A comprehensive picture of non-site specific oxidation of methionine residues by peroxides in protein pharmaceuticals.
In this article, a comprehensive picture of the oxidation of protein pharmaceuticals by peroxides is developed based on our earlier computational and experimental studies. We propose a new mechanism, the water-mediated mechanism, for the oxidation of methionine residues, and it has been shown to satisfy all available experimental data including new data reported here. Based on the water-mediated mechanism, we found a structural property, average 2-shell water coordination number, that correlates well to the relative rates of oxidation of methionine groups. We used this to study the oxidation of granulocyte colony-stimulating factor (G-CSF) and 1-34 human parathyroid hormone hPTH(1-34). We believe that this comprehensive picture should aid researchers in the pharmaceutical sciences to develop solvent formulations for therapeutic proteins in a more rational way.
Chu
Jhih-Wei
JW
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Yin
Jin
J
Brooks
Bernard R
BR
Wang
Daniel I C
DI
Ricci
Margaret Speed
MS
Brems
David N
DN
Trout
Bernhardt L
BL
D001665:Binding Sites / Q000502:physiology; D008715:Methionine / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010545:Peroxides / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*
D010545:Peroxides; D004364:Pharmaceutical Preparations; D011506:Proteins; D008715:Methionine