A combined computational strategy of sequence and structural analysis predicts the existence of a functional eicosanoid pathway in Drosophila melanogaster

Abstract

This study reports on a putative eicosanoid biosynthesis pathway in Drosophila melanogaster and challenges the currently held view that mechanistic routes to synthesize eicosanoid or eicosanoid-like biolipids do not exist in insects, since to date, putative fly homologs of most mammalian enzymes have not been identified. Here we use systematic and comprehensive bioinformatics approaches to identify most of the mammalian eicosanoid synthesis enzymes. Sensitive sequence analysis techniques identified candidate Drosophila enzymes that share low global sequence identities with their human counterparts. Twenty Drosophila candidates were selected based upon (a) sequence identity with human enzymes of the cyclooxygenase and lipoxygenase branches, (b) similar domain architecture and structural conservation of the catalytic domain, and (c) presence of potentially equivalent functional residues. Evaluation of full-length structural models for these 20 top-scoring Drosophila candidates revealed a surprising degree of conservation in their overall folds and potential analogs for functional residues in all 20 enzymes. Although we were unable to identify any suitable candidate for lipoxygenase enzymes, we report structural homology models of three fly cyclooxygenases. Our findings predict that the D . melanogaster genome likely codes for one or more pathways for eicosanoid or eicosanoid-like biolipid synthesis. Our study suggests that classical and/or novel eicosanoids mediators must regulate biological functions in insects–predictions that can be tested with the power of Drosophila genetics. Such experimental analysis of eicosanoid biology in a simple model organism will have high relevance to human development and health.

Immune Response of Drosophila suzukii Larvae to Infection with the Nematobacterial Complex Steinernema carpocapsae–Xenorhabdus nematophila

“…These authors related the secretion of a phospholipase A 2 (PLA 2 ) inhibitor with the suppression of the proPO activation in hemolymph and the alteration of cellular response. Despite no homologous genes were identified in D. melanogaster, Scarpati et al [47] found other genes involved in eicosanoid pathway that could be functional equivalents.…”

Overexpression of PGE2 synthase by in vivo transient expression enhances immunocompetency along with fitness cost in a lepidopteran insect

“…In mammals, cytosolic or membrane-bound PGES isomerizes PGH 2 to PGE 2 . Insects also have been considered to have all biosynthetic machinery to synthesize PGE 2 , as predicted in previous bioinformatics analysis of Drosophila melanogaster (Scarpati et al, 2019). Indeed, three different PLA 2 s have been identified in S. exigua and include one secretory PLA 2 and two cellular PLA 2 s. Also, COX-like peroxynectins have been identified and play a role in oxygenating AA (Park et al, 2014).…”

Discovery of aspirin-triggered eicosanoid-like mediators in a Drosophila metainflammation blood tumor model

“…Thus, selective spz KD in hop Tum-l blood cells improves organismal viability, much as aspirin treatment does. We envision two possible mechanisms of action: (1) aspirin may block the activities of COX-like enzymes (Scarpati et al, 2019;Tootle and Spradling, 2008), which may, in turn, act through the NF-κB/STAT axis in hop Tum-l blood cells to reduce levels of pro-mitotic/pro-inflammatory proteins, or (2) it may directly block the observed cell cycle progression, for example, by interacting with cell cycle proteins. The anti-mitotic effects of aspirin and reduction in tumorigenesis in flies are consistent with reported salutary effects in epidemiological studies of cancer patients (Elwood et al, 2009;Qiao et al, 2018;Schreinemachers and Everson, 1994).…”

“…In addition, C20 polyunsaturated fatty acid (PUFA)-fed flies generate hydroxyeicosatetraenoic acid (13-HETE) (Tan et al, 2016), an AA metabolite, suggesting that flies express enzymes for eicosanoid synthesis. Our computational studies show that many functional enzymes for eicosanoid biosynthesis are encoded in the fly genome, including two other COX-like enzymes in addition to Pxt (Scarpati et al, 2019). We therefore analyzed inflammation readouts in flies after aspirin treatment and searched for anti-inflammatory C18-derived PUFAs.…”