Jonathan A Doorn

Jonathan A Doorn

, PhD
  • Associate Professor, Department of Pharmaceutical Sciences and Experimental Therapeutics / Division of Medicinal and Natural Products Chemistry
  • Division Head, Medicinal and Natural Products Chemistry

Office

S328 PHAR

Phone

(319) 335-8834

Research Narrative

In general, Dr. Doorn's work involves examining the role of reactive intermediates in toxicity and disease. Specifically, his mechanistic, hypothesis-driven research focuses on the potential role of protein modification by a reactive metabolite of dopamine metabolism in neurotoxicity and neurodegenerative disease, i.e. Parkinson’s disease. Dopamine (DA) is an important neurotransmitter that is metabolized by monoamine oxidase to 3,4-dihydroxyphenylacetaldehyde (DOPAL), an intermediate shown to be reactive toward proteins and toxic to dopaminergic cells. Specifically, the following areas are being investigated. (1) Characterize the chemistry of DOPAL, with emphasis on determining DOPAL reactivity toward proteins and identifying novel ways to synthesize the DA-derived aldehyde. (2) Elucidate mechanisms for generation of DOPAL at aberrant concentrations, involving exposure to drugs, oxidative stress and environmental agents. (3) Identify proteins modified by DOPAL. The Doorn lab is developing a proteomics-based approach to isolate and identify proteins with DOPAL adducts. (4) Determine the functional consequence of protein modification by DOPAL. Several potential targets are being studied, including the proteasome and proteins involved in DA synthesis and trafficking. In summary, the Dr. Doorn is studying the biological chemistry of DOPAL, as aberrant levels of the DA-derived aldehyde may represent a “chemical trigger” for neurodegeneration (e.g. PD). This work is highly significant as outcomes of the research may yield novel targets for therapeutic intervention, and future work will evaluate the potential of aldehyde-scavenging drugs to attenuate DOPAL-mediated toxicity and neurodegeneration.

Curriculum vitae

Education
PhD, Toxicology; University of Michigan, Ann Arbor, MI, 2001.
MS, Toxicology; University of Michigan, Ann Arbor, MI, 1998.
BS, Biochemistry; Calvin College, Grand Rapids, MI, 1996.

Professional Experience
2010 – Present, Associate Professor, Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, IA.
2004 – 2010, Assistant Professor, Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, IA.
2001 – 2004, Postdoctoral Fellow (NIH Traineeship 2001-2002; NRSA Fellowship 2002-2004), Dept. of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO.
1996 – 2001, Graduate Student (NIH Traineeship 1998-2001), Toxicology Program, School of Public Health, University of Michigan, Ann Arbor, MI.
1997, Summer Internship/Professional, Dept. of Drug Delivery Research and Development, Pharmacia and Upjohn Corporation, Kalamazoo, MI.

Affiliations
2006 – Present. Member, Human Toxicology Training Program, University of Iowa.
2006 – Present. Member, Biosciences Training Program, University of Iowa.
2005 – Present. Associate Member, Center for Environmental Health Sciences Research Center, Oxidative Stress and Metabolism Core, University of Iowa.
2004 – Present. Member, Center for Biocatalysis and Bioprocessing, University of Iowa.

Awards/Honors
Class of 2010 Teacher of the Year, University of Iowa College of Pharmacy (2007).
Transition to Independent Position Award (K22), National Institute of Environmental Health Sciences (National Institutes of Health), 2004-2007.
First Place, Postdoctoral Presentation, Dept. of Pharm. Sci. Annual Retreat, UCHSC, June 2003.
Society of Toxicology 2003 Best Paper of the Year Award, Paper: Doorn et al., (2002) Toxicol. Appl. Pharmacol. 176, 73-80. Society of Toxicology Annual Meeting, Salt Lake City, UT, March 2003.
National Research Service Award, National Institute of Environmental Health Sciences (National Institutes of Health), 2002-2004.
First Place in Graduate Student Poster Competition, University of Michigan Annual Toxicology Symposium, Ann Arbor, MI, April 2001.
Designed Artwork Featured on Front Cover of Chemical Research in Toxicology, December 2000. Paper: Doorn et al., (2000) Chem.Res. Toxicol. 13, 1313-1320.
First Place in Neurotoxicology Specialty Section Poster Competition Society of Toxicology Annual Meeting, Philadelphia, PA, March 2000.

Representative Publications (2007 - Present)
Vermeer, L.M., Florang, V.R., and Doorn, J.A. (2012) Catechol and Aldehyde Moieties of 3,4-Dihydroxyphenylacetaldehyde Contribute to Tyrosine Hydroxylase Inhibition and Neurotoxicity. Brain Res. 1494, 100-9.

Higgins, C.A ., Vermeer, L.M., Doorn, J.A. and Roman, D.L. (2012) Expression and Purification of Recombinant Human Tyrosine Hydroxylase as a Fusion Protein in Escherichia coli. Protein Expr. Purif. 84(2), 219-23. 

Dean, E.D., Mexas, L.M., Cápiro, N.L., McKeon, J.E., DeLong, M.R., Pennell, K.D., Doorn, J.A., Tangpricha, V., Miller, G.W. and Evatt, M. L. (2012) 25-Hydroxyvitamin D depletion does not exacerbate MPTP-induced dopamine neuron damage in mice. PLoS One. 7(7):e39227.

