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Oxidation of recombinant human parathyroid hormone: effect of oxidized position on the biological activity
Y Nabuchi1, E Fujiwara, K Ueno
1Preliminary Drug Evaluation Laboratory, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
Purpose:
To determine the oxidation products of recombinant human parathyroid hormone (rhPTH) treated with H2O2, the amino acid residue oxidized, and the biological activity of the oxidation products.
Methods:
Oxidized residues were determined by CNBr cleavage, trypsin digestion and subsequent fast atom bombardment mass spectrometry. The biological activity of each oxidized rhPTH was examined in rat osteosarcoma cell adenylate cyclase assay.
Results:
Three oxidized products were isolated, namely, Met at position 8 (Met8) sulfoxide, Met at position 18 (Met18) sulfoxide and both positions Met sulfoxide. It appears that the Met8 and Met18 oxidized forms are intermediates in the generation of the Met doubly oxidized form. All oxidized forms possessed reduced biological activity, more so for oxidation at Met8 than at Met18.
Conclusions:
The region around Met8 is important for the activity of the parathyroid hormone.