The structural comparison between membrane‐associated human carbonic anhydrases provides insights into drug design of selective inhibitors

Abstract

Carbonic anhydrase isoform XIV (CA XIV) is the last member of the human (h) CA family discovered so far, being localized in brain, kidneys, colon, small intestine, urinary bladder, liver, and spinal cord. It has recently been described as a possible drug target for treatment of epilepsy, some retinopathies as well as some skin tumors. Human carbonic anhydrase (hCA) XIV is a membrane-associated protein consisting of an N-terminal extracellular domain, a putative transmembrane region, and a small cytoplasmic tail. In this article, we report the expression, purification, and the crystallographic structure of the entire extracellular domain of this enzyme. The analysis of the structure revealed the typical α-CA fold, in which a 10-stranded β-sheet forms the core of the molecule, while the comparison with all the other membrane associated isoforms (hCAs IV, IX, and XII) allowed to identify the diverse oligomeric arrangement and the sequence and structural differences observed in the region 127-136 as the main factors to consider in the design of selective inhibitors for each one of the membrane associated α-CAs.

Carbonic Anhydrase XIV: Structure, Functions, and Potential Medical Applications

“…Very recently, De Simone and coworkers succeed to obtain the high-resolution crystal structure of the hCA XIV (17). In agreement to the very high sequence identity (78%) between hCA XIV and mCA XIV, their 3D structures are very similar (Figure 12.1).…”

“…Residues which are different in the two isoforms are reported in stick representation. Zinc ion and its coordinating residues are also shown(17).…”

Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one

“…To this aim, a detailed comparison of hCA IX with hCA IV, hCA XII, and hCA XIV has been performed, revealing important differences both in the structure and in the sequence of the region 257–268, located on the border of the enzyme active site (Figure A). Consequently, this region has been identified as an interesting target in the rational drug design of selective CA IX inhibitors . However, in our opinion the most important perspectives in the drug design field come from the two main features of CA IX enzyme: its dimeric nature with both active sites exposed on the same side of the dimer and the location of the PG domain at the edge of the active site cleft (Figure ).…”

Carbonic anhydrase inhibitors: Design, synthesis and structural characterization of new heteroaryl-N-carbonylbenzenesulfonamides targeting druggable human carbonic anhydrase isoforms

“…[36,[38][39][40][41][42][43][44] So the high selectivity towards several isoforms is conditioned by profitable interactions between the hydrophobic/hydrophilic residues on the CA cleft and suitable functional groups of the most selective hCAIs. [45][46][47] …”