Crystallography and Its Impact on Carbonic Anhydrase Research.

Jacob T. Andring,Robert McKenna,Carrie L. Lomelino

doi:10.1155/2018/9419521

Jacob T. Andring, Robert McKenna

Open Access

https://doi.org/10.1155/2018/9419521

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Abstract

X-ray and neutron crystallography are powerful techniques utilized to study the structures of biomolecules. Visualization of enzymes in complex with substrate/product and the capture of intermediate states can be related to activity to facilitate understanding of the catalytic mechanism. Subsequent analysis of small molecule binding within the enzyme active site provides insight into mechanisms of inhibition, supporting the design of novel inhibitors using a structure-guided approach. The first X-ray crystal structures were determined for small, ubiquitous enzymes such as carbonic anhydrase (CA). CAs are a family of zinc metalloenzymes that catalyze the hydration of CO2, producing HCO3− and a proton. The CA structure and ping-pong mechanism have been extensively studied and are well understood. Though the function of CA plays an important role in a variety of physiological functions, CA has also been associated with diseases such as glaucoma, edema, epilepsy, obesity, and cancer and is therefore recognized as a drug target. In this review, a brief history of crystallography and its impact on CA research is discussed.

Highlights

The search for isoform selective CA inhibitors (CAIs) has led to the discovery of nonsulfonamide-based inhibitors that exhibit unique mechanisms of inhibition, including compounds that anchor to the zinc-bound water and CAIs that bind outside the active site, occluding entrance of substrate
carbonic anhydrase (CA) are an essential class of enzymes in every class of life, from marine diatoms and bacteria to humans
The crystal structure of CA II was amongst the first structures to be determined and was one of the seven structures that contributed to the development of the PDB

Summary

Introduction

The active site structure of δ CAs is hypothesized to be similar to that of the α class with a catalytic zinc ion coordinated by three His residues (x, x+3, x+112, where x=114 in TweCA) [32, 44]. At basic pHs above 8.3, the Asp residue is removed from the zinc, allowing a water molecule to bind and activate the enzyme [59] This results in the formation of an AspArg dyad, similar to the Type I structures, that serves as a hydrogen bond acceptor of the ligand. No crystal structures of CA VA, CAVB, CA X, or CA XI have been deposited in the PDB Occupancy of this site is hypothesized to restrict the Type II class from undergoing conformational change, inactivating the enzyme [60]. Rotation of the Cys residues that are no longer coordinating a metal ion contributes to this structural change [37]

Mechanism

Drug Design

Findings

Conclusion