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A Hydrogen-Deuterium Exchange Mass Spectrometry HDX-MS Platform for Investigating Peptide Biosynthetic Enzymes
Published on: May 4, 2020
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Divergent Evolution of Lanthipeptide Stereochemistry.
Raymond Sarksian1, Wilfred A van der Donk1,2
1Department of Chemistry and Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61822, United States.
ACS Chemical Biology
|August 24, 2022
Summary
This study compares two lanthipeptide biosynthetic gene clusters, revealing how a unique Thr-glutamyl lyase enzyme controls stereochemistry in natural product synthesis, leading to distinct methyllanthionine structures.
Area of Science:
- Biochemistry
- Natural Product Synthesis
- Structural Biology
Background:
- Lanthipeptides are complex natural products with critical 3D structures for biological activity.
- Stereochemistry of lanthionine (Lan) and methyllanthionine (MeLan) residues is precisely controlled by specific enzymes.
- Class I lanthipeptide biosynthetic gene clusters (BGCs) in Actinobacteria share common genes for peptide modification.
Purpose of the Study:
- To compare the coi and olv class I lanthipeptide BGCs from Actinobacteria.
- To investigate the role of a fused Thr-glutamyl lyase (GL) domain in controlling stereochemistry.
- To elucidate the mechanism of natural product stereochemical divergence in lanthipeptide biosynthesis.
Main Methods:
- Comparative analysis of the coi and olv lanthipeptide BGCs.
- Characterization of precursor peptides and their post-translational modifications.
- Enzymatic assays to determine the function of the GL domain in stereochemical control.
Main Results:
- The coi BGC contains a unique fused GL-methyltransferase (MT) enzyme (CoiSA) absent in the olv BGC.
- CoiA1 is processed into a polymacrocyclic product (mCoiA1) with analogous ring patterns to mOlvA.
- Significant stereochemical differences were observed in two MeLan rings of mCoiA1, including a rare d-allo-l-MeLan residue, guided by CoiSA.
Conclusions:
- Nature employs distinct GL enzymes to precisely control stereochemistry in lanthipeptide biosynthesis.
- The fused GL domain in CoiSA is key to generating unique stereoisomers, such as d-allo-l-MeLan.
- This study highlights a novel mechanism for generating stereochemical diversity in natural products.
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