Faculty

Among the functionalities found in nature, the thiol group (R-SH) is endowed with remarkable chemical reactivity. The thiol's distinguishing features stem from its unique pKa, nucleophilicity and bonding characteristics. Together, these properties make it a versatile site for chemical processes that define many essential biological functions. Interestingly, humans and their pathogens have diverged significantly in the synthesis and use of thiol-containing biomolecules. Combining biochemical, organic chemistry and chemical biology approaches with high-resolution mass spectrometry analysis, we are poised to investigate and exploit these differences with an eye toward identifying new avenues for therapeutic intervention and drug development. Three main project areas are currently under investigation:

Sulfur metabolism in Mycobacterium tuberculosis. The thiol group within cysteine residues plays pivotal roles in metal binding to proteins and enzymatic catalysis. In humans, cysteine is formed from the catabolism of the essential amino acid methionine. By contrast, many important human pathogens such as Mycobacterium tuberculosis synthesize cysteine de novo via the sulfate assimilation pathway. We are focusing a major effort toward the development and synthesis of mechanism-based inhibitors of APS reductase, the enzyme that catalyzes the first irreversible step in cysteine biosynthesis.

Mining prokaryotic metabolomes for novel thiols. Many important human pathogens possess the extraordinary capacity to survive and replicate within inhospitable intracellular environments. These organisms evade the host immune system, in part, through the production of specialized thiol-containing compounds that exploit the chemical reactivity of sulfur for cellular detoxification of reactive oxygen and nitrogen species. We are currently developing methods for the enrichment, identification and profiling of thiol-containing metabolites in microorganisms. The goal is to identify thiol-containing virulence-associated biomolecules, and ultimately, their biosynthetic and recycling enzymes.

Redox regulation of protein function. In vivo, cysteine occurs in at least ten different post-translationally modified forms, making it the most diverse amino acid building block in proteins. Among these, the thiol and the disulfide oxidation states are best known, but modifications such as sulfenic, sulfinic, and sulfonic acids are increasingly found to play important roles in catalysis, detoxification and as sensors of oxidative stress. To better understand how nature uses sulfur oxidation state to regulate protein function, we are developing new chemical tools to study these post-translational modifications in living systems.

Awards

2006 Leukemia and Lymphoma Society Special Fellow Award
2003 Damon Runyon Postdoctoral Fellow Award

Representative Publications

1. Reddie, K.G, Seo, Y.H., Muse III, W.B., Leonard, S.E. and Carroll, K.S., "A chemical approach for detecting sulfenic acid-modified proteins in living cells", Mol. BioSyst., 2008, DOI: 10.1039/b719986d.

2. Chang, M.W., Belew, R.K., Carroll, K.S., Olson, A.J., Goodsell, D.S., "Empirical entropic contributions in computational docking: Evaluation in APS reductase complexes", Mol. BioSyst., 2008, DOI: 10.1002/jcc.20936a.

3. Bhave, D.P., Muse III, W.B., Carroll, K.S., "Drug Targets in mycobacterial sulfur metabolism", Infectious Disorders- Drug Targets, 2007, 140.

4. Chartron, J., Shiau, C., Stout, C.D., Carroll, K.S., "3'-Phopspoadenosine-5'-phosphosulfate reductase in complex with thioredoxin: a structural snapshot in the catalytic cycle", Biochemistry, 2007, 46, 3942.

5. Gao, H., Leary, J.A., Carroll, K.S., Bertozzi, C.R., Chen, H., "Noncovalent complexes of APS Reductase from Mycobacterium tuberculosis: delineating a mechanistic model using ESI-FTICR MS", J. Am. Chem. Soc., 2007, 18, 167.

6. Charton, J., Carroll, K.S., Shiau, C., Gao, H., Leary, J.A., Bertozzi, C.R., Stout, C.D., "Substrate recognition protein dynamics adn novel iron-sulfur cluster in Pseudomonas aeruginosa APS reductase", J. Mol. Biol., 2006, 364, 152.

7. Carroll, K.S., Gao, H., Chen, H., Leary, J.A. and Bertozzi, C.R., "Investigation of the iron-sulfur cluster in Mycobacterium tuberculosis APS reductase: Implications for substrate binding and catalysis", Biochem., 2005, 44, 14647.