Abstract
The degradation of the immunomodulatory octapeptide, thymic humoral factor γ2 (THF-γ2, thymoctonan) has been studied in whole blood samples from human, rat and mouse. The peptide, Leu-Glu-Asp-Gly-Pro-Lys-Phe-Leu, was shown to be rapidly degraded by peptidases. The half-life of the intact peptide was less than 6 min at 37 °C in blood from the three species tested. The main fragments formed from THF-γ2 were found to be Glu-Asp-Gly-Pro-Lys-Phe-Leu (2–8), Asp-Gly-Pro-Lys-Phe-Leu (3–8) and Glu-Asp-Gly-Pro-Lys (2–6) in human and in rat blood and 2–8 and 2–6 in mouse blood. Analysis of the time course of degradation revealed a sequential removal of single amino acids from the N-terminus (aminopeptidase activities) in a process that was apparently unable to cleave the Gly-Pro bond (positions 4–5 in the peptide) together with an independent cleavage of the Lys-Phe bond (positions 6–7 in the peptide) to release the dipeptide Phe-Leu. This behaviour and the effects of inhibitors showed the involvement of metallo-exopeptidases in the N-terminal digestion and a phosphoramidon-sensitive metallo-endopeptidase in the cleavage of the Lys-Phe bond. The degradation patterns in human blood were modelled in terms of the competing pathways involved approximating to first-order kinetics, and an analytical solution obtained via the method of Laplace Transforms. The half-life of THF degradation in whole rat blood sample was found to be significantly lower than in human or mouse.
Highlights
Thymic humoral factor γ2 (THF-γ2, thymoctonan; THF) is an immunomodulatory octapeptide that was originally isolated from calf thymus and shown to have the amino-acid sequence: Leu-Glu-Asp-GlyPro-Lys-Phe-Leu [1]
The peptide was shown to account for the observed effects of crude thymus extracts in stimulating T-cell functions [2,3] and interleukin 2 (IL-2) production [4]
This led to the synthesis of analogues with greater stability [9], a process that could be aided by the identification of sites that are susceptible to degradative enzymes in blood
Summary
Thymic humoral factor γ2 (THF-γ2, thymoctonan; THF) is an immunomodulatory octapeptide that was originally isolated from calf thymus and shown to have the amino-acid sequence: Leu-Glu-Asp-GlyPro-Lys-Phe-Leu [1]. The half-life of THF in human plasma was reported to be about 12 min [7] and preliminary studies suggested that metabolism was faster in whole blood [8]. This led to the synthesis of analogues with greater stability [9], a process that could be aided by the identification of sites that are susceptible to degradative enzymes in blood. Since the behaviour in whole blood might be expected to be more complicated because of the contributions of cell-associated peptidases, an aim of the present study was to examine the rates of degradation product formation in human blood in vitro for comparison with the behaviour reported in plasma. As there may be species differences in THF metabolism the behaviour in mouse and rat blood was studied for comparison with that determined in the human
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