Characterization of Prostaglandin E₂Production byCandida albicans

Abstract

Candida albicans produces lipid metabolites that are functionally similar to host prostaglandins. These studies, using mass spectrometry, demonstrate that C. albicans produces authentic prostaglandin E 2 (PGE 2 ) from arachidonic acid. Maximal PGE 2 production was achieved at 37°C in stationary-phase culture supernatants and in cell-free lysates generated from stationary-phase cells. Interestingly, PGE 2 production is inhibited by both nonspecific cyclooxygenase and lipoxygenase inhibitors but not by inhibitors specific for the cyclooxygenase 2 isoenzyme. The C. albicans genome does not possess a cyclooxygenase homolog; however, several genes that may play a role in prostaglandin production from C. albicans were investigated. It was found that a C. albicans fatty acid desaturase homolog (Ole2) and a multicopper oxidase homolog (Fet3) play roles in prostaglandin production, with ole2/ole2 and fet3/fet3 mutant strains exhibiting reduced PGE 2 levels compared with parent strains. This work demonstrates that the synthesis of PGE 2 in C. albicans proceeds via novel pathways.The eicosanoids are a family of 20-carbon fatty acid metabolites that include prostaglandins and leukotrienes. Prostaglandin E 2 (PGE 2 ) is an oxygenated metabolite of arachidonic acid (AA) and is produced via a two-step process beginning with the initial action of a cyclooxygenase (COX-1 or COX-2) to form PGH 2 followed by specific PGE synthases in the mammalian host (4,16,42,43; reviewed in reference 26).

Eicosanoid biosynthesis influences the virulence of Candida parapsilosis

“…In C. albicans however, the fatty acid desaturase OLE2 and a multicopper oxidase FET3 play a role in prostaglandin production via novel pathways using exogenous arachidonic acid as precursor [9]. CaFET3 , a laccase homolog (and also a member of the Fet family of multicopper oxidases) is suggested to regulate PGE 2 biosynthesis through a mechanism similar to that of LAC1 in C. neoformans .…”

“…CaFET3 , a laccase homolog (and also a member of the Fet family of multicopper oxidases) is suggested to regulate PGE 2 biosynthesis through a mechanism similar to that of LAC1 in C. neoformans . On the other hand, Ole2, a putative delta9 desaturase also containing a cytochrome B domain, is hypothesized to regulate PGE 2 production via the oxidation of exogenous arachidonic acids [9]. …”

“…While CaFET3 is known to interfere with fungal prostaglandin production [9], no such role has been associated with CaPOX1-3 , and CaPOT1 in C. albicans , suggesting a novel function of the corresponding homologues in C. parapsilosis .…”

“…Human pathogenic fungi can also produce eicosanoids, mainly PGE 2 , themselves [9]. However, they lack COX and LOX required for their production, which suggests the presence of alternative routes for prostaglandin biosynthesis.…”

“…However, they lack COX and LOX required for their production, which suggests the presence of alternative routes for prostaglandin biosynthesis. Such routes have been identified in C. albicans ( FET3 and OLE2 mediated pathways) [9], C. neoformans ( LAC1 ) [10] and Aspergillus ( PPO gene family) species [11]. These fungal eicosanoids play a role in fungal pathogenesis, as deletion of LAC1 in C. neoformans resulted in attenuated virulence while disruption of PPO genes drastically reduced asexual spore formation in Aspergillus nidulans and leads to a hyper-virulent phenotype in A. fumigatus [11].…”