Lipid discovery enabled by sequence statistics and machine learning
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Updated: Jul 12, 2025
Isolation of Lipoprotein Particles from Chicken Egg Yolk for the Study of Bacterial Pathogen Fatty Acid Incorporation into Membrane Phospholipids
Published on: May 15, 2019
Abstract:
Bacterial membranes are complex and dynamic, arising from an array of evolutionary pressures. One enzyme that alters membrane compositions through covalent lipid modification is MprF. We recently identified that Streptococcus agalactiae MprF synthesizes lysyl-phosphatidylglycerol (Lys-PG) from anionic PG, and a novel cationic lipid, lysyl-glucosyl-diacylglycerol (Lys-Glc-DAG), from neutral glycolipid Glc-DAG. This unexpected result prompted us to investigate whether Lys-Glc-DAG occurs in other MprF-containing bacteria, and whether other novel MprF products exist. Here, we studied protein sequence features determining MprF substrate specificity. First, pairwise analyses identified several streptococ-cal MprFs synthesizing Lys-Glc-DAG. Second, a restricted Boltzmann machine-guided approach led us to discover an entirely new substrate for MprF in Enterococcus , diglucosyl-diacylglycerol (Glc 2 -DAG), and an expanded set of organisms that modify glycolipid substrates using MprF. Overall, we combined the wealth of available sequence data with machine learning to model evolutionary constraints on MprF sequences across the bacterial domain, thereby identifying a novel cationic lipid.
Insights
Researchers explored bacterial MprF enzyme functions, discovering new cationic lipids like lysyl-glucosyl-diacylglycerol (Lys-Glc-DAG) and diglucosyl-diacylglycerol (Glc2-DAG) in various bacteria. This work advances our understanding of bacterial membrane modifications.
Area of Science:
- Microbiology
- Biochemistry
- Molecular Biology
Background:
- Bacterial membranes are crucial for cell survival and are shaped by evolutionary pressures.
- The MprF enzyme covalently modifies membrane lipids, influencing membrane composition and properties.
- Previous work identified Streptococcus agalactiae MprF synthesizing lysyl-phosphatidylglycerol (Lys-PG) and a novel cationic lipid, lysyl-glucosyl-diacylglycerol (Lys-Glc-DAG).
Purpose of the Study:
- To investigate the occurrence of Lys-Glc-DAG in other MprF-containing bacteria.
- To identify novel MprF products and understand MprF substrate specificity.
- To model evolutionary constraints on MprF sequences using machine learning.
Main Methods:
- Comparative sequence analysis of MprF proteins across bacterial species.
- Machine learning, specifically restricted Boltzmann machines, to predict MprF substrate specificity.
- Investigating MprF activity in various bacterial genera, including Streptococcus and Enterococcus.
Main Results:
- Several streptococcal MprF enzymes were confirmed to synthesize Lys-Glc-DAG.
- A novel MprF substrate, diglucosyl-diacylglycerol (Glc2-DAG), was identified in Enterococcus species.
- An expanded range of bacteria utilizing MprF for glycolipid modification was discovered.
Conclusions:
- MprF exhibits broader substrate specificity than previously known, including glycolipids.
- Machine learning approaches are effective in predicting enzyme function and discovering novel substrates.
- This study reveals new cationic lipids and expands the known functions of MprF in bacterial membrane biosynthesis.
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