15-Hydroperoxy-PGE2: Intermediate in Mammalian and Algal Prostaglandin Biosynthesis

Article abstract of DOI:10.1002/anie.201910461

Arachidonic-acid-derived prostaglandins (PGs), specifically PGE₂, play a central role in inflammation and numerous immunological reactions. The enzymes of PGE₂ biosynthesis are important pharmacological targets for anti-inflammatory drugs. Besides mammals, certain edible marine algae possess a comprehensive repertoire of bioactive arachidonic-acid-derived oxylipins including PGs that may account for food poisoning. Described here is the analysis of PGE₂ biosynthesis in the red macroalga Gracilaria vermiculophylla that led to the identification of 15-hydroperoxy-PGE₂, a novel precursor of PGE₂ and 15-keto-PGE₂. Interestingly, this novel precursor is also produced in human macrophages where it represents a key metabolite in an alternative biosynthetic PGE₂ pathway in addition to the well-established arachidonic acid-PGG₂-PGH₂-PGE₂ route. This alternative pathway of mammalian PGE₂ biosynthesis may open novel opportunities to intervene with inflammation-related diseases.

Full text of DOI:10.1002/anie.201910461

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Accepted Article
Title: 15-Hydroperoxy-PGE2 – A Novel Intermediate in Mammalian and
Algal Prostaglandin Biosynthesis
Authors: Hans Jagusch, Markus Werner, Oliver Werz, and Georg
Pohnert
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201910461
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15-Hydroperoxy-PGE2 – A Novel Intermediate in Mammalian and
Algal Prostaglandin Biosynthesis
Hans Jagusch, Markus Werner, Oliver Werz*[b], and Georg Pohnert*[a]
Abstract: Oxidized metabolites of C20 fatty acids are potent lipid
mediators contributing to the initiation and resolution of inflammation
in mammals. One important class are the arachidonic acid-derived
prostaglandins (PGs) with PGE2 playing
a central role in
inflammation and numerous immunological reactions. The enzymes
of PGE2 biosynthesis are important pharmacological targets for anti-
inflammatory drugs. Besides mammals, certain edible marine algae
possess a comprehensive repertoire of bioactive arachidonic acid-
derived oxylipins including PGs that may account for food poisoning.
Here we describe the analysis of PGE2 biosynthesis in the red
macroalga Gracilaria vermiculophylla that led to the identification of
15-hydroperoxy-PGE2, a novel precursor of PGE2 and 15-keto-PGE2.
Interestingly, this novel precursor is also produced in human
macrophages where it represents a key metabolite in an alternative
biosynthetic PGE2 pathway in addition to the well-established
arachidonic acid-PGG2-PGH2-PGE2 route. This alternative pathway
of mammalian PGE2 biosynthesis may open novel opportunities to
intervene with inflammation-related diseases.
Arachidonic acid (AA)-derived oxylipins are potent tissue
hormones involved in numerous homeostatic biological functions
but also in the pathogenesis of a variety of disorders.[1,2] In
mammals, these lipid mediators are generated in response to
extracellular stimuli by cyclooxygenases (COXs) and/or
lipoxygenases (LOXs).[3] One class of these tissue hormones are
the prostaglandins (PGs) that play a central role in regulating
inflammation.[4] Increase of PG levels during acute inflammation
is part of the immune responses to injury and infections.
Chronically elevated PG levels are connected to the
pathogenesis of arthritis, cancer, atherosclerosis, stroke, and
neurodegeneration.[2,5,6] Non-steroidal anti-inflammatory drugs
(NSAIDs) and coxibs (selective COX-2 inhibitors) block the
biosynthesis of PGs.[7] PGE2 1 is involved in diverse biological
processes that include ovulation, bone metabolism, blood vessel
tone, and pain.[8] Its action is mediated via the G protein-coupled
receptors EP1-4.[3,9] The well-known AA-PGG2-PGH2-PGE2
biosynthetic pathway involving COX-1 and-2 as key enzymes
(red arrows Figure 1) is a widely accepted route to 1 and no
alternative branches for the generation of 1 in mammals were
considered till today.
