HISTIDYL-PROLINE DIKETOPIPERAZINE - NOVEL FORMATION THAT DOES NOT ORIGINATE FROM THYROTROPIN-RELEASING-HORMONE

We asked whether cyclo(His-Pro) may arise from a substance other than the initially found progenitor thyrotropin-releasing hormone (TRH). In cubation of TRH-Gly (pGlu-His-Pro-Gly), a TRH precursor, with brain hy pothalamic cytosols caused significant formation of His-Pro-Gly follow ed by the generation of histidyl-proline diketopiperazine (cyclo(His-P ro)), whereas TRH was not formed. The addition of purified pyroglutamy l aminopeptidase resulted in the transformation of TRH-Gly to His-Pro- Gly and cyclo(His-Pro) but not to TRH. Neither TRH nor cyclo(His-Pro) was produced from TRH-Gly in the presence of alpha-amidating enzyme un der the present conditions. Nonenzymatic conversion of His-Pro-Gly to cyclo(His-Pro) occurred. The present results provide evidence that cyc lo(His-Pro) can emanate from a direct predecessor form of TRH by pyrog lutamyl aminopeptidase action, not through TRH formation.