Boronic acids are an interesting but still poorly studied class of carbonic anhydrase inhibitors. Previous investigations proved that derivatives incorporating aromatic, arylalkyl, and arylalkenyl moieties are low micromolar to millimolar inhibitors for several α- and β-CAs involved in pathologic states. Here we report a high-resolution X-ray study on two classes of boronic acids (phenyl and vinyl) in complex with hCA II. Our results unambiguously clarify the binding mode of these molecules to the human carbonic anhydrase active site, which occurs through their tetrahedral anionic form, regardless of the nature of the organic scaffold. Data here presented contribute to the understanding of the inhibition mechanism of boronic acids that can be fruitfully used for the rational design of novel and effective isozyme-specific carbonic anhydrase inhibitors.
The Carbon Concentration Mechanism (CCM) allows phytoplakton species to accumulate the dissolved inorganic carbon (DIC) necessary for an efficient photosynthesis even under carbon dioxide limitation. In this mechanism of primary importance for diatoms, a key role is played by carbonic anhydrase (CA) enzymes which catalyze the reversible hydration of CO2, thus taking part in the acquisition of inorganic carbon for photosynthesis. A novel CA, named CDCA1, has been recently discovered in the marine diatom Thalassiosira weissflogii. CDCA1 is a cambialistic enzyme since it naturally uses Cd2+ as catalytic metal ion, but if necessary can spontaneously exchange Cd2+ to Zn2+. Here, the biochemical and structural features of CDCA1 enzyme will be presented together with its putative biotechnological applications for the detection of metal ions in seawaters.
Topiramate is a widely used antiepileptic drug, which has been demonstrated to act as an efficient weight loss agent. Since several studies have pointed out that TPM is a potent in vitro inhibitor of several Carbonic anhydrase (CA) isozymes, it has been hypothesized that its anti-obesity properties could be ascribed to the inhibition of the CAs involved in de novo lipogenesis. Consequently, the study of the interactions of TPM with all human CA isoforms represents an important step for the rational drug design of selective CA inhibitors to be used as anti-obesity drugs. In this paper we report the crystallographic structure of the adduct that TPM forms with hCA I, showing for the first time a profound reorganization of the CA active site upon binding of the inhibitor. Moreover, a structural comparison with hCA II–TPM and hCA VA–TPM adducts, previously investigated, has been performed showing that a different H-bond network together with the movement of some amino acid residues in the active site may account for the different inhibition constants of TPM toward these three CA isozymes.
