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Enzymes are proteins made of amino acids. The functional group of each constituent amino acid catalyzes a wide variety of chemical reactions via ionic interactions or acid-base reactions. However, amino acids cannot catalyze oxidation-reduction and group transfer reactions and need to be aided by non-protein components called cofactors. Cofactors are also referred to as the chemical teeth of an enzyme.
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Updated: Jun 1, 2025

Extraction of Cofactor F420 for Analysis of Polyglutamate Tail Length from Methanogenic Pure Cultures and Environmental Samples
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"Cofactors" for Natural Products.

Shao-Lun Chiou1, Chin-Yuan Chang2, John Chu1

  • 1Department of Chemistry, National Taiwan University, 106319, Taipei City, Taiwan.

Chemmedchem
|January 17, 2025
PubMed
Summary

Cofactors, non-protein molecules, are crucial for natural product function, enabling diverse activities. Recognizing cofactor-mediated mechanisms of action (MOA) in natural products is key to discovering novel chemistry.

Keywords:
Calcium dependent antibiotic (CDA)CofactorsMetal cationsNatural productsRedox reactions

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Area of Science:

  • Biochemistry
  • Natural Product Chemistry

Background:

  • Cofactors are essential non-protein molecules that expand protein functional capabilities beyond the 20 canonical amino acids.
  • The role of cofactors in the mechanisms of action (MOA) of natural products is often overlooked.
  • This concept highlights the significance of cofactors in natural product chemistry.

Purpose of the Study:

  • To emphasize the prevalence and importance of cofactor-mediated MOA in natural products.
  • To encourage the identification of novel cofactor-dependent natural products.
  • To shift the perspective on natural product functionality.

Main Methods:

  • Review and conceptual analysis of existing literature on natural products and cofactors.
  • Case study analysis of bleomycin and laspartomycin as examples of cofactor-mediated MOA.
  • Discussion of the implications for future natural product research.

Main Results:

  • Cofactors like iron (Fe(II)) and calcium (Ca(II)) are essential for the biological activities of natural products such as bleomycin and laspartomycin.
  • Bleomycin acts as a pseudoenzyme upon iron binding to generate reactive oxygen species.
  • Calcium binding induces a conformational change in laspartomycin, activating its antibacterial properties.

Conclusions:

  • Cofactor-mediated MOA is likely a widespread phenomenon in natural products, though currently underappreciated.
  • Serendipitous discovery has been common, underscoring the need for a conscious search for cofactor roles.
  • Recognizing cofactor dependence is crucial for unlocking the full potential and novel chemistry of natural products.