Docosahexaenoic acid (DHA), a major ω-3 polyunsaturated fatty acid (PUFA) found in fish oil is the source of D-series resolvins (RvDs), one of the specialized proresolving mediators (SPMs) that show potent anti-inflammatory and pro-resolving actions (Molfino et al. 2017). The biosynthesis of RvDs occurs mainly during the process of inflammation when endothelial cells interact with leukocytes. Dietary DHA circulates in plasma or is present in cellular membranes as it can easily integrate into membranes. On injury or infection, DHA moves with edema into the tissue sites of acute inflammation where it is converted to exudate RvDs to interact with local immune cells (Kasuga et al. 2008). The initial transformation of DHA by aspirin-acetylated cyclooxygenase-2 or cyclooxygenase-mediated catalysis can produce stereospecific D-resolvins (18(R)- or 18(S)-RvDs respectively). Combinations of oxidation, reduction and hydrolysis reactions determine the type of D-resolvin formed (RvD1-6) (Serhan et al. 2002, Serhan & Petasis 2011, Serhan et al. 2014).
View original pathway at Reactome.
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An unknown hydroperoxy reductase mediates the reduction of 4(S)-hydroperoxy-17(S)-hydroxydocosahexaenoic acid (4(S)-Hp-17(S)-HDHA) to 4(S),17(S)-dihydroxydocosahexaenoic acid (AT-RvD6) (Serhan et al. 2002).
Lipoxygenase 5 (ALOX5) can oxidise 17(R)-hydroxydocosahexaenoic acid (17(R)-HDHA) into two hydroperoxy intermediates in human polymorphonuclear leukocytes (PMNs) (Serhan et al. 2002). The formation of 7(S)-hydroperoxy-17(R)-hydroxydocosahexaenoic acid (7(S)-Hp-17(R)-HDHA) is decribed here.
Leukotriene A4 hydrolase (LTA4H) is a monomeric, soluble enzyme that uses a Zn2+ cofactor to catalyse the hydrolysis of the allylic epoxide leukotriene A4 (LTA4) (McGee & Fitzpatrick 1985). LTA4H can also catalyse the hydrolysis of 7S(8)-epoxy-17(R)-hydroxydocosahexaenoic acid (7S(8)-epoxy-17(R)-HDHA) to the trihydroxydocosahexaenoic acids 7(S), 8(R), 17(R)-triHDHA and 7(S), 16(R), 17(R)-triHDHA (AT-RvD1 and AT-RvD2 respectively) (Sun et al. 2007, Spite et al. 2009, Serhan et al. 2002). The D-resolvins are anti-inflammatory, pro-resolving, and non-phlogistic (that is, they mediate the clearance of leukocytes without eliciting an inflammatory response) (Serhan et al. 2008).
Leukotriene A4 hydrolase (LTA4H) is a monomeric, soluble enzyme that uses a Zn2+ cofactor to catalyse the hydrolysis of the allylic epoxide leukotriene A4 (LTA4) (McGee & Fitzpatrick 1985). LTA4H can also catalyse the hydrolysis of 4S(5)-epoxy-17(S)-hydroxydocosahexaenoic acid (4S(5)-epoxy-17(S)-HDHA) to the trihydroxydocosahexaenoic acids 4(S), 11(R), 17(S)-triHDHA and 4(S), 5(R), 17(S)-triHDHA (RvD3 and RvD4 respectively) (Dalli et al. 2013, Serhan et al. 2002, Winkler et al. 2013, 2016). The D-resolvins are anti-inflammatory, pro-resolving, and non-phlogistic (that is, they mediate the clearance of leukocytes without eliciting an inflammatory response) (Serhan et al. 2008).
Leukotriene A4 hydrolase (LTA4H) is a monomeric, soluble enzyme that uses a Zn2+ cofactor to catalyse the hydrolysis of the allylic epoxide leukotriene A4 (LTA4) (McGee & Fitzpatrick 1985). LTA4H may also be able to catalyse the hydrolysis of 17R(6)-epoxy-docosahexaenoic acid (17R(16)-epoxy-DHA) to 10(R),17(R)-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid (aspirin-triggered (neuro)protectin D1, AT-(N)PD1) (Serhan et al. 2011). In human cells, AT-(N)PD1 decreased PMN migration as well as enhancing efferocytosis of apoptotic human PMN by macrophages, indicating AT-(N)PD1 as a potent anti-inflammatory proresolving molecule (Serhan et al. 2011).
