Lipid Metabolism by Cytochrome P450 epoxygenases  

Welcome to Das Lab at Georgia Tech !! 

Scientific Mission: 

We lead an exciting research program in the chemistry of lipid metabolism, an area of great fundamental interest and importance to our understanding of biochemistry, immunology, and cellular regulation. In particular, we focus on the fundamental chemistry of the biotransformation of lipids by enzymes. We delve into elucidating the mechanism of small molecules interaction with proteins such as cytochrome P450s, receptors, ion channels, hydrolases, and others. The small molecules used in our study are the following: endogenous lipids, exogenous lipids, phytocannabinoids and  drugs. 

We use several biophysical tools and analytical methods such as spectroscopy, microscopy, mass spectrometry, nanodiscs. Additionally, we elucidate the immuno-modulatory properties of these small molecules and delve deeper into their molecular pharmacology. 

Specific projects in the laboratory includes the detailed study of the metabolism of endocannabinoids, a key lipid metabolite class that is growing in importance due to its role in control of pain and inflammation. These naturally-produced endocannabinoids derived from fatty acids mediate neurological processes and inflammation, and so are important in problems in neuroscience, addiction, aging, and immune signaling. Current and recent projects include studies of metabolite generation by metalloenzymes, regulation of cannabinoid receptor function, endocannabinoid interactions with pain receptors (TRP channels and cannabinoid receptors). Separately, our laboratory has interest in developing Nanodisc technology for the study and imaging of membrane proteins. In summary, the laboratory focusses on cytochrome P450s-mediated lipid metabolism and drug-lipid interactions.

Minor Cannabinoid Research: Minor cannabinoids such as cannabigerol (CBG) and cannabichromene (CBC) are gaining widespread attention owing to their medicinal benefits like pain relief and neuroprotection without the psychoactivity associated with tetrahydrocarbinol (THC). There are very few studies that have focused on the metabolism of minor cannabinoids by cytochrome P450s. The aim is to study the metabolism of the following phytocannabinoids (pCBs): Cannabigerol (CBG) and cannabichromene (CBC) by different Cytochrome P450 (CYPs) enzymes present in the liver. We have carried out CBG and CBC metabolism in presence of different liver and brain CYPs: CYP3A4, 2C9,2D6, 2C8 and 2J2. We quantified the metabolites using targeted liquid chromatography-mass spectrometry (LC/MS/MS) method using synthesized authentic standards from Sarlah group. We identified epoxy and hydroxy products of CBG and CBC which forms the predominant products. We show that the rates of metabolite production vary depending on the CYPs used. Kinetics of minor cannabinoid metabolism by CYPs shows deviation from Michaelis-Menten equation and indicates the involvement of multiple sites. Interestingly the products obtained from in vitro studies are also isolated from blood plasma of mice fed with CBG or CBC from Hellman group. In addition, computational studies (protein-ligand docking and molecular dynamics) were used to delineate the mechanism of this binding and inhibition. The computational analysis shows that the orientation of CBG or CBC at the heme pocket of CYPs can significantly regulate the site of metabolism. On a separate note, all the metabolites obtained from CBG and CBC showed the concentration dependent effect on inflammation by slowing down the expression of pro-inflammatory cytokines and increasing production of antiinflammatory cytokines. Overall, the study of the metabolism of minor cannabinoids by cytochrome P450s will lead to the identification of CBG and CBC metabolites with potential bioactivity towards pain and inflammation

Diversity Statement:   

In our Lab, we are committed to performing basic science research, developing new technologies, training scientists to serve humanity. We strongly believe in a diverse and inclusive working environment. We welcome researchers of all races, ethnicities, sexual orientations, gender identities, and abilities. We foster an open space where we can learn from each other, share innovative thoughts and be proactive to make science a more equitable working space. 

Mentoring Philosophy

Our laboratory is dedicated to the belief that the fundamental purpose of academic research lies in advancing scientific knowledge, uncovering basic principles, and nurturing the next generation of scientists. Each of these objectives holds equal significance in fostering the growth and perpetuation of knowledge for the greater benefit of the community.

Mentor-Mentee relationship: The journey from a novice to an expert in scientific research encompasses various dimensions. As a cohesive team, we aspire to guide our students and trainees through this multifaceted training process via transparent communication. Fostering an open and interactive relationship between students and advisors is imperative for the successful culmination of research training, aiming to make the experience both enjoyable and productive.