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Developing novel drugs targeting gut microbiota-accelerated heart diseases

Principal Supervisor: Dr Yin Chen, School of Life Sciences

Co-supervisor: Prof Tim Bugg, Department of Chemistry

PhD project title: Developing novel drugs targeting gut microbiota-accelerated heart diseases

University of Registration: University of Warwick

Project outline:

It is increasing evident that human is a “super-organism”. We co-exist with trillions of microorganisms in our body (collectively named as microbiota), and our health can largely depend on the interrelationship between ourselves and associated microbiome. Although we start to appreciate the enormous diversity of the microbiome and their biogeography in our body thanks to the technology advance of next-generation sequencing, our knowledge on the exact functions of majority of the human microbiome is very limited.

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). 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. It is a hexamer with two back-to-back stacked homotrimer.

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.

References:

  1. Wang et al 2011 Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472:57-63.
  2. Koeth et al., 2013 Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Medicine. 19, 576–585.
  3. Zhu et al., 2014 Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota PNAS 111: 4268-4273.

 BBSRC Strategic Research Priority: Bioenergy and Industrial Biotechnology

Techniques that will be undertaken during the project:

  • RNA-seq and subsequent data analysis;
  • Molecular cloning and construction of expression vectors in E. coli;
  • UV-Vis spectrometry;
  • Marker exchange mutagenesis;
  • Complementation of targeted mutants;
  • Gas and ion chromatography Molecular cloning and construction of expression vectors;
  • Site directed mutagenesis, protein purification;
  • Steady state enzyme kinetics;
  • Homology modelling;
  • UV-Vis spectrometry;
  • ICP-MS

Contact: Dr Yin Chen, University of Warwick