Kinetic study of methionine oxidation in human parathyroid hormone

Development and validation of RP-HPLC and RP-UPLC methods for quantification of parathyroid hormones (1-34) in medicinal product formulated with meta-cresol

“…The measurement of PTH and its metabolites has been problematic due to the diversity of the circulating PTH metabolites, differences in the pharmacokinetic profiles of PTH and its metabolites and significant differences in specificity and sensitivity of PTH radioimmunoassay [11] , [12] , [13] . Methionine oxidation in PTH was studied by Nabuchi et al by using RP-HPLC [14] . WHO International collaborative study of the proposed 1st international standard for recombinant human PTH (1-84) was done by RP-HPLC method in different laboratories [15] .…”

Comparison of methionine oxidation in thermal stability and chemically stressed samples of a fully human monoclonal antibody

“…While the other two Met residues in hGH as well as the other five Met residues in hCS had dramatically different oxidation rates depending on their microenvironments. Different oxidation rates of Met residues in the same protein were also obtained for human parathyroid hormone [6], recombinant human granulocyte colony stimulating factor [7], recombinant interferon ␥ and recombinant tissue-type plasminogen activator [8], human cystatin C expressed in E. Coli [9], recombinant human leptin [10], recombinant coagulation factor exposed to H 2 O 2 [11] and wheat germ calmodulin [12]. Met oxidation is a concern for protein therapeutics due to the possible adverse effects such as in the case of recombinant human leptin [10], where decreased thermostability and a significant loss of in vitro bioactivity was observed when Met1 and Met69 were both oxidized.…”

A comprehensive picture of non‐site specific oxidation of methionine residues by peroxides in protein pharmaceuticals

“…Formulating proteins in aqueous solutions is preferred, and significant effort is expended to develop formulations that will stabilize protein pharmaceuticals against oxidation 1–4. Examples of proteins that have had oxidation problems include human α‐1 proteinase inhibitor,5 calmodulin,6,7 human parathyroid hormone,8 antithrombin,9 glutamine synthetase,10 α1‐antitrypsin,11 and granulocyte colony‐stimulating factor 12. An understanding of the mechanisms of oxidation processes, in addition to the reasons for which different sites in each protein are susceptible to oxidation to different degrees, would aid in the development of protein formulations.…”

“…Linked to this general question is another unknown: why are different methionine residues in a protein oxidized at different rates? As a simple example, methionine residues on the surface of a protein are oxidized at higher rates than the buried ones 8,11,12,17,21,27. An obvious explanation is that the rate of oxidation is governed by the accessibility of the sites to oxidants.…”