Relationships between the structure and biological activities of corticotropin and related peptides

Abstract

The relationship of the structure of corticotropin to its biological activities has been investigated by studies on the adrenal and extra-adrenal effects of a number of modified and synthetic corticotropins. The adrenal effects studied were in vivo and in vitro adrenal steroidogenesis. The extra-adrenal effects investigated were in vivo and in vitro adipokinetic activities and in vivo hypoglycemic activity. The structural alterations were: (1) alterations in the N-terminal serine, (2) changes in the chain length, (3) blockage of certain active groups and, (4) changes in the internal structure of the polypeptide chain. The studies with several modified corticotropins in which the N-terminal serine was altered revealed that a free N-terminal α amino group was necessary for full in vivo adrenal-stimulating activity. Destruction of the α amino group caused a dissociation of in vivo adrenal and extra-adrenal activities, while blockage of it by N-acetylation markedly reduced all activities. The minimal chain length which carried the full in vivo adrenal and extra-adrenal activity of the molecule was that comprising the N-terminal 20 amino acid residues. Blockage of several active groups in the molecule (acetylation of the free α amino group of serine, formylation of the ∈ amino groups of all the lysines and conversion of glutamic acid in position 5 to glutamirie) caused hyperglycemia in mice rather than the expected hypoglycemia. Replacement of the methionine in position 4 by an α amino-butyryl group only modestly reduced activity. The significance of these findings in terms of the relationship of corticotropin structure to adrenal and extra-adrenal activities is discussed. The relationship of the structure of corticotropin to its biological activities has been investigated by studies on the adrenal and extra-adrenal effects of a number of modified and synthetic corticotropins. The adrenal effects studied were in vivo and in vitro adrenal steroidogenesis. The extra-adrenal effects investigated were in vivo and in vitro adipokinetic activities and in vivo hypoglycemic activity. The structural alterations were: (1) alterations in the N-terminal serine, (2) changes in the chain length, (3) blockage of certain active groups and, (4) changes in the internal structure of the polypeptide chain. The studies with several modified corticotropins in which the N-terminal serine was altered revealed that a free N-terminal α amino group was necessary for full in vivo adrenal-stimulating activity. Destruction of the α amino group caused a dissociation of in vivo adrenal and extra-adrenal activities, while blockage of it by N-acetylation markedly reduced all activities. The minimal chain length which carried the full in vivo adrenal and extra-adrenal activity of the molecule was that comprising the N-terminal 20 amino acid residues. Blockage of several active groups in the molecule (acetylation of the free α amino group of serine, formylation of the ∈ amino groups of all the lysines and conversion of glutamic acid in position 5 to glutamirie) caused hyperglycemia in mice rather than the expected hypoglycemia. Replacement of the methionine in position 4 by an α amino-butyryl group only modestly reduced activity. The significance of these findings in terms of the relationship of corticotropin structure to adrenal and extra-adrenal activities is discussed.