Chemical modifications in aggregates of recombinant human insulin induced by metal-catalyzed oxidation: covalent cross-linking via michael addition to tyrosine oxidation products.

Pharmaceutical Research
Riccardo TorosantucciWim Jiskoot

Abstract

To elucidate the chemical modifications in covalent aggregates of recombinant human insulin induced by metal catalyzed oxidation (MCO). Insulin was exposed for 3 h at room temperature to the oxidative system copper(II)/ascorbate. Chemical derivatization with 4-(aminomethyl) benzenesulfonic acid (ABS) was performed to detect 3,4-dihydroxyphenylalanine (DOPA) formation. Electrospray ionization-mass spectrometry (ESI-MS) was employed to localize the amino acids targeted by oxidation and the cross-links involved in insulin aggregation. Oxidation at different pH and temperature was monitored with size exclusion chromatography (SEC) and ESI-MS analysis to further investigate the chemical mechanism(s), to estimate the aggregates content and to quantify DOPA in aggregated insulin. The results implicate the formation of DOPA and 2-amino-3-(3,4-dioxocyclohexa-1,5-dien-1-yl) propanoic acid (DOCH), followed by Michael addition, as responsible for new cross-links resulting in covalent aggregation of insulin during MCO. Michael addition products were detected between DOCH at positions B16, B26, A14, and A19, and free amino groups of the N-terminal amino acids Phe B1 and Gly A1, and side chains of Lys B29, His B5 and His B10. Fragments origin...Continue Reading

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Citations

Sep 26, 2013·Pharmaceutical Research·Riccardo TorosantucciWim Jiskoot
Mar 13, 2014·Journal of Pharmaceutical Sciences·Riccardo TorosantucciWim Jiskoot
Mar 31, 2015·Journal of Pharmaceutical Sciences·Alexander JaraschHubert Kettenberger
Feb 14, 2013·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Riccardo TorosantucciWim Jiskoot
Mar 5, 2016·Molecular Pharmaceutics·Olivier MozziconacciChristian Schöneich
Oct 3, 2012·Biotechnology Journal·Miranda M C van Beers, Muriel Bardor
Apr 6, 2016·Journal of Pharmaceutical Sciences·Wim JiskootLinda O Narhi
Nov 28, 2013·Scientifica·Richard C Petersen
Jul 21, 2016·Journal of Immunology Research·Anshu KuriakosePradip Nair
Aug 10, 2018·Expert Review of Proteomics·Per HägglundMichael J Davies
Mar 31, 2016·The Biochemical Journal·Michael J Davies
Nov 22, 2020·Journal of Pharmaceutical Sciences·Adam GrabarekWim Jiskoot
Apr 27, 2021·Molecular Therapy. Methods & Clinical Development·Jared A DelmarXiaoyu Chen
Oct 22, 2020·Journal of the American Society for Mass Spectrometry·Simon K GammelgaardPeter Kresten Nielsen
Apr 17, 2015·Molecular Pharmaceutics·Gregory M CockrellChristian Schöneich

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Methods Mentioned

BETA
NMR

Software Mentioned

Xcalibur
Swiss pdb viewer
Masslynx MaxEnt
MassMatrix

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