AI Article Synopsis
- Cystargolides and belactosins are natural compounds that inhibit proteases, making them potential treatments for cancers and neurodegenerative diseases.
- Recent genetic analyses suggest that these inhibitors share similarities in their biosynthetic pathways.
- Researchers identified a specific motif (His-His-Asp) in enzymes BelI and CysG that is essential for function, revealing a unique metal-dependent mechanism in their synthesis.
Article Abstract
Cystargolides and belactosins are natural products with a distinct dipeptide structure and an electrophilic β-lactone warhead. They are known to inhibit proteases such as the proteasome or caseinolytic protease P, highlighting their potential in treating cancers and neurodegenerative diseases. Recent genetic analyses have shown homology between the biosynthetic pathways of the two inhibitors. Here, we characterize the O-methyltransferases BelI and CysG, which catalyze the initial step of β-lactone formation. Employing techniques such as crystallography, computational analysis, mutagenesis, and activity assays, we identified a His-His-Asp (HHD) motif in the active sites of the two enzymes, which is crucial for binding a catalytically active calcium ion. Our findings thus elucidate a conserved divalent metal-dependent mechanism in both biosynthetic pathways that distinguish BelI and CysG from previously characterized O-methyltransferases.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11408123 | PMC |
| http://dx.doi.org/10.1016/j.jbc.2024.107646 | DOI Listing |
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