ArticleJournal of the American Chemical Society2011
Chemical rescue of enzymes: proton transfer in mutants of human carbonic anhydrase II.
Article in Journal of the American Chemical Society, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
20 citing papers in PubMed, 58 citations in OpenAlex.
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- Computational models for the classification of antibody specificity using heavy chain features.PloS one · 2026Article
- Protein semisynthesis reveals plasticity in HECT E3 ubiquitin ligase mechanisms.Nature chemistry · 2024Article
- Carbonic anhydrase activation profile of indole-based derivatives.Journal of enzyme inhibition and medicinal chemistry · 2021Article
- Conformational Change of H64 and Substrate Transportation: Insight Into a Full Picture of Enzymatic Hydration of COFrontiers in chemistry · 2021Article
- Zeta-carbonic anhydrases show CSComputational and structural biotechnology journal · 2021Article
- Multiscale modelization in a small virus: Mechanism of proton channeling and its role in triggering capsid disassembly.PLoS computational biology · 2018Article
- Crystallography and Its Impact on Carbonic Anhydrase Research.International journal of medicinal chemistry · 2018Review
- Classical Molecular Dynamics with Mobile Protons.Journal of chemical information and modeling · 2017Article
- Metal Ion Modeling Using Classical Mechanics.Chemical reviews · 2017Review
- Coupling Protein Dynamics with Proton Transport in Human Carbonic Anhydrase II.The journal of physical chemistry. B · 2016Article
- Synthesis, X-ray Structure, Optical, and Electrochemical Properties of a White-Light-Emitting Molecule.Materials (Basel, Switzerland) · 2016Article
- Multiscale simulation reveals a multifaceted mechanism of proton permeation through the influenza A M2 proton channel.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Transitioning pharmacoperones to therapeutic use: in vivo proof-of-principle and design of high throughput screens.Pharmacological research · 2014Review
- Structural insight into activity enhancement and inhibition of H64A carbonic anhydrase II by imidazoles.IUCrJ · 2014Article
- Modification of residue 42 of the active site loop with a lysine-mimetic side chain rescues isochorismate-pyruvate lyase activity in Pseudomonas aeruginosa PchB.Biochemistry · 2012Article
- (E)-4-[(4-Diethyl-amino-2-hy-droxy-benzyl-idene)amino]-benzonitrile.Acta crystallographica. Section E, Structure reports online · 2012Article
- (Z)-4-(2-Hy-droxy-benzyl-idene)-1-methyl-2-phenyl-1H-imidazol-5(4H)-one.Acta crystallographica. Section E, Structure reports online · 2012Article
- 3-{[(4Z)-1,2-Dimethyl-5-oxoimidazol-4-yl-idene]meth-yl}-4-hy-droxy-benzonitrile.Acta crystallographica. Section E, Structure reports online · 2012Article
- Water in the active site of ketosteroid isomerase.Biochemistry · 2011Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
In human carbonic anhydrase II (HCA II), the mutation of position 64 from histidine to alanine (H64A) disrupts the rate limiting proton transfer (PT) event, resulting in a reduction of the catalytic activity of the enzyme as compared to the wild-type. Potential of mean force (PMF) calculations utilizing the multistate empirical valence bond (MS-EVB) methodology for H64A HCA II yields a PT free energy barrier significantly higher than that found in the wild-type enzyme. This high barrier, determined in the absence of exogenous buffer and assuming no additional ionizable residues in the PT pathway, indicates the likelihood of alternate enzyme pathways that utilize either ionizable enzyme residues (self-rescue) and/or exogenous buffers (chemical rescue). It has been shown experimentally that the catalytic activity of H64A HCA II can be chemically rescued to near wild-type levels by the addition of the exogenous buffer 4-methylimidazole (4MI). Crystallographic studies have identified two 4MI binding sites, yet site-specific mutations intended to disrupt 4MI binding have demonstrated these sites to be nonproductive. In the present work, MS-EVB simulations show that binding of 4MI near Thr199 in the H64A HCA II mutant, a binding site determined by NMR spectroscopy, results in a viable chemical rescue pathway. Additional viable rescue pathways are also identified where 4MI acts as a proton transport intermediary from the active site to ionizable residues on the rim of the active site, revealing a probable mode of action for the chemical rescue pathway.
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