About the Project
This PhD project aims to address a highly topic issue: the production of trimethylamine (and its oxidative product trimethylamine oxide) by human microbiota. Production of these small amines in our bodies has been shown to promote plaque formation in blood vessels and hence development of cardiovascular disease (Wang et al. 2011; Koeth et al., 2013). This metabolic pathway is primarily driven by oral and intestinal microbes through the degradation of dietary quaternary amines, such as carnitine which is an essential micronutrient for human.
We have recently identified a novel Rieske type monooxygenase, CntA, involved in the transformation of carnitine to trimethylamine from representative human microbiota (Zhu et al., 2014) and have solved the structure of this protein. CntA represents a large group of previously uncharacterized Rieske type proteins and has a number of unusual features. For example, it has a “bridging” glutamate rather than an aspartate residue coordinating cross-subunit electron transfer.
The aim of this project is therefore twofold: 1) to study the structure-function relationship of CntA; 2) using the structural data to rational-design specific inhibitors through chemical biosynthesis as well as screening from natural product libraries for diminishing carnitine-dependent atherosclerosis in humans.
Techniques that will be undertaken during the project:
- Molecular cloning and construction of expression vectors in E. coli;
- Molecular cloning and construction of expression vectors;
- Site directed mutagenesis, protein purification;
- Steady state enzyme kinetics;
- Homology modelling;
- UV-Vis spectrometry; ICP-MS
- Drug design
- Inhibitor testing using gut microbiota
Koeth et al., 2013 Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine. 19, 576–585.
Zhu et al., 2014 Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota PNAS 111:4268-4273.
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