Leveraging Anaerobic Biochemistry for Novel Therapeutics
Metalloenzymes catalyze some of the most complex chemical reactions found in Nature. The Grove lab studies and exploits a wide range of oxygen-sensitive metalloenzymes for fundamental mechanistic analysis, functional annotation and inhibitor/lead discovery. The primary focus of our lab is on catalytic iron-sulfur cluster (Fe/S) enzymes involved in human health and disease. To exploit these enzymes, the Grove lab utilizes a highly multi-disciplinary approach that includes a range of classical enzymology analyses, high-resolution crystallography, mass spectrometric methods, spectroscopic approaches (e.g., Mössbauer and electron paramagnetic resonance spectroscopies), and high-throughput inhibitor screening, that allow us to define the chemical and physical determinants responsible for substrate selectivity and reactivity. In addition, we take advantage of a variety of cell biological approaches, so as to move beyond the accrual of in vitro activities and to begin defining the complex in vivo biological functions. As a new lab, we have many projects in nascent stages:
- High-throughput drug discovery targeting anaerobic enzymes
- Metabolic profiling and optimization of novel antivirals
- Mechanistic understanding of Fe/S enzymes as a strategy for drug development
- Discovery of novel chemistry of radical SAM enzymes
- Anaerobic biochemistry involved in epigenetic reprogramming
Selected References
Narrow-Spectrum Antibiotic Targeting of the Radical SAM Enzyme MqnE in Menaquinone Biosynthesis. Ayala G Carl, Lawrence D Harris, Mu Feng, Lars U Nordstrøm, Gary J Gerfen, Gary B Evans, Alexey Silakov, Steven C Almo, Tyler L Grove. Biochemistry. 2020 Jul 14;59(27):2562-2575. doi: 10.1021/acs.biochem.0c00070.
Viperin Reveals Its True Function. Efraín E Rivera-Serran, Anthony S Gizzi, Jamie J Arnold, Tyler L Grove, Steven C Almo, Craig E Cameron. Annu Rev Virol. 2020 Jun 30. doi: 10.1146/annurev-virology-011720-095930.
A metabolic pathway for bile acid dehydroxylation by the gut microbiome. Masanori Funabashi*, Tyler L. Grove*, Min Wang , Yug Varma, Molly E McFadden, Laura C Brown, Chunjun Guo, Steven Higginbottom, Steven C Almo, Michael A Fischbach. Nature. 2020 Jun;582(7813):566-570. doi: 10.1038/s41586-020-2396-4.
Discovery of novel bacterial queuine salvage enzymes and pathways in human pathogens. Yifeng Yuan1*, Rémi Zallot*, Tyler L. Grove*, Daniel J. Payan, Isabelle Martin-Verstraete, Sara Sepic, Peter C. Dedon, Steven C. Almo, John A. Gerlt, Valérie de Crécy-Lagard. Proceedings of the National Academy of Sciences. 2019, accepted.
The active site of the Mycobacterium tuberculosis branched-chain amino acid biosynthesis enzyme dihydroxyacid dehydratase contains a 2Fe-2S cluster. Ghader Bashiri,* Tyler L. Grove,* Subray S. Hegde, Thomas Lagautriere , Gary J. Gerfen, Steven C. Almo, Christopher J. Squire, John S. Blanchard, Edward N. Baker. Journal of Biological Chemistry 2019 Jul 16. doi: 10.1074/jbc.RA119.009498
A naturally occurring antiviral ribonucleotide encoded by the human genome. Anthony S. Gizzi*, Tyler L. Grove*,+, Jamie J. Arnold, Joyce Jose, Rohit K. Jangra, Scott J. Garforth, Qaun Du, Sean M. Cahill, Natalya G. Dulyaninova, James D. Love, Kartik Chandran, Anne R. Bresnick, Craig E. Cameron, Steven C. Almo. Nature. 2018 Jun 20; 558(7711):610-614. doi: 10.1038/s41586-018-0238-4
Crystallographic capture of a radical S-adenosylmethionine enzyme in the act of modifying tRNA. Erica L. Schwalm*, Tyler L. Grove*, Squire J. Booker, Amie K. Boal. Science. 2016 Apr 15;352(6283):309-12. DOI: 10.1126/science.aad5367
A Kinetically Competent Substrate Radical Intermediate in Catalysis by the Antibiotic Resistance Protein Cfr. Tyler L. Grove, Jovan Livada, Michael T. Green, Squire J. Booker, and Alexey Silakov. Nature Chemical Biology. 2013; Vol 9, Pages 422-427
