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Related Experiment Videos

An insulin with the native sequence but virtually no activity

A Wollmer1, G Gilge, D Brandenburg

  • 1Institut für Biochemie, Rheinisch-Westfälische Technische Hochschule Aachen, Germany.

Biological Chemistry Hoppe-Seyler
|March 1, 1994
PubMed
Summary
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Replacing a peptide bond with an ester in insulin, researchers created novel depsipeptides. Surprisingly, these modified insulins showed significantly reduced potency, challenging initial hypotheses about flexibility and receptor binding.

Area of Science:

  • Biochemistry
  • Endocrinology
  • Protein Chemistry

Background:

  • Insulin's structure is critical for its biological activity.
  • Hydrogen bonds within insulin contribute to its conformational stability.
  • Modifying key bonds may alter insulin's interaction with its receptor.

Purpose of the Study:

  • To investigate the impact of replacing the B24-B25 peptide bond with an ester bond in insulin.
  • To assess if increased flexibility enhances insulin receptor binding and activity.
  • To synthesize and characterize novel insulin analogs (depsi-insulin).

Main Methods:

  • Chemical synthesis of insulin analogs with an ester bond at the B24-B25 position.
  • Biochemical assays to measure receptor binding affinity.

Related Experiment Videos

  • In vitro studies to determine biological potency.

    • Main Results:

    • The synthesized porcine [B24-B25 CO-O]insulin (depsi-insulin) and depsipeptide des-(B26-B30)insulin-B25-amide exhibited only 3-4% of the potency of native insulin.
    • The modification did not enhance, but rather significantly reduced, insulin activity.
    • This suggests the eliminated H-bond is crucial for maintaining activity, not just flexibility.

    Conclusions:

    • Replacing the B24-B25 peptide bond with an ester bond in insulin drastically reduces its biological potency.
    • Contrary to expectations, increased flexibility at this site does not enhance receptor binding or activity.
    • The structural integrity maintained by the peptide bond and its associated hydrogen bond appears essential for insulin's function.