Carroll Lab

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Research: Sulfur in Chemistry and Biology

Redox Signaling | Microbial Sulfur Metabolism

Redox Signaling

Cysteine has been found to occur in up to 10 different sulfur oxidation states in vivo , making it the most diverse amino acid building block in proteins. Among these, the thiol (R–SH) and the disulfide (R–S–S–R) oxidation states are best known, but modifications such as sulfenic (R–SOH), sulfinic (R–SO2H), and sulfonic (R–SO3H) acids play an increasingly important role in biochemistry. Considering that each of these cysteine oxidation states represents a separate post-translational protein modification, with its own chemical reactivity and metal-binding properties, the functional diversity that can arise from these modifications is unrivaled. Moreover, many thiol modifications are also reversible by the action of enzymes. Thus, oxidation of pivotal cysteine residues on a protein or peptide can operate like a switch, activating or deactivating its cellular function in a manner analogous to more widely studied modifications, such as phosphorylation and dephosphorylation. Despite studies implicating oxidative thiol modification as a modulator of cellular processes, the molecular details of the majority of these modifications, including the repertoire of proteins containing cysteine post-translational modifications (PTMs) and the specific sites of modification remain largely unknown. With the goal of answering these questions, we aim to develop a novel proteomics approach for probing thiol modifications that exploits the unique reactivity of each cysteine “oxoform” for selective recognition. In turn, we apply these new 'tools' to examine changes in protein thiol modification in a variety of biological processes including cell migration, differentiation and death.

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Microbial Sulfur Metabolism

Sulfur metabolic pathways are essential for the virulence and survival of human pathogens. In microbial cysteine biosynthesis, sulfonucleotide reductases (SRs) catalyze the reduction of adenosine 5'-phosphosulfate (APS) or 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to sulfite using reducing equivalents from a protein cofactor, thioredoxin (Trx). In later stages, sulfite is further reduced to sulfide, which is used for the production of essential sulfur-containing metabolites including cysteine, methionine, coenzymes, iron-sulfur clusters and antioxidants. SRs are excellent new targets for antibiotic development because of their critical role in bacterial survival and the lack of analogous enzymes in humans. However, many fundamental questions about their mechanism and structure remain unknown. Because the chemistry and biology of bacterial SRs is not well understood, the potential of these enzymes as anti-infective targets remains unexplored. The broad goal of this project area is directed towards obtaining detailed mechanistic and structural information on bacterial SRs, and on identifying small molecule inhibitors of SRs. This work may lead to the development of inhibitors of bacterial SRs that can be used to combat resistant bacteria. Furthermore, we anticipate that these experiments will provide important new insights into, and new methods for studying, bacterial sulfur metabolism.

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Carroll Lab

Research: Sulfur in Chemistry and Biology

Redox Signaling

Microbial Sulfur Metabolism