Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1980 Jan;77(1):82–86. doi: 10.1073/pnas.77.1.82

Amino acid side chain conformation in angiotensin II and analogs: Correlated results of circular dichroism and 1H nuclear magnetic resonance

F Piriou *, K Lintner *, S Fermandjian *, P Fromageot *, M C Khosla †, R R Smeby †, F M Bumpus †
PMCID: PMC348212  PMID: 6928653

Abstract

[1-Sarcosine,8-isoleucine]angiotensin II (Sar-Arg-Val-Tyr-Ile-His-Pro-Ile) has been shown to be a potent antagonist of the pressor action of angiotensin II. With a view to increase half-life in vivo of this peptide, the amino acid residue at position 4 (tyrosine) or position 5 (isoleucine) was replaced with the corresponding N-methylated residue. This change drastically reduced the antagonistic properties of this analog. The present work was therefore undertaken to investigate the effect of N-methylation on overall conformation of these peptides and to determine the conformational requirements for maximum agonistic or antagonistic properties. Conformation studies were carried out by circular dichroism and proton nuclear magnetic resonance spectroscopy in aqueous solution as a function of pH. The results indicated that: (i) angiotensin II and [1-sarcosine,8-isoleucine]angiotensin II gave practically identical spectroscopic data; and (ii) N-methylation in either position 4 or position 5 resulted in remarkable changes in the peptide backbone and a severe limitation in rotational freedom of side chains in tyrosine, isoleucine, and histidine residues. However, rotational restriction of the tyrosine side chain was found to be less pronounced in [1-sarcosine,4-N-methyltyrosine,8-isoleucine]angiotensin II than in [1-sarcosine,5-N-methylisoleucine,8-isoleucine]angiotensin II. Thus, these results suggest that: (i) the backbone and side chain structure of a potent angiotensin II antagonist should resemble that of the hormone, angiotensin II, so that it can mimic the hormone in recognizing and binding with the receptor on the cell membrane; and (ii) greater impact of N-methylation in position 5 on the overall conformation of these peptides points to the controlling influence of position 5 (isoleucine) in aligning the residues in the central segment (tyrosine-isoleucine-histidine) of angiotensin II and its potent agonist and antagonist analogs in a nearly extended structure. Any change in this arrangement may lead to reduced biological activity.

Keywords: peptide hormones, competitive inhibitor, N-methylation, pH titration

Full text

PDF
82

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Glickson J. D., Cunningham W. D., Marshall G. R. Proton magnetic resonance study of angiotensin II (Asn1Va15) in aqueous solution. Biochemistry. 1973 Sep 11;12(19):3684–3692. doi: 10.1021/bi00743a018. [DOI] [PubMed] [Google Scholar]
  2. Khosla M. C., Hall M. M., Smeby R. R., Bumpus F. M. Synthesis of analogs of (8-isoleucine)angiotensin II with variations in position 1. J Med Chem. 1974 Apr;17(4):431–433. doi: 10.1021/jm00250a013. [DOI] [PubMed] [Google Scholar]
  3. Khosla M. C., Mũnoz-Ramírez H., Hall M. M., Smeby R. R., Khairallah P. A., Bumpus F. M., Peach M. J. Synthesis of angiotensin II antagonists containing N- and O-methylated and other amino acid residues. J Med Chem. 1976 Feb;19(2):244–250. doi: 10.1021/jm00224a009. [DOI] [PubMed] [Google Scholar]
  4. Lintner K., Fermandjian S., Fromageot P., Khosla M. C., Smeby R. R., Bumpus F. M. Circular dichroism studies of angiotensin II and analogues: effects of primary sequence, solvent, and pH on the side-chain conformation. Biochemistry. 1977 Feb 22;16(4):806–812. doi: 10.1021/bi00623a037. [DOI] [PubMed] [Google Scholar]
  5. Lintner K., Fermandjian S., Fromageot P. pH titration effects on the CD spectra of angiotensin II, truncated peptides and other analogues: aromatic region. FEBS Lett. 1975 Aug 15;56(2):366–369. doi: 10.1016/0014-5793(75)81129-x. [DOI] [PubMed] [Google Scholar]
  6. Lintner K., Fermandjian S., Regoli D., Barabé J. Conformational features of bradykinin. A circular dichroism study of the aromatic side-chains. Eur J Biochem. 1977 Dec 1;81(2):395–401. doi: 10.1111/j.1432-1033.1977.tb11964.x. [DOI] [PubMed] [Google Scholar]
  7. Patel D. J., Tonelli A. E. N-methylleucine gramicidin-S and (di-N-methylleucine) gramicidin-S conformations with cis L-Orn-L-N-MeLeu peptide bonds. Biopolymers. 1976 Aug;15(8):1623–1635. doi: 10.1002/bip.1976.360150815. [DOI] [PubMed] [Google Scholar]
  8. Regoli D., Park W. K., Rioux F. Pharmacology of angiotensin. Pharmacol Rev. 1974 Jun;26(2):69–123. [PubMed] [Google Scholar]
  9. Tonelli A. The effects of isolated N-methylated residues on the conformational characteristics of polypeptides. Biopolymers. 1976 Aug;15(8):1615–1622. doi: 10.1002/bip.1976.360150814. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES