Inhibitory neurotransmitters, such as y-aminobutyric acid (GABA), taurine, taurine analogs and β-alanine, have been associated with neurological disorders such as epilepsy, schizophrenia, dementia, autism, Alzheimer’s disease (AD) and more. Additionally, gut microbiome dysbiosis has also been linked to many neurological disorders, with modulations in the abundance of microbes of the genus Bacteroides often observed. Recent evidence shows that Bacteroides has the glutamate decarboxylase (GAD)-encoding gene, which catalyzes conversion of an excitatory neurotransmitter glutamate to an inhibitory neurotransmitter GABA. However, very little is known about the chemistry of the glutamate decarboxylases encoded by Bacteroides sp.
Prof. Dhara Shah, at the Biodesign Institute of Arizona State University has developed a chemical strategy to modulate the production of neuromodulatory molecules by gut microbes. She found that glutamate decarboxylase (BfGAD) from Bacteroides fragilis produces multiple neuromodulatory molecules such as gamma-aminobutyric acid (GABA), hypotaurine, taurine, homotaurine, and β-alanine. Through rational protein engineering of BfGAD, variants with altered enzymatic activities were produced; one variant showed a two-fold increase in taurine productivity, and in another enhanced specificity towards the substrate L-glutamate was seen. She has developed a chemical strategy via which the BfGAD activity could be fine-tuned and used to modulate the production of neuromodulatory molecules.
This strategy shows great potential for modulating neuroactive metabolites produced by gut microbial enzymes and could potentially pave the road to therapeutic interventions.
Potential Applications
- Gut-produced neuromodulatory molecules
- Treatment of neurological disorders
- Studying the gut microbiome and its impact on neural health
Benefits and Advantages
- Enhanced catalytic efficiency and substrate specificity with engineered gut microbial enzymes
- GAD from a prominent gut microbe can decarboxylate substrates other than L-glutamate
- Increased production of multiple neuroactive molecules
- Rational protein engineering of BfGAD produces a resilient enzyme in nature that is able to tolerate changes to the active site
- This approach has the ability to generate additional BfGAD variants
- Could produce neuromodulator molecules in specific ratios
- Could synthesize a particular neuromodulatory molecule exclusively
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