EHSRC Investigator Detail
| Jonathan A. Doorn, Ph.D. | |
| Assistant Professor of Medicinal and Natural Products Chemistry |
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| Email: jonathan-doorn@uiowa.edu | |
| Phone: (319) 335-8834 | |
| Doorn Research Group Site | |
| EHSRC Role(s): | Associate Member, Oxidative Stress and Metabolism Research Cluster |
Research Interests
Dr. Doorns' 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.
Recent Publications
- Stewart BJ, Doorn JA, Petersen DR. Residue-Specific Adduction of Tubulin by 4-Hydroxynonenal and 4-Oxononenal Causes Cross-Linking and Inhibits Polymerization. Chem Res Toxicol. 2007 Jul 13; [Epub ahead of print] PMID: 17630713 [PubMed - as supplied by publisher]
- Sampey BP, Carbone DL, Doorn JA, Drechsel DA, Petersen DR. 4-Hydroxy-2-nonenal adduction of extracellular signal-regulated kinase (Erk) and the inhibition of hepatocyte Erk-Est-like protein-1-activating protein-1 signal transduction. Mol Pharmacol. 2007 Mar;71(3):871-83. Epub 2006 Dec 12.
- Florang VR, Rees JN, Brogden NK, Anderson DG, Hurley TD, Doorn JA. Inhibition of the oxidative metabolism of 3,4-dihydroxyphenylacetaldehyde, a reactive intermediate of dopamine metabolism, by 4-hydroxy-2-nonenal. Neurotoxicology. 2007 Jan;28(1):76-82. Epub 2006 Aug 1.
- Doorn JA, Hurley TD, Petersen DR. Inhibition of human mitochondrial aldehyde dehydrogenase by 4-hydroxynon-2-enal and 4-oxonon-2-enal. Chem Res Toxicol. 2006 Jan;19(1):102-10.
- Carbone DL, Doorn JA, Kiebler Z, Petersen DR. Cysteine modification by lipid peroxidation products inhibits protein disulfide isomerase. Chem Res Toxicol. 2005 Aug;18(8):1324-31.
- Carbone DL, Doorn JA, Kiebler Z, Ickes BR, Petersen DR. Modification of heat shock protein 90 by 4-hydroxynonenal in a rat model of chronic alcoholic liver disease. J Pharmacol Exp Ther. 2005 Oct;315(1):8-15. Epub 2005 Jun 10.