ArticleProtein science : a publication of the Protein Society2010
Impact of oxidation on protein therapeutics: conformational dynamics of intact and oxidized acid-β-glucocerebrosidase at near-physiological pH.
Article in Protein science : a publication of the Protein Society, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Stability of Protein Pharmaceuticals: Recent Advances.Pharmaceutical research · 2024Review
- Simultaneous Evaluation of a Vaccine Component Microheterogeneity and Conformational Integrity Using Native Mass Spectrometry and Limited Charge Reduction.Journal of the American Society for Mass Spectrometry · 2021Article
- Mass spectrometry-based methods in characterization of the higher order structure of protein therapeutics.Journal of pharmaceutical and biomedical analysis · 2020Review
- QUDeX-MS: hydrogen/deuterium exchange calculation for mass spectra with resolved isotopic fine structure.BMC bioinformatics · 2014Article
- Effect of arginine on pre-nucleus stage of interferon beta-1b aggregation.AAPS PharmSciTech · 2014Article
- HDX-MS guided drug discovery: small molecules and biopharmaceuticals.Current opinion in structural biology · 2014Review
- Hydrogen/deuterium exchange mass spectrometry for probing higher order structure of protein therapeutics: methodology and applications.Drug discovery today · 2014Review
- A new approach to measuring protein backbone protection with high spatial resolution using H/D exchange and electron capture dissociation.Analytical chemistry · 2013Article
- Hydrogen-exchange mass spectrometry for the study of intrinsic disorder in proteins.Biochimica et biophysica acta · 2013Review
- Mass spectrometry-based methods to study protein architecture and dynamics.Protein science : a publication of the Protein Society · 2013Review
- Advanced mass spectrometry-based methods for the analysis of conformational integrity of biopharmaceutical products.Current pharmaceutical biotechnology · 2011Review
- Advances and challenges in analytical characterization of biotechnology products: mass spectrometry-based approaches to study properties and behavior of protein therapeutics.Biotechnology advancesReview
Corrections and comments
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Authors and funding
5 authors.
Funding
Abstract
The solution dynamics of an enzyme acid-β-glucocerebrosidase (GCase) probed at a physiologically relevant (lysosomal) pH by hydrogen/deuterium exchange mass spectrometry (HDX-MS) reveals very uneven distribution of backbone amide protection across the polypeptide chain. Highly mobile segments are observed even within the catalytic cavity alongside highly protective segments, highlighting the importance of the balance between conformational stability and flexibility for enzymatic activity. Forced oxidation of GCase that resulted in a 40-60% reduction in in vitro biological activity affects the stability of some key structural elements within the catalytic site. These changes in dynamics occur on a longer time scale that is irrelevant for catalysis, effectively ruling out loss of structure in the catalytic site as a major factor contributing to the reduction of the catalytic activity. Oxidation also leads to noticeable destabilization of conformation in remote protein segments on a much larger scale, which is likely to increase the aggregation propensity of GCase and affect its bioavailability. Therefore, it appears that oxidation exerts its negative impact on the biological activity of GCase indirectly, primarily through accelerated aggregation and impaired trafficking.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.