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PrintSteven Rokita
Professor, Associate Chair
Personal Data
Education
- B.S. Chemistry (1979), University of California, Berkeley, CA (research with W. Dauben)
- Ph.D. Biological Chemistry (1983), MIT, Cambridge, MA (research with C. T. Walsh)
- Post-doctoral Fellowship (NIH) (1983-1985), Rockefeller Univ., New York, NY (with E. T. Kaiser)
Professional Experience
- Assistant & Associate Professor, Dept. of Chemistry, SUNY at Stony Brook, 1986-1995
- Professor of Chemistry and Biochemistry, University of Maryland, 1995 - present
- Member, University of Maryland Greenebaum Cancer Center; Maryland Nanocenter, 2007 - present
Research Interests
Bioorganic chemistry and biochemistry. Nucleic acid structure and reactivity; therapeutic and toxicology aspects of DNA modification; redox processes in enzymology, enzyme mechanisms of dehalogenation; biomimetic reactions of nickel and copper and electron transfer in nucleic acids.
Major Recognitions and Honors
- Summa Cum Laude, Phi Beta Kappa, University of California, Berkeley, 1979
- Catacosinos Young Investigator in Cancer Research, SUNY at Stony Brook, 1988
- University Exploratory Research Investigator (Procter and Gamble Company), 1987-1990
- Outstanding Invention (Novel Copper Complexes), University of Maryland, 2001
- Faculty Excellence in Research, College of Life Science, University of Maryland, 2005
- Faculty Excellence in Service, College of Life Sciences, University of Maryland, 2006
Significant Professional Service and Activities
- Member, Molecular Biochemistry Advisory Panel (NSF), 1993-1997
- Advisory Board, Bioconjugate Chemistry, 1997-99
- Member, Bioorganic and Natural Products Study Section (NIH), 1997-2001
- Chair, Bioorganic Chemistry Gordon Conference, 1999
- Alternative Councilor, Biological Chemistry Division (Am. Chem. Soc.), 2002-2004
- Program Review (Site Visit), Food and Drug Administration, 2007
- Series Editor, Wiley Series on Reactive Intermediates in Chemistry and Biology, 2007 - present
Publications
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Bioorganic Chemistry and Biochemistry
Our research program is united by a common interest in describing the structure and activity of biological macromolecules through their essential chemical reactivity. The methods of organic synthesis, physical organic chemistry, protein and nucleic acid chemistry, biochemistry and genetic manipulation are applied to questions of enzyme catalysis and nucleic acid modification. Current projects are summarized below.
(1) Enzymatic dehalogenation. The catalytic properties of the enzyme iodotyrosine deiodinase are currently under investigation to identify the source of its unique reactivity. This enzyme is necessary for conserving iodide in thyroid glands for biosynthesis of thyroxine and is one of only two types of mammalian enzymes known to effect reductive dehalogenation. Iodotyrosine deiodinase is particularly fascinating due to the unprecedented role of flavin in reduction of the carbon-iodine bond. Our description of catalysis to date has relied on a) reversible enzyme inhibition to define both
substrate recognition patterns and transition-state (reactive intermediate) properties, b) mechanism-based inactivation to characterize substrate activation and c) protein expression and mutagenesis to identify amino acid residues responsible for its key catalytic and structural properties.
(2) DNA photochemistry and electron transfer. Genetic changes caused by exposure to sunlight occur along sequences of DNA at widely variable rates. Often pre-mutagenic lesions are localized at sites referred to as hotspots. The molecular
determinants of this phenomenon are under investigation by examining the photochemistry of defined oligonucleotide and polynucleotide models. In a complementary approach, we are also characterizing the nature of excess electron transfer through DNA using aromatic amines as photoactivated electron donors (D) and bromodeoxyuridine (BrU) as an electron acceptor. Reductive electron transfer has yet to be described to the extent known for the complementary process of oxidative transfer. Both types of transfer affect the distribution of lesions in DNA formed by environmental stress.
(3) Quinone methide reactivity and its use in target promoted alkylation of nucleic acids. The reversibility of quinone methide alkylation has provided a strategy to create stable derivatives that unfurl a latent quinone methide only after they bind to their target sequence of nucleotides. (a) Intramolecular and reversible formation of a self adduct generated between a quinone methide and its conjugated oligonucleotide remains dominant in the presence of
non-complementary DNA and even strong nucleophiles such as 2-mercaptoethanol. (b) The intermolecular reaction only becomes competitive when the thermodynamics of base pairing drives a conformational change that allows for efficient transfer of the quinone methide to its intended target. Our efforts now focus on developing related conjugates for applications in vivo.
Our research program is united by a common interest in describing the structure and activity of biological macromolecules through their essential chemical reactivity. The methods of organic synthesis, physical organic chemistry, protein and nucleic acid chemistry, biochemistry and genetic manipulation are applied to questions of enzyme catalysis and nucleic acid modification. Current projects are summarized below.
(1) Enzymatic dehalogenation. The catalytic properties of the enzyme iodotyrosine deiodinase are currently under investigation to identify the source of its unique reactivity. This enzyme is necessary for conserving iodide in thyroid glands for biosynthesis of thyroxine and is one of only two types of mammalian enzymes known to effect reductive dehalogenation. Iodotyrosine deiodinase is particularly fascinating due to the unprecedented role of flavin in reduction of the carbon-iodine bond. Our description of catalysis to date has relied on a) reversible enzyme inhibition to define both
substrate recognition patterns and transition-state (reactive intermediate) properties, b) mechanism-based inactivation to characterize substrate activation and c) protein expression and mutagenesis to identify amino acid residues responsible for its key catalytic and structural properties. (2) DNA photochemistry and electron transfer. Genetic changes caused by exposure to sunlight occur along sequences of DNA at widely variable rates. Often pre-mutagenic lesions are localized at sites referred to as hotspots. The molecular
determinants of this phenomenon are under investigation by examining the photochemistry of defined oligonucleotide and polynucleotide models. In a complementary approach, we are also characterizing the nature of excess electron transfer through DNA using aromatic amines as photoactivated electron donors (D) and bromodeoxyuridine (BrU) as an electron acceptor. Reductive electron transfer has yet to be described to the extent known for the complementary process of oxidative transfer. Both types of transfer affect the distribution of lesions in DNA formed by environmental stress.(3) Quinone methide reactivity and its use in target promoted alkylation of nucleic acids. The reversibility of quinone methide alkylation has provided a strategy to create stable derivatives that unfurl a latent quinone methide only after they bind to their target sequence of nucleotides. (a) Intramolecular and reversible formation of a self adduct generated between a quinone methide and its conjugated oligonucleotide remains dominant in the presence of
non-complementary DNA and even strong nucleophiles such as 2-mercaptoethanol. (b) The intermolecular reaction only becomes competitive when the thermodynamics of base pairing drives a conformational change that allows for efficient transfer of the quinone methide to its intended target. Our efforts now focus on developing related conjugates for applications in vivo.