Anderson, D.G., Mariappan, V.S., Buettner, G.R. and Doorn, J.A. (2011) Oxidation of 3,4-Dihydroxy phenylacetaldehyde, a Toxic Dopaminergic Metabolite, to a Semiquinone Radical and an Ortho-Quinone. J. Biol. Chem., 286, 26978-26986.

Mexas, L.M., Florang, V.R. and Doorn, J.A. (2011) Inhibition and Covalent Modification of Tyrosine Hydroxylase by 3,4‑Dihydroxyphenylacetaldehyde, a Toxic Dopamine Metabolite. Neurotoxicology.32, 471-477.

Jinsmaa, Y., Florang, V.R., Rees, J.N., Mexas, L.M., Eckert, L.L., Allen, M.G., Anderson, D.G., and Doorn, J.A. (2011) Dopamine-Derived Biological Reactive Intermediates and Protein Modifications: Implications for Parkinson’s Disease. Chem. Biol. Interact. 192, 118-121.

Allen, E.M.G., Anderson, D.G.R., Florang, V.R., Khanna, M., Hurley, T.D., and Doorn, J.A. (2010) Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase. Chem. Res. Toxicol. 23, 1843-1850.

Doorn, J.A. (2010) Dopamine catabolism and Parkinson’s Disease: Role of a Reactive Aldehyde Intermediate. In Endogenous Toxins, Volume 1, Targets for Disease Treatment and Prevention. (O’Brien, P.J., and Bruce, W.R., Eds.) pp. 715-726, Wiley VCH, Weinheim.

Roberts, R., Laskin, D.L., Smith, C.V., Robertson, F.M., Allen, E.M.G., Doorn, J.A., and Slikker, W. (2009) Nitrative and oxidative stress in toxicity and disease. Toxicol. Sci. 112, 4-16.

Rees, J.N., Florang, V.F., Eckert, L.L., and Doorn, J.A. (2009) Protein reactivity of 3,4-dihydroxyphenyl acetaldehyde, a toxic intermediate of dopamine catabolism, involves both aldehyde and catechol groups. Chem. Res. Toxicol. 22, 1256-1263.

Yunden, J., Florang, V.R., Rees, J.N., Anderson, D.G., Strack, S., Doorn, J.A. (2009) Products of oxidative stress inhibit aldehyde oxidation and reduction pathways in dopamine catabolism yielding elevated levels of a reactive intermediate. Chem. Res. Toxicol. 22, 835-841.

Stewart, B.J., Roede, J.R., Doorn, J.A., and Petersen, D.R. (2009) Lipid aldehyde-mediated cross-linking of apolipoprotein B-100 inhibits secretion from HepG2 cells. Biochim. Biophys. Acta. 1791, 772-780.

Gall, A.J., Joshi, B., Best, J., Florang, V.F., Doorn, J.A., and Blumberg, M.S. (2009) Developmental emergence of power-law wake behavior depends upon the functional integrity of the locus coeruleus. Sleep. 32, 920-926.

Roede, J.R., Carbone, D.L., Doorn, J.A., Kirichenko, O.V., Reigan, P., Petersen, D.R. (2008) In Vitro and in Silico Characterization of Peroxiredoxin 6 Modified by 4-Hydroxynonenal and 4-Oxononenal. Chem. Res. Toxicol. 21, 2289-2299.

Rees, J.N., Florang, V.F., Anderson, D.G., and Doorn, J.A. (2007) Lipid peroxidation products inhibit dopamine catabolism yielding aberrant levels of a reactive intermediate. Chem. Res. Toxicol.20, 1536-42.

Stewart, B.J., Doorn, J.A., and Petersen, D.R. (2007) Residue-specific adduction of tubulin by 4-hydroxynonenal and 4-oxononenal causes cross-linking and inhibits polymerization. Chem. Res. Toxicol. 20, 1111-1119.

Florang, V.F., Rees, J.R., Brogden, N.K., Anderson, D.G., Hurley, T.D., and Doorn, J.A. (2007) Inhibition of the oxidative metabolism of 3,4-dihydroxyphenylacetaldehyde, a reactive intermediate of dopamine metabolism, by 4-hydroxy-2-nonenal. Neurotoxicology. 28, 76-82.

Sampey, B.P., Carbone, D.L., Doorn, J.A., and Petersen, D.R. (2007) 4-Hydroxynonenal adduction and modulation of hepatocellular Erk 1/2 mitogen-activated protein kinase. Mol. Pharmacol. 71, 871-883.

Florang, V.F., Rees, J.R., Brogden, N.K., Anderson, D.G., Hurley, T.D., and Doorn, J.A. (2007) Inhibition of mitochondrial aldehyde dehydrogenase-mediated oxidation of 3,4-dihydroxyphenylacetaldehyde. In Enzymology and Molecular Biology of Carbonyl Metabolism 13. (Weiner, E., Maser, E., Lindahl, R. and Plapp, B., Eds.) pp. 33-39, Purdue University Press, West Lafayette, Indiana.