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Donovan C. Haines
Office: CFS 317
Phone: (936) 294-1530
My research involves the structure and mechanism of action of monooxygenase systems, especially those involved in metabolism of natural products, neurotransmitters, drugs, and hormones. This fundamental research has direct medical relevance as aberrant behavior of oxygen utilizing enzymes has been implicated to varying degrees in many neurodegenerative diseases including Amyotrophic Lateral Sclerosis (Lou Gehrig's disease), Parkinson's disease, and Alzheimer's disease. We specificially focus on lipid metabolizing enzymes, especially the fatty acid hydroxylases. These enzymes have been linked to immune function, regulation of blood pressure and other aspects of the vasculature, and play a role in skin formation (CYP4F22 defects cause the rare disease lamellar ichthyosis type 3). To study these enzymes my laboratory employs organic synthesis to produce enzyme inhibitors, biochemistry to measure the effects of the inhibitors and probe enzyme mechanism, molecular biology to probe the effects of changes in protein sequence on enzyme properties, and biophysics via spectroscopy and crystallography to study the structure and physical properties of the enzymes. In addition to using small molecules to study enzymes, we also use enzymes to synthesize and study interesting small molecules on a research (200 mg) scale.Our major project involves identifying the enzymes involved in acyl homoserine lactone (AHL) metabolism. AHLs are signal molecules used by bacteria to sense their population density. These signals are important in infection, especially by organisms like Pseudomonas aeruginosa which is a major cause of death in cystic fibrosis patients and cause of limb amputation in diabetics and burn victims. We study how the body repsonds to these signals and modifies them to prevent infections from establishing biofilms and/or expressing virulence factors (things that help the bacteria attack our bodies). We collaborate with John Teiber at the University of Texas Southwestern Medical Center at Dallas in his study of the role of paraoxonase in this quorum quenching infection defense, and study in our lab the role of P450 cytochromes and related enzymes Other projects in the lab include develepment of molecular tools to study the role of CYP4F22 in lamellar ichthyosis, aspects of the function of CYP46A1 which oxidizes cholesterol and other steroids in the brain, studies of model P450 enzyme structure and function, and the engineering of microbes to directly produce the components of biodiesel.
For more information, visit my Lab Home Page.
Horke S, Witte I, Altenhöfer S, Wilgenbus P, Goldeck M, Förstermann U, Xiao J, Kramer GL, Haines DC, Chowdhary PK, Haley RW, and Teiber JF, "Dominant Paraoxonase 2 is downregulated by the Pseudomonas aeruginosa quorum sensing signal N-(3-oxododecanoyl)-L-homoserine lactone and attenuates oxidative stress induced by pyocyanin.", Biochemical Journal, in press, 2009.
Chowdhary, P.K, Stewart, L., Lopez, C., and
Teiber, J.F., Horke, S., Haines, D.C., Chowdhary, P.K., Xiao, J., Kramer, G.L., Haley, R.W. and Draganov, D.I., "Dominant Role of Paraoxonases in the Inactivation of the Pseudomonas aeruginosa Quorum Sensing Signal N-(3-Oxododecanoyl)-L-Homoserine Lactone", Infection and Immunity, 76, 6, pp. 2512-9, 2008.
Chowdhary, P.K., Keshavan,
N., Nguyen, H., Peterson, J.A., Gonzalez, J.E., and
Chowdhary, P.K, Alemseghed,
Keshavan, N.D., Chowdhary, P.K., Haines, D.C., and Gonzalez, J.E., "L-Canavanine Made By Alfalfa Interferes With Quorum Sensing in Sinorhizobium meliloti", Journal of Bacteriology, 187, 24, pp. 8427-36, 2005.
Kou, W., Kolla, H.S., Ortiz-Acevedo, A., Haines, D.C., Junker, M., and Dieckmann, G.R. , "Modulation of Zinc- and Cobalt-Binding Affinites Through Changes in the Stability of the Zinc Ribbon Protein L36" , Journal of Biological Inorganic Chemistry, 10, 2, pp. 167-80, 2005.
Wanduragala, S., Wimalasena, D.S., Haines, D.C., Kahol, P.K., and Wimalasena, K., , pH-Induced Alteration and Oxidative Destruction of Heme in Purified Chromaffin Granule Cytochrome b561: Implications for the Oxidative Stress in Catecholaminergic Neurons, Biochemistry, 42, n. 12, pp. 3617-26, 2003.
Wimalasena, D.S., Jayatillake,
S.P., Haines, D.C., Wimalasena, K., Plausible
Molecular Mechanism for Fumarate Activation and
Electron Transfer of the Dopamine Beta-Monooxygenase
Reaction, Biochemical Journal, v.
Haines, D.C., Tomchick, D.R., Machius, M., and Peterson, J.A., The Pivotal Role of Water in the Mechanism of P450BM-3, Biochemistry, 40, n. 45, pp. 13456-65, 2001.
Falck, J.R., Reddy, Y.K, Haines, D.C., Reddy, K.M., Krishna, U.M., Graham, S., Murry, B., and Peterson, J.A., Practical, Enantiospecific Syntheses of 14,15-EET and Leukotoixn B (Vernolic Acid), Tetrahedron Letters, 42, 4131-3, 2001.
Wimalasena, K., Wimalasena,
D.S., Dharmasena, S.,
Wimalasena, K. and Haines, D.C., A General Progress Curve Method for the Kinetic Analysis of Suicide Enzyme Inhibitors, Analytical Biochemistry, 234, pp. 175-82, 1996.
Wimalasena, K. and Haines, D.C., Nucleophilic Substitution Reactions of Phenacyl
Bromide Oxime: Effect of the Solvent and the Basicity of the Nucleophile,
Journal of Organic Chemistry, 59, pp. 6472-4, 1994.
Last modified 11/21/2009 .