?36 J. lEUAN HARRIS [18 



of a-MSH now reveals that the structure essential for melanocyte-stimulating 

 activity must reside v^^ithin the A^-terminal tridecapeptide fragment of 

 corticotropin ; and from a comparison of the structures of the two melanocyte- 

 stimulating hormones it would appear that the structure essential for 

 biological activity is in both cases to be found within a sequence of eleven amino 

 acid residues (i.e. positions 2-12 in a-MSH, and 5-15 in j3-MSH), since the iV- 

 terminal tetrapeptide and C-terminal tripeptide sequences in jS-MSH can 

 be replaced by the A^-substituted serine, and valine amide moieties, respec- 

 tively, in a-MSH. 



Although the entire amino acid sequence of a-MSH is contained within 

 the corticotropin molecule, its actual melanocyte-stimulating activity is con- 

 siderably less than that of a-MSH. This suggests that the additional struc- 

 tural features which are necessary for adrenocorticotropic activity may at 

 the same time inhibit the potential melanocyte-stimulating properties of the 

 corticotropin molecule. For example, the A^-terminal serine residue has been 

 shown to be essential for the adrenocorticotropic activity, but not for the 

 melanocyte-stimulating activity, of corticotropin (Dixon, 1956/?). a-MSH, 

 on the other hand, in which the A^-terminal serine occurs as an N-substituted 

 derivative, acquires enhanced melanocyte-stimulating activity, and it could 

 be inferred that the unsubstituted CH2 — CH — structure may, at least in 



I I 



OH NH2 



part, be responsible for the reduced melanocyte-stimulating activity of 



corticotropin. In accord with this hypothesis, it has now been shown (Dixon 



and Lerner, unpublished results) that when the TV-terminal serine residue in 



corticotropin is oxidized with periodate, loss of adrenocorticotropic activity 



is accompanied by a significant increase in the melanocyte-stimulating activity 



of the periodate modified corticotropin. Similarly, Shepherd et al. (1956) 



have shown that when corticotropin is subjected to mild alkaline hydrolysis 



(which results in the cleavage of peptide bonds in the A^-terminal Ser.Tyr.Ser. 



structure), loss of adrenocorticotropic activity is again accompanied by an 



increase in melanocyte-stimulating activity. 



Although a conclusive evaluation of these results must await the isolation 

 and characterization of the periodate and alkali degradation products of 

 corticotropin, it is clear that corticotropin can be changed into a pre- 

 dominantly melanocyte-stimulating substance, and that the A^-terminal serine 

 plays an important role in determining which of the two biological properties 

 shall predominate. 



The other outstanding question concerns the nature of the smallest active 

 adrenocorticotropic peptide. It is already clear that, in addition to the 

 common heptapeptide sequence, a free A^-terminal serine, and in all prob- 

 ability the entire Ser.Tyr.Ser sequence, is essential for adrenocorticotropic 

 activity. Preliminary studies on the selective removal of the //-terminal sub- 

 stituent in a-MSH show that the unsubstituted tridecapeptide does not 



