7 research outputs found
Structure and mechanism of copper-carbonic anhydrase II: A nitrite reductase
Nitric oxide (NO) promotes vasodilation through the activation of guanylate cyclase, resulting in the relaxation of the smooth muscle vasculature and a subsequent decrease in blood pressure. Therefore, its regulation is of interest for the treatment and prevention of heart disease. An example is pulmonary hypertension which is treated by targeting this NO/vasodilation pathway. In bacteria, plants and fungi, nitrite (NO2 -) is utilized as a source of NO through enzymes known as nitrite reductases. These enzymes reduce NO2 - to NO through a catalytic metal ion, often copper. Recently, several studies have shown nitrite reductase activity of mammalian carbonic anhydrase II (CAII), yet the molecular basis for this activity is unknown. Here we report the crystal structure of copper-bound human CAII (Cu-CAII) in complex with NO2 - at 1.2 ?? resolution. The structure exhibits Type 1 (T-1) and 2 (T-2) copper centers, analogous to bacterial nitrite reductases, both required for catalysis. The copper-substituted CAII active site is penta-coordinated with a 'side-on' bound NO2 -, resembling a T-2 center. At the N terminus, several residues that are normally disordered form a porphyrin ring-like configuration surrounding a second copper, acting as a T-1 center. A structural comparison with both apo-(without metal) and zinc-bound CAII (Zn-CAII) provides a mechanistic picture of how, in the presence of copper, CAII, with minimal conformational changes, can function as a nitrite reductase. ?? 2020 Andring et al
Handling drug-target selectivity: A study on ureido containing Carbonic Anhydrase inhibitors
Here we report the synthesis of a series of taurine substituted sulfonamide derivatives 1-29 having the ureido moiety installed at the tail section as selective inhibitors of the tumor associated human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) IX and XII. The series was deeply investigated for their kinetic features which demonstrated a strong dependence on the ureido moiety. High resolution X-ray crystallographic investigation on selected ligand adducts complexed with hCA II and hCA IX-mimic revealed a strong correlation between the ureido moiety and the amino acid residues Q92 and Q67 in both the hCA II and hCA IX-mimic, contributing to highly stabilized ligand-protein complex. (C) 2020 Elsevier Masson SAS. All rights reserved.This study was supported by The Scientific and Technological Research Council of Turkey (TUBITAK; Project number: 116S705) and research grants from Ege University (Project number: 18-B_IL002).Scientific and Technological Research Council of Turkey (TUBITAK) [116S705]; Ege University [18-B_IL002
Discovery of β‑Adrenergic Receptors Blocker–Carbonic Anhydrase Inhibitor Hybrids for Multitargeted Antiglaucoma Therapy
The
combination of a β-adrenergic receptors (AR) blocker
and a carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in eye drops formulations
is one of the most clinically used treatment for glaucoma. A novel
approach consisting of single-molecule, multitargeted compounds for
the treatment of glaucoma is proposed here by designing compounds
which concomitantly interact with the β-adrenergic and CA targets.
Most derivatives of the two series of benzenesulfonamides incorporating
2-hydroxypropylamine moieties reported here exhibited striking efficacy
against the target hCA II and XII, whereas a subset of compounds also
showed significant modulation of β<sub>1</sub>- and β<sub>2</sub>-ARs. X-ray crystallography studies provided rationale for
the observed hCA inhibition. The best dual-agents decreased IOP more
effectively than clinically used dorzolamide, timolol, and the combination
of them in an animal model of glaucoma. The reported evidence supports
the proof-of-concept of β-ARs blocker–CAI hybrids for
antiglaucoma therapy with an innovative mechanism of action