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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
Lipid discovery enabled by sequence statistics and machine learning
Priya M Christensen1, Jonathan Martin1, Aparna Uppuluri1
1Department of Biological Sciences, University of Texas at Dallas, Richardson, United States.
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 streptococcal 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 (Glc2-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 through sequence analysis and machine learning.
Area of Science:
- Microbiology
- Biochemistry
- Bioinformatics
Background:
- Bacterial membranes are crucial for cell function and are shaped by evolutionary pressures.
- The MprF enzyme modifies membrane lipids through covalent attachment of amino acids.
Purpose of the Study:
- To investigate the substrate specificity of the MprF enzyme.
- To identify novel MprF products and the organisms that synthesize them.
- To model evolutionary constraints on MprF sequences.
Main Methods:
- Comparative sequence analysis of MprF proteins across different bacterial species.
- Application of machine learning (restricted Boltzmann machine) to predict MprF substrate specificity.
- Identification and characterization of novel lipid products.
Main Results:
- Streptococcal MprF enzymes were found to synthesize lysyl-glucosyl-diacylglycerol (Lys-Glc-DAG).
- A novel MprF substrate, diglucosyl-diacylglycerol (Glc2-DAG), and its product were identified in Enterococcus.
- An expanded range of bacteria utilizing MprF for glycolipid modification was discovered.
Conclusions:
- MprF exhibits diverse substrate specificities across bacterial species.
- Machine learning approaches can effectively predict enzyme function and uncover novel biochemical pathways.
- The study expands the known repertoire of bacterial cationic lipids and the enzymes responsible for their synthesis.
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