Profile

We are interested in the mechanism of biosynthesis of oxygenated metabolites of arachidonic acid, and their role in pathophysiological processes. Dr Brash is also a member of the Chemistry-Biology Interface program. 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.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. The structural basis for specificity in lipoxygenase catalysis. Newcomer ME, Brash AR (2015) Protein Sci 24(3): 298-309
    › Primary publication · 25524168 (PubMed) · PMC4353356 (PubMed Central)
  2. Lipoxygenase-catalyzed transformation of epoxy fatty acids to hydroxy-endoperoxides: a potential P450 and lipoxygenase interaction. Teder T, Boeglin WE, Brash AR (2014) J Lipid Res 55(12): 2587-96
    › Primary publication · 25293588 (PubMed) · PMC4242451 (PubMed Central)
  3. Crystal structure of a lipoxygenase in complex with substrate: the arachidonic acid-binding site of 8R-lipoxygenase. Neau DB, Bender G, Boeglin WE, Bartlett SG, Brash AR, Newcomer ME (2014) J Biol Chem 289(46): 31905-13
    › Primary publication · 25231982 (PubMed) · PMC4231669 (PubMed Central)
  4. Inhibitory effects of a novel Val to Thr mutation on the distal heme of human catalase. Mashhadi Z, Boeglin WE, Brash AR (2014) Biochimie : 180-3
    › Primary publication · 25086217 (PubMed) · PMC4250446 (PubMed Central)
  5. An ancient relative of cyclooxygenase in cyanobacteria is a linoleate 10S-dioxygenase that works in tandem with a catalase-related protein with specific 10S-hydroperoxide lyase activity. Brash AR, Niraula NP, Boeglin WE, Mashhadi Z (2014) J Biol Chem 289(19): 13101-11
    › Primary publication · 24659780 (PubMed) · PMC4036322 (PubMed Central)
  6. The importance of the lipoxygenase-hepoxilin pathway in the mammalian epidermal barrier. Muñoz-Garcia A, Thomas CP, Keeney DS, Zheng Y, Brash AR (2014) Biochim Biophys Acta 1841(3): 401-8
    › Primary publication · 24021977 (PubMed) · PMC4116325 (PubMed Central)
  7. Isolation and characterization of two geometric allene oxide isomers synthesized from 9S-hydroperoxylinoleic acid by cytochrome P450 CYP74C3: stereochemical assignment of natural fatty acid allene oxides. Brash AR, Boeglin WE, Stec DF, Voehler M, Schneider C, Cha JK (2013) J Biol Chem 288(29): 20797-806
    › Primary publication · 23709224 (PubMed) · PMC3774351 (PubMed Central)
  8. Demonstration of HNE-related aldehyde formation via lipoxygenase-catalyzed synthesis of a bis-allylic dihydroperoxide intermediate. Jin J, Zheng Y, Brash AR (2013) Chem Res Toxicol 26(6): 896-903
    › Primary publication · 23668325 (PubMed) · PMC3719183 (PubMed Central)
  9. Steric analysis of epoxyalcohol and trihydroxy derivatives of 9-hydroperoxy-linoleic acid from hematin and enzymatic synthesis. Thomas CP, Boeglin WE, Garcia-Diaz Y, O'Donnell VB, Brash AR (2013) Chem Phys Lipids : 21-32
    › Primary publication · 23352713 (PubMed) · PMC3678760 (PubMed Central)
  10. Biosynthesis, isolation, and NMR analysis of leukotriene A epoxides: substrate chirality as a determinant of the cis or trans epoxide configuration. Jin J, Zheng Y, Boeglin WE, Brash AR (2013) J Lipid Res 54(3): 754-61
    › Primary publication · 23242647 (PubMed) · PMC3617949 (PubMed Central)
  11. Cytochrome P450-type hydroxylation and epoxidation in a tyrosine-liganded hemoprotein, catalase-related allene oxide synthase. Boeglin WE, Brash AR (2012) J Biol Chem 287(29): 24139-47
    › Primary publication · 22628547 (PubMed) · PMC3397841 (PubMed Central)
  12. Conversion of human 5-lipoxygenase to a 15-lipoxygenase by a point mutation to mimic phosphorylation at Serine-663. Gilbert NC, Rui Z, Neau DB, Waight MT, Bartlett SG, Boeglin WE, Brash AR, Newcomer ME (2012) FASEB J 26(8): 3222-9
    › Primary publication · 22516296 (PubMed) · PMC3405276 (PubMed Central)
  13. Applications of stereospecifically-labeled Fatty acids in oxygenase and desaturase biochemistry. Brash AR, Schneider C, Hamberg M (2012) Lipids 47(2): 101-16
    › Primary publication · 21971646 (PubMed) · PMC3315059 (PubMed Central)
  14. Lipoxygenases mediate the effect of essential fatty acid in skin barrier formation: a proposed role in releasing omega-hydroxyceramide for construction of the corneocyte lipid envelope. Zheng Y, Yin H, Boeglin WE, Elias PM, Crumrine D, Beier DR, Brash AR (2011) J Biol Chem 286(27): 24046-56
    › Primary publication · 21558561 (PubMed) · PMC3129186 (PubMed Central)
  15. The structure of human 5-lipoxygenase. Gilbert NC, Bartlett SG, Waight MT, Neau DB, Boeglin WE, Brash AR, Newcomer ME (2011) Science 331(6014): 217-9
    › Primary publication · 21233389 (PubMed) · PMC3245680 (PubMed Central)
  16. Dioxygenase activity of epidermal lipoxygenase-3 unveiled: typical and atypical features of its catalytic activity with natural and synthetic polyunsaturated fatty acids. Zheng Y, Brash AR (2010) J Biol Chem 285(51): 39866-75
    › Primary publication · 20921226 (PubMed) · PMC3000968 (PubMed Central)
  17. Mechanistic aspects of CYP74 allene oxide synthases and related cytochrome P450 enzymes. Brash AR (2009) Phytochemistry 70(13-14): 1522-31
    › Primary publication · 19747698 (PubMed) · PMC2783490 (PubMed Central)
  18. The 1.85 A structure of an 8R-lipoxygenase suggests a general model for lipoxygenase product specificity. Neau DB, Gilbert NC, Bartlett SG, Boeglin W, Brash AR, Newcomer ME (2009) Biochemistry 48(33): 7906-15
    › Primary publication · 19594169 (PubMed) · PMC4715880 (PubMed Central)