Purification and structure of exendin-3, a new pancreatic secretagogue isolated from Heloderma horridum venom.
An amino-terminal histidyl structure (His1) is characteristic of most peptides in the glucagon superfamily. An assay for His1 peptides performed by amino-terminal amino acid sequencing was used to screen venom from the Gila monster lizard, Heloderma horridum. Two His1 peptides were identified: helospectin and a new His1 peptide that has been named exendin-3 to indicate that it is the third peptide to be found in an exocrine secretion of Heloderma lizards which has endocrine activity, the first two being helospectin (exendin-1) and helodermin (exendin-2). In the lot of H. horridum venom tested, exendin-3 was 5-10-fold more abundant in molar concentration than helospectin. The structure of exendin-3 was analyzed by amino acid sequencing and mass spectrometry. Exendin-3 is a 39-amino acid peptide with a mass of 4200. It contains a carboxyl-terminal amide and has a strong homology with secretin at its amino-terminal 12 amino acids. The complete structure of exendin-3 is His-Ser-Asp-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala- Val-Arg - Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro- Ser- amide. It is 32 and 26% homologous with helospectin and helodermin, respectively. It has greatest homology with glucagon (48%) and human glucagon-like peptide-1 (50%). Exendin-3 (3 microM) stimulated increases in cellular cAMP and amylase release from dispersed guinea pig pancreatic acini.
Solomon A. Berson Research Laboratory, Veterans Affairs Medical Center, Bronx, New York 10468.
J
J
Eng
P C
PC
Andrews
W A
WA
Kleinman
L
L
Singh
J P
JP
Raufman
D000595:Amino Acid Sequence; D000681:Amylases / Q000378:metabolism*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D005934:Glucagon / Q000737:chemistry; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008116:Lizards; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology*; D010446:Peptide Fragments / Q000302:isolation & purification; D010455:Peptides; D011506:Proteins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D012689:Sequence Homology, Nucleic Acid; D014688:Venoms
D010446:Peptide Fragments; D010455:Peptides; D011506:Proteins; D014688:Venoms; C066448:exendin 3; D005934:Glucagon; D000681:Amylases