Crystal Structure of a Tetrameric Type II β-Carbonic Anhydrase from the Pathogenic Bacterium Burkholderia pseudomallei.

Andrea Angeli,Clemente Capasso,Fabrizio Carta,Bogdan C Simionescu,Marta Ferraroni,Stelian S Maier,Sonia Del Prete,Claudiu T Supuran,Mariana Pinteala

doi:10.3390/molecules25102269

Abstract

Carbonic anhydrase (CA) is a zinc enzyme that catalyzes the reversible conversion of carbon dioxide to bicarbonate and proton. Currently, CA inhibitors are widely used as antiglaucoma, anticancer, and anti-obesity drugs and for the treatment of neurological disorders. Recently, the potential use of CA inhibitors to fight infections caused by protozoa, fungi, and bacteria has emerged as a new research line. In this article, the X-ray crystal structure of β-CA from Burkholderia pseudomallei was reported. The X-ray crystal structure of this new enzyme was solved at 2.7 Å resolution, revealing a tetrameric type II β-CA with a “closed” active site in which the zinc is tetrahedrally coordinated to Cys46, Asp48, His102, and Cys105. B. pseudomallei is known to encode at least two CAs, a β-CA, and a γ-CA. These proteins, playing a pivotal role in its life cycle and pathogenicity, offer a novel therapeutic opportunity to obtain antibiotics with a different mechanism of action. Furthermore, the new structure can provide a clear view of the β-CA mechanism of action and the possibility to find selective inhibitors for this class of CAs.

Highlights

Burkholderia pseudomallei is the etiologic agent of a severe and often fatal syndrome known as melioidosis, or Whitmore’s disease [1]
The results indicated that certain Carbonic anhydrase (CA) inhibitors were able to highly inhibit most of the CAs identified in the genome of the aforementioned bacteria
Pseudomallei and ι-CA from B. territorii measured at 20 ◦ C, pH 8.3 in 20 mM TRIS buffer, and 20 mM

Summary

Introduction

Burkholderia pseudomallei is the etiologic agent of a severe and often fatal syndrome known as melioidosis, or Whitmore’s disease [1]. In recent years, the tolerance to antimicrobials has increased considerably [6,7] In this scenario, a novel and promising approach for fighting antibiotic resistance is represented by the inhibition of carbonic anhydrases The last identified ι-CA, which is encoded in the genome of the marine diatom, Thalassiosira pseudonana, prefers Mn2+

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Conclusion