Figure 1. Biosynthetic pathways for PGE2 1 and 15-keto-PGE2 2 in mammals
and algae. In the canonic pathway (thick red arrows), AA is converted by
COX-1 or -2 to PGG2 that is subsequently reduced by the peroxidase activity
of the COX to PGH2 and converted by PGE2 synthase (PGES) to 1. In the
novel pathway introduced here (thin red and thick green arrows), PGG2 is
metabolized by a PGES-like activity to the novel intermediate 15-hydroperoxy-
PGE2 3 that is reduced enzymatically or non-enzymatically to 1. 15-keto-PGE2
2 occurs as a metabolic by-product. The contribution of both pathways to the
formation of 1 differs between algae and mammals probably due to different
COX peroxidase activity.
Besides mammals, also marine algae generate AA-derived
oxylipins including PGs that function primarily as defense
molecules.[10,11] PGs derived from the red macroalga Gracilaria
vermiculophylla are involved in the chemical defense against
grazers of the alga and are therefore associated with its invasive
spreading after introduction from the northwest Pacific.[12,13] The
oxylipins are rapidly biosynthesized in response to wounding of
the algal tissue. They can also be induced in intact algae upon
reception of signals from pathogens and serve to increase
resistance.[10] Work on algal oxylipins has often stimulated novel
concepts about oxylipin biosynthesis with implications for
mammalian, plant, and algal pathways.[14,15] Edible red
seaweeds of the genus Gracilaria contain high amounts of 1
related to numerous reported cases of food poisoning in East
Asia upon ingestion of raw alga.[16] The algal formation of 1 and
metabolic intermediates are not fully elucidated yet. To explore
the algal biosynthesis of 1, we systematically mined G.
vermiculophylla for AA-derived oxylipins.
[a]
[b]
H. Jagusch, Prof. Dr. G. Pohnert
Institute for Inorganic and Analytical Chemistry, Department of
Instrumental Analytics / Bioorganic Analytics, Friedrich-Schiller-
University Jena, Lessingstraße 8, 07743 Jena (Germany)
E-mail: georg.pohnert@uni-jena.de
We collected fresh specimens of G. vermiculophylla from
the Baltic Sea near Kieler Förde (Germany) for oxylipin
extraction. To elucidate the complex oxylipin profile, we
extracted G. vermiculophylla after mechanical wounding, a
procedure that was previously shown to initiate the lipase- and
M. Werner, Prof. Dr. O. Werz
Institute of Pharmacy, Department of Pharmaceutical / Medicinal
Chemistry, Friedrich-Schiller-University Jena, Philosophenweg 14,
07743 Jena (Germany)
E-mail: oliver.werz@uni-jena.de
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LOX-mediated formation of C20 oxylipins.[11,13] Briefly, the alga
was frozen in liquid nitrogen and ground. After thawing and
incubation at room temperature, the oxylipins were taken up in
methanol. Solid phase extraction (SPE) provided samples for
ultra-high performance liquid chromatography coupled with mass
spectrometry (UHPLC-MS).[17] We identified the common algal
PGE2 1 and 15-keto PGE2 2 as well as a novel putative oxylipin
3 (Figure 2).
Figure 3. Structure of 15-hydroperoxy-PGE2 3 with characteristic NMR
correlations given as bold lines for 1H,1H-COSY and as arrows for HMBC.
The hydroperoxide 3 was thermally unstable forming 1 and
2 (confirmed with commercially available standards Figure 4, SI-
Figure 1 and SI-Figure 3). The ratio of both metabolites
generated upon heating of 3 to 37 °C for 24 h was ca. 1:1, in
accordance with a disproportion reaction. In wounded G.
vermiculophylla this ratio was ca. 3:2 indicating an enzymatic
contribution to their formation or metabolization.
