A Short, Strong Hydrogen Bond in the Active Site of Human Carbonic Anhydrase II

Avvaru, Balendu Sankara; Kim, Chae Un; Sippel, Katherine H.; Grüner, Sol M.; Agbandje‐McKenna, Mavis; Silverman, David N.; McKenna, Robert

doi:10.1021/bi902007b

Cited by 139 publications

(155 citation statements)

References 25 publications

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“…Initial phases for the HCA II-cholate complex were calculated via molecular replacement using Phaser (McCoy et al, 2007) with the coordinates of the high-resolution HCA II structure (PDB entry 3ks3; Avvaru et al, 2010). Electron density in the initial mF o À DF c maps revealed positive density at >5 suggesting cholate binding in the active site of HCA II.…”

Section: Structure Refinementmentioning

confidence: 99%

Structural elucidation of the hormonal inhibition mechanism of the bile acid cholate on human carbonic anhydrase II

Boone¹,

Tu²,

McKenna³

2014

Acta Crystallogr D Biol Crystallogr

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The carbonic anhydrases (CAs) are a family of mostly zinc metalloenzymes that catalyze the reversible hydration/dehydration of CO 2 into bicarbonate and a proton. Human isoform CA II (HCA II) is abundant in the surface epithelial cells of the gastric mucosa, where it serves an important role in cytoprotection through bicarbonate secretion. Physiological inhibition of HCA II via the bile acids contributes to mucosal injury in ulcerogenic conditions. This study details the weak biophysical interactions associated with the binding of a primary bile acid, cholate, to HCA II. The X-ray crystallographic structure determined to 1.54 Å resolution revealed that cholate does not make any direct hydrogen-bond interactions with HCA II, but instead reconfigures the well ordered water network within the active site to promote indirect binding to the enzyme. Structural knowledge of the binding interactions of this nonsulfur-containing inhibitor with HCA II could provide the template design for high-affinity, isoform-specific therapeutic agents for a variety of diseases/ pathological states, including cancer, glaucoma, epilepsy and osteoporosis.

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Section: Structure Refinementmentioning

confidence: 99%

Structural elucidation of the hormonal inhibition mechanism of the bile acid cholate on human carbonic anhydrase II

Boone¹,

Tu²,

McKenna³

2014

Acta Crystallogr D Biol Crystallogr

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“…Such a residue swings back and forth between two opposite conformations, thus facilitating the extrusion of protons to the external medium from the inner enzymatic cavity (Figure 4) [22,23]. From the mechanistic viewpoint, the CAAs act at the last step of the CA catalytic cycle (conversion of D to A in Scheme 2), which is also the rate-determining one.…”

Section: Polyamines and Casmentioning

confidence: 99%

“…Such a residue swings back and forth between two opposite conformations, thus facilitating the extrusion of protons to the external medium from the inner enzymatic cavity (Figure 4) [22,23]. Among the α-CAs, the deprotonation of D to restore the enzyme to the active state A is supported by a histidine residue (His64 according to the h CA II numbering), which is located at the middle of the enzymatic cavity.…”

Section: Polyamines and Casmentioning

confidence: 99%

“…Among the α-CAs, the deprotonation of D to restore the enzyme to the active state A is supported by a histidine residue (His64 according to the h CA II numbering), which is located at the middle of the enzymatic cavity. Such a residue swings back and forth between two opposite conformations, thus facilitating the extrusion of protons to the external medium from the inner enzymatic cavity (Figure 4) [22,23]. [23]) is shown as yellow sticks to represent the 'in' and 'out' conformations [22].…”

Section: Polyamines and Casmentioning

confidence: 99%

“…Thus, the enzyme is catalytically more efficient in the hydration of the natural ligand carbon dioxide [16][17][18][19][20][21][22][23].…”

Section: Polyamines and Casmentioning

confidence: 99%

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Polyamines and α-Carbonic Anhydrases

2016

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Natural products represent a straightforward source for molecular structures bearing a vast array of chemical features and potentially useful for biomedical purposes. Recent examples of this type include the discovery of the coumarins and the polyamine natural products as atypical chemotypes for the inhibition of the metalloenzymes carbonic anhydrases (CAs; EC 4.2.2.1). CA enzymes are established pharmacological targets for important pathologies, which, among others, include glaucoma, hypoxic tumors, and central nervous system (CNS)-affecting diseases. Moreover, they are expressed in many bacteria, fungi and helminths which are the etiological agents of the majority of infectious diseases. In this context, natural products represent the ideal source of new and selective druggable CA modulators for biomedical purposes. Herein we report the state of the art on polyamines of natural origin as well as of synthetic derivatives as inhibitors of human CAs.

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Calorimetry

Emerson¹,

Le²,

Lewis³

2012

Encyclopedia of Life Sciences

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In biology, particularly in studies relating the structure of biopolymers to their functions, two of the most important questions are: (1) how tightly does a small molecule bind to a specific interaction site? and (2) if the small molecule is a substrate and is converted to a product, how fast does the reaction take place? Because almost any chemical reaction or physical change is accompanied by a change in heat or enthalpy, an isothermal titration calorimeter is an ideal instrument to measure either how much of a reaction has taken place or the rate at which a reaction is occurring. In contrast to optical methods, calorimetric measurements can be done with reactants that are spectroscopically silent (a chromophore or fluorophore tag is not required), can be done on opaque, turbid or heterogeneous solutions (e.g. cell suspensions) and can be done over a range of biologically relevant conditions (temperature, salt, pH, etc ). Key Concepts: Almost all chemical reactions are accompanied by a change in heat or enthalpy. Calorimetry can determine the complete set of thermodynamic parameters that characterise binding reactions, for example K, Δ G °, Δ H °, Δ S ° and Δ C p . Binding reactions are typically pH, salt and temperature dependant.

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A Short, Strong Hydrogen Bond in the Active Site of Human Carbonic Anhydrase II

Cited by 139 publications

References 25 publications

Structural elucidation of the hormonal inhibition mechanism of the bile acid cholate on human carbonic anhydrase II

Structural elucidation of the hormonal inhibition mechanism of the bile acid cholate on human carbonic anhydrase II

Polyamines and α-Carbonic Anhydrases

Calorimetry

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