Leukotriene A4 hydrolase (LTA4H) is a monomeric, soluble enzyme that uses a Zn2+ cofactor to catalyse the hydrolysis of the allylic epoxide leukotriene A4 (LTA4) (McGee & Fitzpatrick 1985). LTA4H can also catalyse the hydrolysis of 7S(8)-epoxy-17(S)-hydroxydocosahexaenoic acid (7S(8)-epoxy-17(S)-HDHA) to the trihydroxydocosahexaenoic acids 7(S), 8(R), 17(S)-triHDHA and 7(S), 16(R), 17(S)-triHDHA (RvD1 and RvD2 respectively) (Sun et al. 2007, Spite et al. 2009, Serhan et al. 2002). The D-resolvins are anti-inflammatory, pro-resolving, and non-phlogistic (that is, they mediate the clearance of leukocytes without eliciting an inflammatory response) (Serhan et al. 2008).
Lipoxygenase 5 (ALOX5) can oxidise 17(R)-hydroxydocosahexaenoic acid (17(R)-HDHA) into two hydroperoxy intermediates in human polymorphonuclear leukocytes (PMNs) (Serhan et al. 2002). The formation of 4(S)-hydroperoxy-17(R)-hydroxydocosahexaenoic acid (4(S)-Hp-17(R)-HDHA) is decribed here.
An unknown hydroperoxy reductase mediates the reduction of 7(S)-hydroperoxy-17(S)-hydroxydocosahexaenoic acid (7(S)-Hp-17(S)-HDHA) to 7(S),17(S)-dihydroxydocosahexaenoic acid (AT-RvD5) (Serhan et al. 2002).
Normally, cyclooxygenases (COX) carry out stereospecific oxygenation of arachidonic acid to generate prostaglandins. When treated with aspirin (acetylsalicylic acid, ASA), dimeric cyclooxygenase-2 (COX2, PTGS2 dimer) can be acetylated. ASA covalently modifies PTGS2 by acetylating a serine residue at position 530 within the cyclooxygenase active site (Lucido et al. 2016). Acetylated PTGS2 dimer (Ac-PTGS2 dimer) changes the oxygenation stereospecificity towards its substrates, perhaps by steric shielding effects (Tosco 2013), producing a shift in lipid mediator production. Ac-PTGS2 dimer is able to incorporate molecular oxygen into ω-3 fatty acid docosahexaenoic acid (DHA), present in inflammatory exudates, to form the 17(R) epimer 17(R)-hydroperoxy-docosahexaenoic acid (17(R)-Hp-DHA) (Serhan et al. 2002, Sun et al. 2007). The product can either be transformed into aspirin-triggered D-resolvins or aspirin-triggered protectin D1 (Serhan et al. 2015).
The hydroperoxide intermediate of docosahexaenoic acid (17(R)-Hp-DHA) undergoes a second hydrogen abstraction by 15-lipoxygenase (ALOX15) to form the intermediate epoxide 17R(16)-epoxy-DHA (Serhan et al. 2011).
Lipoxygenase 5 (ALOX5) can oxidise 17(S)-hydroxydocosahexaenoic acid (17(S)-HDHA) into two hydroperoxy intermediates in human polymorphonuclear leukocytes (PMNs) (Serhan et al. 2002). The formation of 4(S)-hydroperoxy-17(S)-hydroxydocosahexaenoic acid (4(S)-Hp-17(S)-HDHA) is decribed here.
Leukotriene A4 hydrolase (LTA4H) is a monomeric, soluble enzyme that uses a Zn2+ cofactor to catalyse the hydrolysis of the allylic epoxide leukotriene A4 (LTA4) (McGee & Fitzpatrick 1985). LTA4H can also catalyse the hydrolysis of 4S(5)-epoxy-17(R)-hydroxydocosahexaenoic acid (4S(5)-epoxy-17(R)-HDHA) to the trihydroxydocosahexaenoic acids 4(S), 11(R), 17(R)-triHDHA and 4(S), 5(R), 17(R)-triHDHA (AT-RvD3 and AT-RvD4 respectively) (Dalli et al. 2013, Serhan et al. 2002, Winkler et al. 2013, 2016). The D-resolvins are anti-inflammatory, pro-resolving, and non-phlogistic (that is, they mediate the clearance of leukocytes without eliciting an inflammatory response) (Serhan et al. 2008).
