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Novel Fatty Acid Dioxygenases of Human and Plant Pathogenic Fungi : Studies by Gene Deletion and Expression
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- Jernerén, Fredrik (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Biokemisk farmakologi
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- Oliw, Ernst (thesis advisor)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Feussner, Ivo, Prof. Dr. (opponent)
- Univeristy of Göttingen, Department for Plant Biochemistry
- (creator_code:org_t)
- ISBN 9789155479879
- Uppsala : Acta Universitatis Upsaliensis, 2011
- English 68 s.
- Series: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 1651-6192 ; 135
- Doctoral thesis (other academic/artistic)
Abstract
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- The dioxygenase-cytochrome P450 fusion proteins (DOX-CYP) comprise a heme-containing enzyme family that shares structural and catalytic properties with mammalian prostaglandin H (PGH) synthases. 7,8-Linoleate diol synthase (7,8-LDS) of Gaeumannomyces graminis was first characterized, and DOX-CYP enzymes are of mechanistic and biological interest. The growing number of fungal genome sequences has revealed DOX-CYP homologues in medically and economically important species. The aim of this thesis was to identify novel members of the DOX-CYP fusion protein family. The devastating rice pathogen Magnaporthe oryzae contains two DOX-CYP genes. The fungus synthesizes 7S,8S-dihydroxyoctadecadienoic acid (7,8-DiHODE) by dioxygenation of linoleic acid to 8R-hydroperoxyoctadecadienoic acid (8R-HPODE), and subsequent isomerisation to the diol. 7,8-LDS of M. oryzae was identified by gene deletion, but the infection and reproduction processes of the Δ7,8-LDS strain were not altered. A mutant with constitutive protein kinase A activity profoundly changed the oxygenation profile, possibly due to post-translational modification. The human pathogens Aspergillus fumigatus and A. clavatus contain three DOX-CYP, designated psi producing oxygenase A (ppoA), ppoB, and ppoC, and form three oxylipins: 5S,8R-DiHODE, 8R,11S-DiHODE, and 10R-hydroxyoctadecadienoic acid. PpoA was identified as 5,8-LDS, and ppoC as 10R-DOX. The 8,11-linoleate hydroperoxide isomerase activity was reduced by two imidazole-containing P450 inhibitors, miconazole and 1-benzylimidazole. PpoB could not be linked to the biosynthesis of 8,11-DiHODE for the following reasons: First, the 8,11-hydroperoxide isomerase activity was retained in A. fumigatus ΔppoB strains. Second, the P450 domain of the deduced ppoB of A. clavatus lacks a heme-thiolate cysteine ligand, presumably essential for hydroperoxide isomerase activity. Linoleate 9R-DOX activities of Aspergillus terreus and Lasiodiplodia theobromae were discovered. 9R-HPODE was further converted into unstable allene oxides, as judged by the accumulation of their hydrolysis products, α- and γ-ketols. These allene oxide synthase activities were specific for 9R-hydroperoxides. The 9R-DOX and AOS were found to have unique characteristics. In conclusion, novel DOX-CYP enzymes were identified in human and plant pathogenic fungi. These enzymes might be involved in biological processes, and show interesting catalytic similarities to human PGH synthase and thromboxane synthase (CYP5A).
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- aspergilli
- dioxygenase
- oxygenase
- Magnaporthe oryzae
- Gaeumannomyces graminis
- Lasiodiplodia theobromae
- jasmonic acid
- linoleate diol synthase
- cyclooxygenase
- prostaglandin H synthase
- cytochrome P450
- oxylipin
- hydroperoxide isomerase
- allene oxide synthase
- Pharmaceutical pharmacology
- Farmaceutisk farmakologi
- Biochemical Pharmacology
- Biokemisk farmakologi
Publication and Content Type
- vet (subject category)
- dok (subject category)
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