Symposium on Aldo-Keto Reductases & Toxicant Metabolism
Principal Investigator: TREVOR PENNING
Abstract: This proposal is a request for financial support for a half-day symposium on "The Emerging Role of Aldo-keto reductases (AKRs) in the Metabolism of Toxic Substances" to be presented at the American Chemical Society National Meeting, Boston, MA August 18-22nd, 2002. AKRs are a superfamily of monomeric oxidoreductases that play central roles in the metabolism of aldose-sugars, prostaglandins, steroid hormones, and chemical carcinogens. Often they catalyze the conversion of carbonyl groups to alcohols so that the parent compound can be conjugated and eliminated. AKRs are highly conserved in both prokaryotes and eukaryotes. There are currently 150 proteins classified into 12 families and crystal structures exist for many of the proteins. In humans, these enzymes also catalyze the formation of hyperosmotic sugars, the detoxification of reactive a,B-unsaturated aldehydes that result from the decomposition of lipid hydroperoxides, and the metabolism of chemical carcinogens including aflatoxin dialdehyde, nicotine derived nitrosamino-ketones and polycyclic aromatic trans-dihydrodiols. Their emerging role in the metabolism of endogenous and exogenous toxins suggests that the family may be ultimately as important as the well-studied CYP superfamily in drug and xenobiotic metabolism. The speakers chosen for this symposium will cover each of the areas listed. In addition an overview of the AKR superfamily and its nomenclature (accepted by the Human Genome Project) will be given and approaches to studying functional genomics of AKRs in yeast will be presented. Each of the speakers has an international reputation in their area of expertise. The goal of the symposium will be to bring together experts in the AKR field so that they will be able to educate the scientific community concerning these enzymes with the hope of attracting new investigators to the field. Issues that are unexplored include the role of AKR isoforms in drug metabolism; their role in chemotherapeutic drug resistance; the regulation of human AKR genes; and AKR pharmacogenomics with emphasis on human polymorphisms that may affect individual response to toxicants and susceptibility to chemical carcinogenesis.
Funding Period: 2002-08-01 - 2003-07-31
more information: NIH RePORT
- The effect of disease associated point mutations on 5β-reductase (AKR1D1) enzyme functionRebekka Mindnich
University of Pennsylvania, School of Medicine, Department of Pharmacology, Philadelphia, PA 19104 6084, USA
Chem Biol Interact 191:250-4. 2011..Our data show, that all five mutations identified in patients with functional bile acid deficiency strongly affected AKR1D1 enzyme functionality and therefore may be causal for this disease...