Figure 2. UHPLC-MS profile of an extract from wounded G. vermiculophylla.
The novel prostaglandin 15-hydroperoxy-PGE2 3 elutes at 7.38 min next to 15-
keto-PGE2 2 at 6.56 min and PGE2 1 at 7.02 min. Dihydroxy-eicosatetraenoic
acids (diHETEs) eluted at 9.50-11.50 min. The oxylipin profile was recorded in
negative ionization mode and the total ion count in full MS is plotted.
The high-resolution mass of the pseudo molecular ion m/z
367.2116 [M-H]- suggested an elemental composition of
C20H31O6 (calculated mass 367.2120) consistent with a highly
oxidized eicosanoid. For structure elucidation of 3, we
fractionated the algal extract by reversed-phase high-
performance liquid chromatography (RP-HPLC) and obtained
21.4 µg compound g-1 alga (fresh weight). The structure of 3 was
assigned by 1D and 2D nuclear magnetic resonance (NMR) as
well as by MS2 (see Supporting Information SI-Figure 4 and SI-
Table 1). A first comparison of NMR data suggested the
molecule to be very similar to 1 with an intact 3-hydroxy-
cyclopentanone core. The 5Z,13E double bond conformation
was inferred by 1H,1H-coupling. The UV spectrum with maximum
absorption at 215 nm suggested a chromophore similar to that of
1 (see Supporting Information SI-Figure 5).[18] A hydroperoxy
group at position C15 was deduced from NMR and MS2: The 13C-
NMR signal of C15-OOH (85.4 ppm) was downfield shifted
compared the C15-OH of 1 at 70.7 ppm.[19] The hydroperoxide 3
required lower energy for MS2 fragmentation compared to
hydroxy functionalized 1. The MS2 of 3 resembled that of 2,
which can be explained by an initial loss of water at C15 from 3
and further similar fragmentation (see Supporting Information SI-
Figure 4).
To determine the absolute configuration of 3, we reduced
the compound with NaBH4 resulting in 1 and PGF2α/β. Co-
injection with authentic standards confirmed the structures and
further supported the hydroperoxy moiety in 3 (see Supporting
Information SI-Figure 3). The circular dichroism (CD) spectra of
1 and 3 isolated from G. vermiculophylla were similar and
matched with the literature data for mammalian 1, thus
confirming an identical configuration of 3and mammalian 15S-
configured 1 (see Supporting Information SI-Figure 6).[20] The
novel oxylipin was thus elucidated as 15S-hydroperoxy-PGE2 3.
The structure and key NMR-correlations are shown in Figure 3.
Figure 4. UHPLC-MS profiles for 15-hydroperoxy-PGE2 3 (black, red at 7.36
min) and its degradation products 15-keto-PGE2 2 and PGE2 1 (red at 6.5 min
and 7 min) formed at 37 °C (for 24 h) in comparison to PG standards: 1 (blue)
at 7 min; 2 (green) at 6.5 min. All profiles were measured in negative ionization
mode and the total ion count in full MS is plotted. Note that the detector
response for the ionization of 1 and 2 is different and that, after normalization
with external standards, observed peak areas in the treatment at 37°C
correspond to equal molar amounts (see Supporting Information SI-Figure 8
and SI-Table 7).
In mammals, COX-1 or -2 catalyze the conversion of
phospholipase-released
AA
to
PGG2.
Subsequent
transformation of the peroxide to PGH2 is mediated by the
peroxidase activity of the COX enzymes.[21] Subsequently, a
PGES (three different isoenzymes are known) generates 1 from
PGH2.[22] Similar key enzymes were previously found in algae
converting AA to 1, however, isolation and elucidation of
intermediates such as PGH2 was not reported.[23,24] The novel
labile PG 3 can be explained by the action of a COX converting
AA, followed by a PGES-like transformation of the intermediate.