Cytosolic phospholipid hydroperoxide glutathione peroxidase (GPX4 isoform 2, GPX4-2) (Yagi et al. 1996) is a likely candidate for the reduction of organic hydroperoxides such as 17(R)-hydroperoxy-docosahexaenoic acid (17(R)-Hp-DHA) to 17(R)-hydroxydocosahexaenoic acid (17(R)-HDHA) (Han et al. 2013) using glutathione (GSH) as an electron donor (Brigelius-Flohe & Maiorino 2013). 17(R)-HDHA can then be transformed into 17(R)-D-resolvins and a 17-oxo electrophilic product 17-oxo-DHA (Groeger et al. 2010).
Cytosolic phospholipid hydroperoxide glutathione peroxidase (GPX4 isoform 2, GPX4-2) (Yagi et al. 1996) is a likely candidate for the reduction of organic hydroperoxides such as 17(S)-hydroperoxy-docosahexaenoic acid (17(S)-Hp-DHA) to 17(S)-hydroxydocosahexaenoic acid (17(S)-HDHA) (Han et al. 2013) using glutathione (GSH) as an electron donor (Brigelius-Flohe & Maiorino 2013).
Maresins are a family of anti-inflammatory and pro-resolving lipid mediators biosynthesized from docosahexaenoic acid (DHA) by macrophages. In the first step, DHA is oxygenated by lipoxygenase 12 using Fe2+ cofactor (ALOX12:Fe2+) to 14(S)-hydroperoxy-docosahexaenoic acid (14(S)-Hp-DHA) (Serhan et al. 2009, Deng et al. 2014). Maresin-like mediators MaR-L1 and Mar-L2 are produced by leukocytes and platelets and have been shown to restore reparative functions of diabetic macrophages in wounds (Brem & Tomic-Canic 2007, Hong et al. 2014). The same reaction as above can occur in human leukocytes and platelets to produce MaR-L1 and MaR-L2. The 14(S)-Hp-DHA intermediate can also serve as a precursor for maresin conjugates in tissue regeneration (MCTR) (Dalli et al. 2016).
In the absence of aspirin in human whole blood, isolated leukocytes and glial cells, 15-lipoxygenase (ALOX15) can oxygenate docosahexanoic acid (DHA) (Kim et al. 1990) to the 17(S) epimer 17(S)-hydroperoxy-docosahexanoic acid (17(S)-Hp-DHA) (Hong et al. 2003). This intermediate leads to the production of 17(S) epimer D-resolvins (as opposed to aspirin-triggered 17(R) epimer D-resolvins), as well as being the precursor for protectins and the proposed precursor for the production of protectin conjugates in tissue regeneration (PCTRs) and resolvin conjugates in tissue regeneration (RCTRs) (Dalli et al. 2015, Ramon et al. 2016).
Lipoxygenase 5 (ALOX5) can oxidise 17(S)-hydroxydocosahexaenoic acid (17(S)-HDHA) into two hydroperoxy intermediates in human polymorphonuclear leukocytes (PMNs) (Serhan et al. 2002). The formation of 7(S)-hydroperoxy-17(S)-hydroxydocosahexaenoic acid (7(S)-Hp-17(S)-HDHA) is decribed here.
To produce their pro-resolving effects, 17(R)-RvD1-6 are released into the exudate of local inflammation sites (Serhan et al. 2000). The mechanism of translocation is unknown.
An unknown reductase mediates the reduction of 4(S)-hydroperoxy-17(R)-hydroxydocosahexaenoic acid (4(S)-Hp-17(R)-HDHA) to 4(S),17(R)-dihydroxydocosahexaenoic acid (AT-RvD6) (Serhan et al. 2002).
An unknown reductase mediates the reduction of 7(S)-hydroperoxy-17(R)-hydroxydocosahexaenoic acid (7(S)-Hp-17(R)-HDHA) to AT-RvD5 (Serhan et al. 2002), the structure of which has been chemically synthesised as 7(S),17(R)-dihydroxydocosahexaenoic acid (Ogawa et al. 2017). In mice with E.coli infection, several specialized pro-resolving mediators (SPMs) including RvD5, together with antibiotics, accelerated resolution and heightened host antimicrobial responses (Chiang et al. 2012).
