Recent Advances in Structural Studies of the Carbonic Anhydrase Family: The Crystal Structure of Human CA IX and CA XIII

Claudiu      T. Supuran; Anna      Di Fiore; Vincenzo      Alterio; Simona      Maria Monti; Giuseppina      De Simone

doi:10.2174/138161210793429841

Abstract

The carbonic anhydrase (CA) family has recently become an important target for the drug design of inhibitors with potential use as diagnostic and therapeutic tools. However, given the high degree of sequence and structure similarity among the different CA isoforms, no CA-directed drug developed so far has displayed selectivity for a specific isozyme. Since X-Ray crystallography is a very useful tool for the rational drug design of selective enzyme inhibitors, in recent years extensive research efforts have been devoted to the structural studies of all catalytically active α-CA isoforms, with the consequent resolution of the crystallographic structures of nearly all such enzyme isoforms. In this paper we review the progress that has recently been made in this field. In particular, we summarize the main structural features of hCA XIII and hCA IX, the most recently characterized human CA isoforms, and recapitulate how 3D structures of these enzymes, together with kinetic experiments, have been used either to deepen our knowledge on the structural features responsible of the catalytic properties of this protein family or to obtain important information for the rational drug design of inhibitors with better selectivity properties.

Keywords: Carbonic Anhydrase IX, Carbonic Anhydrase XIII, inhibitor, structure based drug design, crystal structure, carbonic anhydrase (CA), isozyme, X-Ray crystallography, 3D structures, ubiquitous metallo-enzymes, CA inhibitors (CAIs), diuretics, antiglaucoma, antiepileptics, submandibular gland, Cytosolic CA Isozymes, mutagenesis, HUMAN CA IX, transmembrane segment (TM), intracytoplasmic (IC) portion, N-terminal proteoglycan, disulfide bond, Mass spectrometry, hypoxic phenotype, anion exchangers (AEs), Na+/bicarbonate cotransporters (NBCs), apoptosis, tumor cells, anticonvulsants, spermatogenesis, Carbonic anhydrase, Human CA, Murine CA, Hypoxia inducible factor, Hypoxia response elements, Anion exchanger, Na+/bicarbonate cotransporter, Transmembrane, Intracytoplasmic, Proteoglycan-like domain