a mechanism more similar to the alpha CAs. The delta CAs are found in marine algae and diflagellates. The epsilon class is found in prokaryotes in which it is part of the carboxysome shell perhaps supplying RuBisCO with CO2 for carbon fixation. With the excitement surrounding the discovery of disease-related CAs, scientists have redoubled their efforts to better understand structure-function relationships, to design high affinity, isotype-specific inhibitors, and to delineate signaling systems that play regulatory roles over expression and activity. We have designed the book to cover basic information of mechanism, structure, and function of the CA families. The authors included in this book bring to light the newest data with regard to the role of CA in physiology and pathology, across phylums, and in unique environmental niches.

This volume assembles and integrates the wealth of diverse information that is now accumulating in this burgeoning field. The existing and potential therapeutic applications of targeting CA cover a remarkably wide-range of diseases and disorders and have generated increasing and extensive interest in recent years. Its inter-disciplinary approach embraces both the most up-to-date therapeutic application of CA-targeting and the latest research data that will provide a platform for the development of novel applications. The interested audience comprises scientists and clinicians from many relevant disciplines within science and medicine.

Carbonic Anhydrase: Its Inhibitors and Activators provides a state-of-the-art overview of the latest developments and challenges in carbonic anhydrase research. Authors describe the mechanisms of action of specific inhibitors in relation to physiological function, and present previously unpublished research on CA activators. Written by a team of in

Carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous metalloenzymes, present throughout most living organisms and encoded by five evolutionarily unrelated gene families. The Carbonic Anhydrases as Biocatalysts: From Theory to Medical and Industrial Applications presents information on the growing interest in the study of this enzyme family and their applications to both medicine and biotechnology. Offers comprehensive coverage of the carbonic anhydrases enzyme family and their properties as biocatalysts Includes current applications of carbonic anhydrases in biotechnology on the basis of their catalytic efficiency, including new technologies for CO2 capture processes Identifies new targets for drug design studies Provides a selectivity profile for the different carbonic anhydrases and their related biomedical applications

Brings together functional and structural informationrelevant to the design of drugs targeting zinc enzymes The second most abundant transition element in living organisms, zinc spans all areas of metabolism, with zinc-containing proteins offering both established and potential drug targets. Drug Design of Zinc-Enzyme Inhibitors brings together functional and structural information relevant to these zinc-containing targets. With up-to-date overviews of the latest developments field, this unique and comprehensive text enables readers to understand zinc enzymes and evaluate them in a drug design context. With contributions from the leaders of today's research, Drug Design of Zinc-Enzyme Inhibitors covers such key topics as: Major drug targets like carbonic anhydrases, matrix metalloproteinases, bacterial proteases, angiotensin-converting enzyme, histone deacetylase, and APOBEC3G Roles of recently discovered zinc-containing isozymes in cancer, obesity, epilepsy, pain management, malaria, and other conditions Cross reactivity of zinc-enzyme inhibitors and activators The extensive use of X-ray crystallography and QSAR studies for understanding zinc-containing proteins Clinical applications An essential resource for the discovery and development of new drug molecules, Drug Design of Zinc-Enzyme Inhibitors gives researchers, professionals, students, and academics the foundation to understand and work with zinc enzyme inhibitors and activators.