Cytosolic, dimeric 15-hydroxyprostaglandin dehydrogenase (HPGD dimer), in the presence of NAD+, can oxidise 17(S)-resolvin D1 (RvD1) to the novel metabolites 17(S)-oxo-RvD1 and 8-oxo-17(S)-RvD1. The 17(S)-oxo transformation effectively inactivates RvD1 activity whereas the 8-oxo metabolite retains most of its RvD1 activity (Sun et al. 2007). The epimeric 17(R) aspirin-triggered form (AT-RvD1) was also found to be able to resist rapid inactivation.
To produce their pro-resolving effects, 17(S)-RvD1-6 are released into the exudate of local inflammation sites (Serhan et al. 2000). The mechanism of translocation is unknown.
15-lipoxygenase (ALOX15) can mediate a second lipoxygenation reaction where 17(S)-Hp-DHA is oxidised to the production of the protectin D1 (PD1) isomer PDX (Hong et al. 2003, Serhan et al. 2006, Chen et al. 2009). The chemical structure of PDX is 10(S),17(S)-dihydroxy-docosahexa-4Z,7Z,11E,13Z,15E,19Z-enoic acid. It differs from PD1, having E,Z,E geometry (PDX) instead of E,E,Z (PD1) and S configuration at carbon 10 instead of R (Chen et al. 2009). PDX is not a major product of leukocytes and has low potency compared to PD1 as a regulator of polymorphonuclear leukocyte (PMN) infiltration (Serhan et al. 2006).
Instead of undergoing a second oxygenation (to form PDX), the hydroperoxide intermediate 17(S)-Hp-DHA undergoes a hydrogen abstraction by 15-lipoxygenase (ALOX15) to form an intermediate epoxide, 16S,17S-epoxy-DHA (Hong et al. 2003, Serhan et al. 2006, Hong et al. 2007, Aursnes et al. 2015). This epoxide has now proved to be the precursor for the production of (neuro)protectin D1 ((N)PD1) as well as production of protectin conjugates in tissue regeneration (PCTRs) (Dalli et al. 2015, Ramon et al. 2016, Aursnes et al. 2015).
Leukotriene A4 hydrolase (LTA4H) is a monomeric, soluble enzyme that uses a Zn2+ cofactor to catalyse the hydrolysis of the allylic epoxide leukotriene A4 (LTA4) (McGee & Fitzpatrick 1985). When produced in neural tissue, where it affords potent tissue protective actions, this docsanoid is called neuroprotectin D1 (NPD1).
Maresin 1 (MaR1, 7(R),14(S)-dihydroxy-docosahexaenoic acid) is the first identified maresin. It is formed by hydrolysis of 13(R),14(S)-epoxy-docosahexaenoic acid (13(R),14(S)-epoxy-DHA) by an unknown epoxide hydrolase (Serhan et al. 2009). MaR1 displays potent anti-inflammatory and pro-resolving actions (Serhan et al. 2012, Chatterjee et al. 2014). MaR1 was found to inhibit proinflammatory mediator production by inhibiting LTA4 hydrolase, thereby shifting macrophage phenotype from proinflammatory mediator to proresolving mediator production (Dalli et al. 2013).
A novel double dioxygenation product can also be formed by non-enzymatic hydrolysis of 13(R),154(S)-epoxy-DHA, namely 7(S),14(S)-dihydroxy-docosahexaenoic acid (7-epi-MaR1). Although 7-epi-MaR1 possesses some bioactivity, it displays lower anti-inflammatory and pro-resolving actions than MaR1 (Serhan et al. 2009).
In macrophages, lipoxygenase 12 (ALOX12:Fe2+) may abstract hydrogen from 14(S)-hydroperoxy-docosaheaenoic acid (14(S)-Hp-DHA) to form 13(S),14(S)-epoxy-DHA (Serhan et al. 2009, Dalli et al. 2013, Deng et al. 2014). This epoxy product is a central intermediate in maresin MaR1 and MaR2 and maresin conjugates in tissue regeneration (MCTR) biosyntheses (Dalli et al. 2016) as well as possessing potent proresolving activity (Dalli et al 2013).
