Graduate Study in - Chemistry - Johns Hopkins University

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Bioorganic Chemistry and Enzymology hendrick@jhu.edu Tamara L. Hendrickson Our research group is interested in evaluating the mechanisms and consequences of complex enzymatic systems, within the broad field of protein translation. We use a multidisciplinary approach, integrating tools from biochemistry, molecular biology, enzymology and synthetic organic chemistry. Several projects focus on an indirect pathway for tRNA aminoacylation. Traditionally, it was believed that all organisms use 20 aminoacyl-tRNA synthetases (one for each encoded amino acid) to biosynthesize a complement of aminoacyl-tRNAs. The wealth of genomic data that has become available over the past few years, however, has revealed that many bacteria and archaea thrive in the absence of glutaminyl- and/or asparaginyl-tRNA synthetase. In these cases, tRNA Gln and tRNA Asn are misacylated respectively by either glutamyl- or aspartyl-tRNA synthetase. Next, a glutamine-dependent amidotransferase (Glu-AdT) converts the misacylated tRNA to the correct species. (Fig. 1 depicts this process for the generation of glutaminylated-tRNA Gln .) Very little is known about Glu-Adt, its mechanism of action or the methods by which it recognizes two different tRNA substrates (tRNA Gln and tRNA Asn ). Several projects in our lab seek to address some of these issues, by evaluating Glu-Adt from the stomach ulcer-inducing pathogenic bacterium H. pylori, from human mitochondria and from the hyperthermophilic archaeon P. furiousus. The second area of interest in the lab is the biosynthesis of glycosyl phosphatidylinositol (GPI) membrane anchored proteins (Fig. 2). GPI anchor attachment converts a soluble protein into a membrane-associated protein. The complexity of this system is due to the specificity with which a putative transamidase (GPI-T) aligns two large substrates, targeting the carbohydrate anchor to a particular amide bond within the protein substrate. GPI proteins are found throughout eukaryotes, and are particularly abundant in some forms of parasitic protozoa, making this modification a potential target for drug design. We are currently developing the first soluble kinetic assay for GPI-T by synthetically incorporating chromophoric groups into a typical peptide substrate. The development of such an assay will enable the first detailed examination of the mechanism of action of this complex enzyme. Selected publications Hendrickson, T. L., Nomanbhoy, T. K., de Crecy-Lagard, V., Schimmel, P. “Mutational Separation of Two Pathways for Editing by a Class I tRNA Synthetase,” Mol. Cell, 2002, 9, 353-362. Ph.D., California Institute of Technology NIH Postdoctoral Fellow, Massachusetts Institute of Technology and The Scripps Research Institute Research Corporation Innovation Award Hendrickson, T. L. “Recognizing the D-Loop of Transfer RNAs,” Proc. Natl. Acad. Sci., 2001, 98, 13473-13475. Döring, V.; Mootz, H. D.; Nangle, L. A.; Hendrickson,T. L.; de Crécy-Lagard, V.; Schimmel, P.; and Marliére, P. “Enlarging the Amino Acid Set of Escherichia coli by Infiltration of the Valine Coding Pathway,” 2001, 292, 501-504. Hendrickson, T. L.; Spencer, J. R.; Kato, M.; Imperiali, B. “Design and Evaluation of Potent Inhibitors of Asparagine-Linked Protein Glycosylation,” J. Am. Chem. Soc., 1996, 118, 7636-7637. Graduate Study in Chemistry at The Johns Hopkins University 13
Kenneth D. Karlin Ph. D., Columbia University Postdoctoral, Cambridge University, England Editor, Progress in Inorganic Chemistry (Wiley) Buck-Whitney Award Biological and Environmental Inorganic Chemistry Synthetic Models for Heme and/or Copper Proteins Reactions with O 2 , NOx & R-Cl; Cu-DNA & peptide interactions karlin@jhu.edu Dr. Karlin’s bioinorganic research focuses on coordination chemistry relevant to biological and environmental processes. Essential proteins with active-site copper aggregates or heme (porphyrin-iron) centers react with O 2 or nitrogen oxides. Thus, we study reactions involving O 2 , NO – 2 (nitrite), NO (nitric oxide), N 2 O (nitrous oxide) as well as organohalides. Metal/O 2 chemistries with organic substrates, DNA and proteins are also under investigation. Our laboratory approaches include (a) the rational design and syntheses of ligands allowing formation of appropriate Cu or Fe complexes, b) elucidation of structure and physical properties using X-ray crystallography and a variety of physical methods, and c) reactivity and kinetic-mechanistic investigations. The studies should provide insights to questions of biological concern, and also may provide a rationale for the chemist to design practical reagents for O 2 -mediated oxidations, NOx-reduction catalysts, or agents which can dehalogenate R-Cl pollutants. Recent notable achievements (also see diagrams below) include: (a) the detailed characterization of several types of copper-dioxygen adducts, including the trans -1,2-peroxodicopper(II) complex shown below, (b) the generation of cytochrome c oxidase (heme-copper) O 2- reactivity models, with -peroxo Fe III -(O 2 2–) -Cu II and -oxo Fe III -(O 2– )-Cu II species, and (c) the demonstration that in a highly specific manner, certain ligand-Cu 2 (or Cu 3 ) complexes oxidatively cleave DNA at the junction of double and single-stranded regions. Recent publications include: Zhang, C. X.; Liang, H.-C.; Kim, E.-i.; Gan, Q.-F.; Tyeklár, Z.; Lam, M.; Rheingold, A. L.; Kaderli, S.; Zuberbühler, A. D.; Karlin, K. D., “Dioxygen Mediated oxo-transfer to an amine and oxidative N-dealkylation chemistry with a dinuclear copper complex”, Chem. Commun., 2001, 631-632. Ghiladi, R. A.; Hatwell, K. R.; Karlin, K. D.; Huang, H.-w.; Moënne-Loccoz, P.; Krebs, C.; Marzilli, L. A.; Cotter, R. J.; Kaderli, S.; Zuberbühler, A. D. “Dioxygen Reactivity of Mononuclear Heme and Copper Components Yielding a High-Spin Heme-Peroxo-Cu Complex”, J. Am. Chem. Soc., 2001, 123, 6183-6184. Humphreys, K. J.; Karlin, K. D.; Rokita, S. E. “Recognition and Strand Scission at Junctions between Single- and Double-Stranded DNA by a Trinuclear Copper Complex”, J. Am. Chem. Soc., 2001, 123, 5588-5589. Fellow, American Association for the Advancement of Science (AAAS) Ira Remsen Chair in Chemistry 14 Graduate Study in Chemistry at The Johns Hopkins University
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