Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology

Abstract

Eicosanoids have been implicated in a vast number of devastating inflammatory conditions, including arthritis, atherosclerosis, pain, and cancer. Currently, over a hundred different eicosanoids have been identified, with many having potent bioactive signaling capacity. These lipid metabolites are synthesized de novo by at least 50 unique enzymes, many of which have been cloned and characterized. Due to the extensive characterization of eicosanoid biosynthetic pathways, this field provides a unique framework for integrating genomics, proteomics, and metabolomics toward the investigation of disease pathology. To facilitate a concerted systems biology approach, this review outlines the proteins implicated in eicosanoid biosynthesis and signaling in human, mouse, and rat. Applications of the extensive genomic and lipidomic research to date illustrate the questions in eicosanoid signaling that could be uniquely addressed by a thorough analysis of the entire eicosanoid proteome.

Fig. 1.

Overview of eicosanoid biosynthesis through COX, LOX, CYP P450, and nonenzymatic pathways acting on arachidonic acid.

Fig. 2.

Major eicosanoid biosynthetic pathways. The metabolites of the major pathways are indicated in color: COX (purple), 5-LOX (orange), 15-LOX (green), 12-LOX (yellow), CYP epoxygenase (red), CYP ω-hydroxylase (cyan), and nonenzymatic oxidation (gray). The products of arachidonic acid metabolism are illustrated, but similar products can be formed from other fatty acids (e.g., linoleic acid, eicosapentenoic acid, and docosahexaenoic acid).

Fig. 3.

PG nomenclature and structure. Arachidonic acid carbons are numbered 1–20, starting from the carboxylate. The prostaglandin letter indicates composition of the prostane ring, with PGH₂ as an example.

Fig. 4.

Structures of 5-lipoxygenase metabolites. 5-Lipoxygenase creates the labile epoxide LTA₄, which can be enzymatically converted into LTB₄, LTC₄, and LXA₄.

Fig. 5.

Structures of 12-lipoxygenase metabolites. 12-Lipoxygenase creates 12-HpETE, which can further isomerize to form HXA₃.

Fig. 6.

Structure of eoxin C₄. Eoxins are the 15-LOX analogs of the cysteinyl leukotrienes, where the thiol attachment occurs at C-14.

Fig. 7.

Structures of cytochrome P450 metabolites. Cytochrome P450 enzymes can catalyze ω-oxidation (example: 20-HETE) and epoxidation (11,12-EET) reactions.

Fig. 8.

Examples of LTB₄ metabolism by β-oxidation, CYP ω-hydrolases, and glucuronidation.

Fig. 9.

Temporal genomic and lipidomic changes in eicosanoid biosynthesis in RAW264.7 macrophages in response to Kdo₂-Lipid A stimulation. Greater intensity of red indicates increasing levels, greater intensity of green indicates decreasing levels, and gray represents no change in levels relative to unstimulated cells. Changes are represented as a function of time (left to right), where rectangles indicate mRNA data and circles indicate lipid data. When enzyme activities can result from multiple genes, each is represented as a separate line. The transcriptomic data will be reported by S. Subramaniam and S. Gupta (unpublished observations), and the lipidomic data will be reported by Gupta et al. (unpublished observations); both data sets are also publicly available at www.lipidmaps.org.