Bacterial carbonic anhydrases: underexploited antibacterial therapeutic targets

摘要

Brief history & physiology of targeting human carbonic anhydrases Carbonic anhydrases (CA) are metalloenzymes that are present in all kingdoms of life. This family of enzymes primarily catalyze the interconversion of CO2 to a bicarbonate anion and a proton; this reaction is mediated through a hydroxide anion bound to a catalytic Zn2+ ion within the active site of the enzyme [1]. This reaction is important for a variety of biological processes that take place within both prokaryotes and eukaryotes. In humans, CAs have been extensively studied and have long been validated as drug targets, beginning with the first clinical use of acetazolamide (AZM) in 1952 as a diuretic [2]. Since that time, 15 isoforms of human CAs have been identified in various tissues, organs and subcellular locations. These isoforms play an important role in many physiological processes, including CO2 transport in the lungs, regulation of CO2 and pH homeostasis in other tissues and electrolyte balance, to name a few [3]. Regulation of these processes has made CA inhibitors (CAIs) effective treatment options for glaucoma, epilepsy, congestive heart failure and altitude sickness, in addition to their aforementioned use as a diuretic [4]. More recently, CAs have become targets for cancer therapy, because tumor-associated CA IX is overexpressed in hypoxic conditions to regulate the pH of cancer cells [3].