Cyclo-oxygenases-1/2 (COX-1/2) catalyse the oxygenation of AA (arachidonic acid) and related polyunsaturated fatty acids to endoperoxide precursors of prostanoids. COX-1 is referred to as a constitutive enzyme involved in haemostasis, whereas COX-2 is an inducible enzyme expressed in inflammatory diseases and cancer. The fungus Dipodascopsis uninucleata has been shown by us to convert exogenous AA into 3(R)-HETE [3(R)-hydroxy-5Z,8Z,11Z,14Z-eicosatetraenoic acid]. 3R-HETE is stereochemically identical with AA, except that a hydroxy group is attached at its C-3 position. Molecular modelling studies with 3-HETE and COX-1/2 revealed a similar enzyme–substrate structure as reported for AA and COX-1/2. Here, we report that 3-HETE is an appropriate substrate for COX-1 and -2, albeit with a lower activity of oxygenation than AA. Oxygenation of 3-HETE by COX-2 produced a novel cascade of 3-hydroxyeicosanoids, as identified with EI (electron impact)–GC–MS, LC–MS–ES (electrospray) and LC–MS–API (atmospheric pressure ionization) methods. Evidence for in vitro production of 3-hydroxy-PGE2 (3-hydroxy-prostaglandin E2) was obtained upon infection of HeLa cells with Candida albicans at an MOI (multiplicity of infection) of 100. Analogous to interaction of AA and aspirin-treated COX-2, 3-HETE was transformed by acetylated COX-2 to 3,15-di-HETE (3,15-dihydroxy-HETE), whereby C-15 showed the (R)-stereochemistry. 3-Hydroxy-PGs are potent biologically active compounds. Thus 3-hydroxy-PGE2 induced interleukin-6 gene expression via the EP3 receptor (PGE2 receptor 3) in A549 cells, and raised cAMP levels via the EP4 receptor in Jurkat cells. Moreover, 3R,15S-di-HETE triggered the opening of the K+ channel in HTM (human trabecular meshwork) cells, as measured by the patch–clamp technique. Since many fatty acid disorders are associated with an ‘escape’ of 3-hydroxy fatty acids from the β-oxidation cycle, the production of 3-hydroxyeicosanoids may be critical in modulation of effects of endogenously produced eicosanoids.
Skip Nav Destination
Article navigation
September 2005
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
September 05 2005
Oxygenation by COX-2 (cyclo-oxygenase-2) of 3-HETE (3-hydroxyeicosatetraenoic acid), a fungal mimetic of arachidonic acid, produces a cascade of novel bioactive 3-hydroxyeicosanoids
Roberto Ciccoli;
Roberto Ciccoli
*Eicosanoid Research Division, Department of Gynecology, University Medical Centre, Benjamin Franklin, Free University Berlin, D-12200 Berlin, Germany
Search for other works by this author on:
Shakti Sahi;
Shakti Sahi
†Institute for Biophysics, All India Institute of Medical Sciences, New Delhi, India
Search for other works by this author on:
Sandhya Singh;
Sandhya Singh
*Eicosanoid Research Division, Department of Gynecology, University Medical Centre, Benjamin Franklin, Free University Berlin, D-12200 Berlin, Germany
Search for other works by this author on:
Hridayesh Prakash;
Hridayesh Prakash
*Eicosanoid Research Division, Department of Gynecology, University Medical Centre, Benjamin Franklin, Free University Berlin, D-12200 Berlin, Germany
Search for other works by this author on:
Maria-Patapia Zafiriou;
Maria-Patapia Zafiriou
*Eicosanoid Research Division, Department of Gynecology, University Medical Centre, Benjamin Franklin, Free University Berlin, D-12200 Berlin, Germany
Search for other works by this author on:
Ganchimeg Ishdorj;
Ganchimeg Ishdorj
*Eicosanoid Research Division, Department of Gynecology, University Medical Centre, Benjamin Franklin, Free University Berlin, D-12200 Berlin, Germany
Search for other works by this author on:
Johan L. F. Kock;
Johan L. F. Kock
‡Department of Microbial, Biochemical and Food Technology, University of Bloemfontein, South Africa
Search for other works by this author on:
Santosh Nigam
Santosh Nigam
1
*Eicosanoid Research Division, Department of Gynecology, University Medical Centre, Benjamin Franklin, Free University Berlin, D-12200 Berlin, Germany
1To whom correspondence should be addressed (email santosh.nigam@charite.de).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
December 01 2004
Revision Received:
April 28 2005
Accepted:
May 04 2005
Accepted Manuscript online:
May 04 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2005
Biochem J (2005) 390 (3): 737–747.
Article history
Received:
December 01 2004
Revision Received:
April 28 2005
Accepted:
May 04 2005
Accepted Manuscript online:
May 04 2005
Citation
Roberto Ciccoli, Shakti Sahi, Sandhya Singh, Hridayesh Prakash, Maria-Patapia Zafiriou, Ganchimeg Ishdorj, Johan L. F. Kock, Santosh Nigam; Oxygenation by COX-2 (cyclo-oxygenase-2) of 3-HETE (3-hydroxyeicosatetraenoic acid), a fungal mimetic of arachidonic acid, produces a cascade of novel bioactive 3-hydroxyeicosanoids. Biochem J 15 September 2005; 390 (3): 737–747. doi: https://doi.org/10.1042/BJ20041995
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.