The abiotic conversion of 3 to 1 and 2 suggests it to be an
alternative intermediate in the biosynthesis of these PGs in the
alga. The product ratio of the algal PGs indicates a mixed
mechanism involving disproportionation of 3 and its enzymatic
transformation. An algal pathway that does not follow the
established AA-PGG2-PGH2-1 route is supported by the fact that
the COX of G. vermiculophylla shares just about 20 % of the
amino acid sequence from the mammalian counterpart rendering
the algal enzymes resistant to commonly available COX
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inhibitors.[23] The peroxidase activity of the algal COX might be
low, leading to the accumulation of PGG2; the algal PGES might
then open the endoperoxide of PGG2 faster than the COX
reduces the hydroperoxide yielding preferably 3, thus privileging
the novel route via
3 as compared to the well-known
(mammalian) pathway via PGH2.
Given the specificity of the abiotic transformation and the
lability of 3 we reasoned that this molecule might also represent
an overlooked intermediate in mammalian PG biosynthesis. We,
therefore, surveyed lipid mediators in human monocyte-derived
macrophages with an M1 phenotype that is known for
substantial PG production during inflammation.[25,26] Stimulation
of M1 with ionophore A23187 was used to induce PG
biosynthesis.[27] Lipid mediator extracts were screened for 3
using the UHPLC-MS protocol described above. Indeed, 3 was
detected (63 pg 2x106 cells) besides 2 (109 pg 2x106 cells-1) and
1 (5370 pg 2x106 cells-1) in stimulated M1 macrophages. The
amount of the hydroperoxide
3 increased upon A23187
stimulation, however it was still only detected in traces (ca.
1.2 %) compared to 1. This would be in accordance with its role
as an intermediate in PGE2 biosynthesis (Figure 5).
Based on mechanistic considerations,
3 has been
postulated in the early 1970s as an intermediate in the sequence
AA-PGG2-3-1 but has, to our knowledge, never been
confirmed.[28] Our finding now substantiates this pathway as an
alternative route for the established sequence AA-PGG2-PGH2-
1.[29] In comparison to M1 macrophages, we only found minor
quantities of 3, 2, and 1 in M2 macrophages regardless of
whether cells were stimulated or not. This is consistent with the
fact that M2 express only low levels of COX-2 and PGES with
moderate capacities to produce PGs (see also Supporting
Information SI-Table 2).[30]
To confirm the hydroperoxide 3 as a direct precursor of 1,
we incubated either stimulated or non-stimulated M1 or M2
macrophages with 3 and analyzed the generated products by
UHPLC-MS. The amounts of 1 in both phenotypes were
significantly elevated in samples amended with 3 (Figure 6, see
also Supporting Information SI-Tables 2 to 4). The amount of 15-
keto-PGE2 2 determined in the samples was lower compared to
2 arising from the disproportionation of 3 in the medium control.
This is possibly due to metabolization of 2 via reductases to
13,14-dihydro-15-keto-PGE2 and eventually via β- and ω-
oxidation to PGE-M (see Supporting Information SI-Table 3 and
SI-Table 4, SI-Figure 9 and SI-Figure 10).[31] Although 3
accounts only for approx. 1.2 % in quantities compared to 1, the
contribution of this intermediate via the alternative biosynthetic
branch to 1 is very likely higher because 3 is endogenously
metabolized by human cells.
Figure 5. A) UHPLC-MS profile of a lipid mediator extract from 2x106
stimulated (blue) or non-stimulated (red) human M1 macrophages measured
in negative ionization mode, plotted as total ion count in full MS. The
enhanced region shows the extracted ion chromatogram for 15-hydroperoxy-
PGE2 3. The novel PG 3 elutes at 6.25 min. Further known lipid mediators
were detected: PGE2 1 at 5.82 min, leukotriene B4 (LTB4) at 8.93 min, 12-
HETE at 11.85 min, AA at 13.73 min. B) Amounts of 1 (grey, black, green,
white) and 3 (red, blue, orange, dark grey) produced in 2x106 stimulated (n=4)
or non-stimulated (n=3) human M1 or M2 macrophages shown as means ±
SEM. Cells were suspended in 1 mL PBS plus 1 mM CaCl2 and incubated for
10 min at 37 °C with or without 2.5 µM A23187 or vehicle (0.5 % methanol).
