Possible involvement of the A20-A21 peptide bond in the expression of the biological activity of insulin. 1. [21-Desasparagine,20-cysteinamide-A]insulin and [21-desasparagine,20-cysteine isopropylamide-A]insulin.
The C-terminal region of the A chain of insulin has been shown to play a significant role in the expression of the biological activity of the hormone. To further delineate the contribution of this segment, we have synthesized [21-desasparagine,20-cysteinamide-A]insulin and [21-desasparagine,20-cysteine isopropylamide-A]insulin, in which the C-terminal amino acid residue of the A chain of insulin, asparagine, has been removed and the resulting free carboxyl group of the A20 cysteine residue has been converted to an amide and an isopropylamide, respectively. Both insulin analogues display biological activity, 14-15% for the unsubstituted amide analogue and 20-22% for the isopropylamide analogue, both relative to bovine insulin. In contrast, a [21-desasparagine-A]insulin analogue has been reported to display less than 4% of the activity of the natural hormone [Carpenter, F. (1966) Am. J. Med. 40, 750-758]. The implications of these findings are discussed, and we conclude that the A20-A21 amide bond plays a significant role in the expression of the biological activity of insulin.
Chu
Y C
YC
Department of Biochemistry, Mount Sinai School of Medicine of the City University of New York, New York 10029.
Wang
R Y
RY
Burke
G T
GT
Chanley
J D
JD
Katsoyannis
P G
PG
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D007328:Insulin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D051381:Rats; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
D007328:Insulin; C054831:insulin, des-Asn(21)-CysNH2(20)(A)-; C054832:insulin, des-Asn(21)-Cys(20)-isopropylamide(A)-; D011972:Receptor, Insulin