Dimeric bifunctional epoxide hydrolase 2 (EPHX2 dimer, soluble epoxide hydrolase, sEH) hydrolyses 13(S),14(S)-epoxy-docosahexaenoic acid (13(S),14(S)-epoxy-DHA) to form 13(R),14(S)-dihydroxy-docosahexaenoic acid, aka maresin 2 (MaR2) (Deng et al. 2014). Like MaR1, MaR2 possesses anti-inflammatory and pro-resolving activities although it is not as potent as MaR1 (Deng et al. 2014).
In macrophages, lipoxygenase 5 (ALOX5) is proposed to further oxygenate 14(S)-hydroperoxy-docosahexaenoic acid (14(S)-Hp-DHA) to 7(S),14(S)-dihydroperoxy-docosaheaenoic acid (7(S),14(S)-diHp-DHA) (Serhan et al. 2009).
An unknown hydroperoxy reductase mediates the production of the double dioxygenation product 7(S),14(S)-hydroxy-docosa-4Z,8E,10Z,12E,16Z,19Z-hexaenoic acid (7(S),14(S)-HDHA aka 7-epi-MaR1) that proved to have less potent pro-resolving and anti-inflammatory activity than either maresin 1 (MaR1) or protectin D1 (PD1) (Serhan et al. 2009, Bannenberg & Serhan 2010).
Maresin 1 (MaR1, 7(R),14(S)-dihydroxy-docosahexaenoic acid) is the first identified maresin and displays potent anti-inflammatory and pro-resolving actions (Serhan et al. 2012, Chatterjee et al. 2014). MaR1 was found to inhibit proinflammatory mediator production by inhibiting LTA4 hydrolase, thereby shifting macrophage phenotype from proinflammatory mediator to proresolving mediator production (Dalli et al. 2013). A novel double dioxygenation product can also be formed by non-enzymatic hydrolysis of 13(R),154(S)-epoxy-DHA, namely 7(S),14(S)-dihydroxy-docosahexaenoic acid (7-epi-MaR1). Although 7-epi-MaR1 possesses some bioactivity, it displays lower anti-inflammatory and pro-resolving actions than MaR1 (Serhan et al. 2009).
In human macrophages, a glutathione hydrolase (GGT) is proposed to cleave the γ-glutamyl moiety of MCTR1 to yield MCTR2, identified as 13(R)-cysteinylglycinyl, 14(S)-hydroxy-docosahexaenoic acid (Dalli et al. 2014, 2016a, 2016b). Incubation of human macrophages with MCTR1 and GGT enzyme inhibitors significantly reduces MCTR2 and MCTR3 production and significantly increases MCTR1 amounts, suggesting a GGT mediates MCTR2 production (Dalli et al. 2016a). In addition, Dalli et al. found the human recombinant GGT used in the experiment has a higher affinity for MCTR1 than leukotriene C4 (Dalli et al. 2016a). MCTR2, given to mice with E. coli peritonitis, showed potent proresolving action in inflammation and infections. With human macrophages, MCTR2 proved to be more potent that MCTR1 in stimulating efferocytosis of apoptotic cells (Dalli et al. 2014).
In human macrophages, a dipeptidase (DPEP) is proposed to hydrolyse maresin conjugates in tissue regeneration 2 (MCTR2) to MCTR3, identified as 13(R)-cysteinyl, 14(S)-hydroxy-4Z,7Z,9E,11E,13R,14S,16Z,19Zdocosahexaenoic acid (Dalli et al. 2014, 2016a, 2016b). Incubation of human macrophages with MCTR2 and a DPEP inhibitor demonstrates significantly higher MCTR2 levels and significantly lower MCTR3 levels, suggesting a DPEP mediates MCTR2 hydrolysis (Dalli et al. 2016a). MCTR3 displays potent activity in proresolution of inflammation and tissue regeneration (Dalli et al. 2016b).
Cytosolic, dimeric glutathione S-transferase Mu 4 (GSTM4 dimer) can catalyse the transfer of a glutathionyl group from glutathione (GSH) to 13(S),14(S)-epoxy-docosahexaenoic acid (13(S),14(S)-epoxy-DHA) to form maresin conjugate in tissue regeneration 1 (MCTR1) (Dalli et al. 2014, 2016a, 2016b). MCTR1, given to mice with E. coli peritonitis, showed potent proresolving action in inflammation and infections. With human macrophages, MCTR1 stimulated efferocytosis of apoptotic cells (Dalli et al. 2014).
