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Macrocyclization and Backbone Rearrangement During RiPP Biosynthesis by a SAM-Dependent Domain-of-Unknown-Function
Richard S Ayikpoe1,2, Lingyang Zhu3, Jeff Y Chen1,2
1Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, 61801, Illinois, United States.
ACS Central Science
|May 30, 2023
Summary
Researchers identified ChrH, a novel enzyme in the DUF692 family, which catalyzes a unique chemical transformation. This discovery expands the known functions of these iron-containing enzymes and suggests a new family name: multinuclear non-heme iron dependent oxidative enzymes (MNIOs).
Area of Science:
- Biochemistry
- Enzymology
- Natural Products Chemistry
Background:
- The DUF692 (domain of unknown function 692) family comprises emerging post-translational modification enzymes.
- These enzymes are crucial in synthesizing ribosomally synthesized and post-translationally modified peptide (RiPP) natural products.
- DUF692 enzymes are multinuclear iron-containing and only MbnB and TglH were previously characterized.
Purpose of the Study:
- To investigate another member of the DUF692 family, ChrH, found in *Chryseobacterium* species.
- To elucidate the chemical transformation catalyzed by the ChrH-ChrI enzyme complex.
- To propose a reaction mechanism and re-classify the DUF692 family.
Main Methods:
- Bioinformatic analysis to identify ChrH and its partner protein ChrI.
- Structural characterization of the ChrH reaction product.
- Isotopic labeling studies to determine the reaction mechanism.
Main Results:
- The ChrH-ChrI complex catalyzes an unprecedented reaction, forming a macrocycle, imidazolidinedione heterocycle, thioaminals, and a thiomethyl group.
- The first S-adenosylmethionine (SAM)-dependent reaction catalyzed by a DUF692 enzyme complex was identified.
- A proposed mechanism for the four-electron oxidation and methylation of the substrate peptide.
Conclusions:
- ChrH expands the known chemical repertoire of DUF692 enzymes.
- The study identifies a novel SAM-dependent enzymatic reaction.
- A proposal to rename the DUF692 family as multinuclear non-heme iron dependent oxidative enzymes (MNIOs) based on characterized members.
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