Crystal Structure of Carbonic Anhydrase II in Complex with an Activating Ligand: Implications in Neuronal Function

Abstract

Carbonic anhydrase (CA) plays a key role in neuronal signaling, providing bicarbonate and proton ions for GABAergic and glutamatergic neuronal function. Activation of CA isoforms expressed in neurons have been shown to have implications in the prognosis of Alzheimer's disease and dementia, while inhibitors of CAs are clinically used in the treatment of epilepsy, emphasizing the importance of this family of enzymes in both disease and normal neuronal function. Previously, compounds have been reported to enhance activity of CAs in an aging rat model, but their mechanism of action was not known. We report the 1.6 Å resolution structure of an imidazole-based CA activator in complex with the ubiquitously-expressed human CA II. Based on the structure, a proposed mechanism of CA activation by the compound and its potential applications in the neurobiology of aging are discussed.

Carbonic anhydrases as disease markers

“…Other promising CA inhibitors are currently under advanced clinical stages in the treatment of hypoxic tumors [1,6,[9][10][11][12][13] and were also used recently in the selective delivery of toxic drugs to tumors [14,15]. Slower isozymes can be activated with CA activators, with potential applications in memory and learning enhancement [1,[16][17][18][19][20][21][22][23] The boundary between CA activation and inhibition was also revealed recently [24].…”

Chloroplast SRP43 subunit Prevents Aggregation of Proteins

“…Carbonic anhydrase (CA), found in all kingdoms of life, catalyzes the reversible conversion of carbon dioxide and water to bicarbonate and also plays a role in ion transport, pH regulation and water and electrolyte balance (23,24). CA II deficiency is responsible for osteopetrosis, an inherited syndrome in humans which is characterized with renal tubular acidosis and brain calcification (25)(26)(27)(28). CA has been studied more closely over the past decade for its role in biological systems pertaining to bone resorption, renal acidification, and for its suggested importance in normal brain development (25,28).…”

“…CA II deficiency is responsible for osteopetrosis, an inherited syndrome in humans which is characterized with renal tubular acidosis and brain calcification (25)(26)(27)(28). CA has been studied more closely over the past decade for its role in biological systems pertaining to bone resorption, renal acidification, and for its suggested importance in normal brain development (25,28). CA was used in this study to illustrate the ability of cpSRP43 to aid in the refolding of a protein other than LHCP and although CA is naturally abundant in chloroplasts, the CA used here originated from bovine erythrocytes.…”

Effect of amino acids and amines on the activity of the recombinant ι-carbonic anhydrase from the Gram-negative bacterium Burkholderia territorii

“…The most extensively investigated CA activators (CAAs) belong to the compound groups of amines and amino acids 2 . The X-ray crystal structure of the human isoforms (hCA I and II) bound to activators, such as histamine, L-/D-histidine, L-/D-phenylalanine, Dtryptophan and others, allowed the comprehension of the activation mechanism and the structure-activity relationship governing it 2,[35][36][37][38][39][40][41] . Contrary to most CA inhibitors (CAIs), such as anions and sulphonamides, 6,9,10,42,43 CAAs bind to molecular regions at the entrance of the enzyme active site enhancing the proton transfer processes between the Zn 2þ -bound water molecule and the reaction medium; this is accomplished by a supplementary pathway provided by the proton-shuttling moieties of the activator 2,44 .…”