Statistical evaluation: one way ANOVA with Tukey Post-hoc test, */+ P≤0.05;
**/++ P≤0.01; ***/+++ P≤0.001, asterisks refer to comparison to non-stimulated
conditions.
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(NSAID) and coxibs.[35] Regarding ingestion of raw alga,
increased levels of leukotriene B4 and 1 are toxic for the
gastrointestinal tract.[36,37] Both lipid mediators may be formed
from labile precursors such as thermally unstable 3 or acid-labile
5R,8R-di hydroxyl eicosatetraenoic acid.[17]
In conclusion, we reveal here an alternative biosynthetic
pathway to PGE2 1 in algae and in mammals. Upon cell
activation, 1 is formed either via the canonical AA-PGG2-PGH2-1
route catalyzed by COX, COX peroxidase and PGES or via the
newly identified AA-PGG2-3-1 pathway mediated by COX, PGES,
and hydroperoxide-reduction. The contribution of each pathway
to the production of 1 differs between algae and mammals.
Whereas the first route via PGH2 dominates in mammals, algae
preferentially rely on the second pathway via 3, which represents
a side route in human macrophages. These species-dependent
preferences are probably due to differences in the COX proteins
affecting the peroxidase activity. Interestingly, the hydroperoxide
3 is reductively converted mainly to 1 in human macrophages
but in macroalgae conversion leads to a mixture of 1 and 2.
Acknowledgement
Stefan Bartram (Max Planck Institute for Chemical Ecology
Jena) and Tim Baumeister (Friedrich-Schiller-University Jena)
are thanked for help on CD measurements and graphic design.
We are grateful for a Kekulé-Stipend (H. J.) of the German
chemical industry association Verband der Chemischen
Industrie (VCI). This work was supported by the German
Research foundation within the framework of the collaborative
research centre CRC1127 ChemBioSys.
Figure 6. Production of PGE2 1 in 2x106 stimulated or non-stimulated A) M1 or
B) M2 macrophages, either treated with 100 nM 15-hydroperoxy-PGE2 3
(stimulated, non-stimulated n=6, respectively) or vehicle (0.5 % methanol)
(non-stimulated n=3; stimulated n=4). Cells were suspended in 1 mL PBS plus
1 mM CaCl2 and pre-incubated with 3 or vehicle for 10 min at 37 °C. Cells
were subsequently stimulated with 2.5 µM A23187 or vehicle (0.5 % methanol)
and incubated for another 10 min at 37 °C. 3 was dissolved in 1 mL PBS plus
1 mM CaCl2 and incubated in absence of cells for 20 min at 37 °C as control
(n=6) to determine formation of 1 due to degradation. All values are shown as
means ± SEM. Statistical evaluation: one way ANOVA with Tukey Post-hoc
test, */+ P≤0.05; **/++ P≤0.01; ***/+++ P≤0.001, asterisks refer to comparison to
non-stimulated conditions.
Keywords: alga · biosynthesis · inflammation · mammal ·
prostaglandins
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A new pathway to a long-
known lipid mediator was
discovered in the red alga
Gracilaria vermiculophylla (top).
Upon re-investigation of the
mammalian biosynthesis 15-
hydroxy-PGE2 was also
established as alternative
pathway toward the inflammation
mediating hormone.
Hans Jagusch, Markus Werner,
Oliver Werz*, Georg Pohnert*
Page No. – Page No.
15-Hydroperoxy-PGE2 – A Novel
Intermediate in Mammalian and
Prostaglandin Biosynthesis
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