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Department of Pharmacology

Alan R. Brash, Ph.D.

Professor, Department of Pharmacology

Research Description

We are interested in the mechanism of biosynthesis of oxygenated metabolites of arachidonic acid, and their role in pathophysiological processes.  Three areas of current interest are the following:

  • (i) “R” and “S” Lipoxygenases Lipoxygenases catalyze the reaction of unsaturated fatty acids with molecular oxygen and thus form fatty acid hydroperoxides. The well known lipoxygenases purified, cloned, and sequenced from mammals and plants insert the O2 on a particular position along the fatty acid carbon chain and usually with ?S? stereochemistry. There exist, however, lipoxygenases that form the mirror image ?R? hydroperoxides. We are characterizing these enzymes to provide new perspectives on the enzyme-substrate interactions that are the basis of the specificity of all lipoxygenases.
  • (ii) Characterization of novel lipoxygenase pathways and the mechanism of biosynthesis of the products – The metabolism of arachidonic acid often leads to the formation of an unstable intermediate that can serve as the precursor of an array of products. One of the more recently discovered intermediates of lipoxygenase pathways is the class of epoxide known as the allene oxide. For the last few years we have been investigating the occurrence of allene oxides in animal systems, the nature of the enzyme that catalyzes the biosynthesis (a catalase-related protein recently cloned as one domain of a fusion protein with an 8R-lipoxygenase), the mechanism of this enzymatic reaction, and the structures of products that can be formed by enzymic or non-enzymic rearrangements of the allene epoxides.
  • (iii) Role of epithelial lipoxygenases Recently we identified two previously unrecognized human lipoxygenases. One of these enzymes, a second type of 15S lipoxygenase, appears to be expressed in epithelial tissues including skin, prostate, breast, lung, and cornea. The other is a 12R-lipoxygenase. We showed that this type of enzyme accounts for the accumulation of 12R-hydroxy-arachidonic acid (12R-HETE) in psoriasis. We are exploring the role of these enzymes in tissue inflammation, hyperplasia, and cancer.

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Vanderbilt Faculty Profile

Pub Med

Vanderbilt Institute of Chemical Biology (VICB)