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Non-cross-linking advanced glycation end products affect prohormone processing.

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The Biochemical Journal
|December 19, 2023
PubMed
Summary

Advanced glycation end products (AGEs) impair protease activity, hindering the processing of essential prohormones like proinsulin into active hormones. This AGE modification may represent a novel mechanism in diabetes and obesity pathogenesis.

Keywords:
advanced glycation end productsdiabetesglycationinsulinproteolysissolid-phase peptide synthesis

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Area of Science:

  • Biochemistry
  • Endocrinology
  • Molecular Biology

Background:

  • Advanced glycation end products (AGEs) are formed through non-enzymatic modifications of amino acids.
  • AGEs are implicated in diabetic complications, potentially through impaired protein processing.
  • The effect of AGEs on prohormone processing to active hormones requires further investigation.

Purpose of the Study:

  • To investigate whether AGE modification of substrates affects their processing by proteases.
  • To determine the impact of AGEs on the processing of proinsulin to insulin.

Main Methods:

  • Solid-phase peptide synthesis was used to create AGE-modified and unmodified protease substrates.
  • Protease activity was quantified using these synthesized substrates.
  • The effect of methylglyoxal-modified proinsulin on insulin formation was assessed.

Main Results:

  • AGE modification (CML, MG-H1) significantly inhibited protease activity, with cysteine cathepsins showing ~50% reduction.
  • Key proteases like trypsin, PCSKs, and CPE were completely inactive towards AGE-modified substrates.
  • Methylglyoxal-modified proinsulin showed up to 80% reduced conversion to insulin in a concentration-dependent manner.

Conclusions:

  • Substrate modification with AGEs inhibits protease activity.
  • The inactivity of essential prohormone processing enzymes (PCSKs, CPE) towards AGE-modified substrates suggests a new pathomechanism in diabetes and obesity.
  • AGE modification's impact on hormone processing is a critical factor in metabolic disease etiology.