Vice Chair of Pharmaceutical Sciences/Assistant Dean for Graduate Stud
7117 Rennebohm Hall
Chuck received his B.S. degree in chemistry (1986) from the Massachusetts Institute of Technology and a Ph.D. degree in chemistry (1992) from the University of California-Berkeley. He was a Damon Runyon-Walter Winchell Cancer Research Fellow in the Department of Molecular Biology at the Massachusetts General Hospital. He joined the School of Pharmacy faculty in the fall of 1996. His research interests are in the area of tRNA modification and sulfur biochemistry.
One of our research interests is the biochemistry of tRNA modification. Protein enzymes that modify individual bases of tRNA are especially interesting because their substrates are single nucleotides within a large tRNA molecule. Thus, these enzymes are able to recognize not only the nucleotide to be modified but also the surrounding RNA structure. Although many tRNA base modifications are simple chemically and have subtle effects on tRNA function, there are also some modifications that have important links to the regulation of metabolites in the cell. Some may even act as environmental sensors. We are interested in studying the mechanistic enzymology of these transformations through the use of organic chemistry (i.e., synthe sis of alternate substrates and inhibitors), enzymology (establishing a chemical and kinetic mechanism) and molecular biology (cloning the genes that code for these enzymes, selecting for optimal RNA substrates). Another goal is to understand the regulatory effects that these modifications have on cellular metabolism. Two examples are the thiolation at C-4 of uridine 8 in eubacterial tRNAs and the thiomethylation of adenosine 37 in a variety of bacterial and eukaryotic tRNAs. Both of these modifications are proposed to act as sensors inside the cell. Thiouridine 8 is crosslinked when exposed to near UV light to give a specific intramolecular adduct that is proposed to act as a signal for the initiation of DNA repair mechanisms. The absence of thiomethyl substitutions at A37 of certain tRNAs may signal a deficiency in soluble iron.
Another area of interest involves the study of biosynthetic pathways involving sulfur. We have discovered through our work in thionucleoside biosynthesis that the cysteine desulfurase IscS is the major cellular catalyst for the mobilization and distribution of sulfur in E. coli. This gene is found in nearly all forms of life and is highly conserved. E. coli mutants lacking iscS grow sluggishly and have mutliple nutriti onal requirements for metabolites that either contain sulfur or require the action of Fe-S cluster enzymes for their synthesis. The form of sulfur that is transferred by IscS is a persulfide, or sulfane, derivative of an active site cysteine. This sulfa ne sulfur can be transferred to cysteine residues on other proteins for use in the biosynthesis of Fe-S clusters or other novel sulfur transfer reactions. Our overall goal is to discover the scope as well as the specificity determinants of this type of sulfur transfer in E. coli as a model organism.
RNA biochemistry and chemistry/biochemistry of sulfur