Trimeric leukotriene C4 synthase (LTC4S trimer), located on the ER membrane, can catalyse the transfer of a glutathionyl group from glutathione (GSH) to 13(S),14(S)-epoxy-docosahexaenoic acid (13(S),14(S)-epoxy-DHA) to form maresin conjugates in tissue regeneration 1 (MCTR1) (Dalli et al. 2014, 2016a, 2016b). Incubation of human macrophages with LTC4S inhibitors significantly reduces cysteinyl leukotriene production and increases resolvin and lipoxin production (Dalli et al. 2016a). MCTR1, given to mice with E. coli peritonitis, showed potent proresolving action in inflammation and infections. With human macrophages, MCTR1 stimulated efferocytosis of apoptotic cells (Dalli et al. 2014).
Human macrophages produce protectin conjugates in tissue regeneration (PCTR). PCTR are named as such because they share a proposed biosynthetic pathway, structural features, and biological actions with DHA-derived protectins as well as displaying potent tissue-regenerative actions. 16S,17S-epoxy-docosahexaenoic acid (16S,17S-epoxy-DHA) was found to be a substrate for a glutathione transferase (GGT) which produces PCTR1 (16-glutathionyl, 17-hydroxy-docosahexaenoic acid) in greater quantities in M2-type macrophages than M1-type macrophages and was found to enhance resolution of infectious inflammation (Ramon et al. 2016, Dalli et al. 2015).
In human macrophages, protectin conjugate in tissue regeneration 3 (PCTR2) is proposed to be hydrolysed to PCTR3 (16-cysteinyl, 17-hydroxy-docosahexaenoic acid) by the actions of a glutathione transferase (GGT). Human macrophages incubated with E. coli and a GGT inhibitor led to increased levels of PCTR1 and decreased levels of PCTR3, suggesting a role for GGT enzyme in PCTR2 and PCTR3 biosynthesis (Dalli et al. 2015).
Just as the addition of glutathione (GSH) to an allylic epoxide is governed by glutathione S-transferase enzymes in the biosynthesis of MCTR (Dalli et al. 2016), 7S(8)-epoxy-17(S)-hydroxy-docosahexaenoic acid (7S(8)-epoxy-17(S)-HDHA) may presumably be conjugated with GSH by trimeric leukotriene C4 synthase (LTC4S trimer) to form resolvin conjugate in tissue regeneration 1 (RCTR1, 8-glutathionyl, 7,17-dihydroxy-docosahexaenoic acid) (Dalli et al. 2015).
In human macrophages, protectin conjugate in tissue regeneration 1 (PCTR1) is proposed to be hydrolysed to PCTR2 (16-cysteinylglycinyl, 17-hydroxy-docosahexaenoic acid) by the actions of a glutathione transferase (GGT). Human macrophages incubated with E. coli and a GGT inhibitor led to increased levels of PCTR1 and decreased levels of PCTR3, suggesting a role for GGT enzyme in PCTR2 and PCTR3 biosynthesis (Dalli et al. 2015).
Presumably following a similar synthesis route to protectin conjugate in tissue regeneration 3 (PCTR3), resolvin conjugate in tissue regeneration 2 (RCTR2) could be hydrolysed to RCTR3 (8-cysteinyl, 7,17-dihydroxy-docosahexaenoic acid) by the actions of a glutathione transferase (GGT) (Dalli et al. 2015).
A lipoxygenase may mediate hydrogen abstraction from 7(S),17(S)-dihydroperoxy-docosahexaenoic acid (7(S),17(S)-diHp-DHA) to form 7S(8)-epoxy-17(S)-hydroxy-docosahexaenoic acid (7S(8)-epoxy-17(S)-HDHA) (Dalli et al. 2015). This epoxy intermediate is the precursor for resolvin conjugates in tissue regeneration (RCTR).
In an alternative route to PCTR production, 17(S)-hydroperoxy-docosahexaenoic acid (17(S)-Hp-DHA) can undergo a second lipoxygenation at carbon 7 position to yield 7S,17S-dihydroperoxy-docosahexaenoic acid (7(S),17(S)-diHp-DHA). A lipoxygenase mediates this reaction although the exact human enzyme is unknown (Dalli et al. 2015).
Presumably following a similar synthesis route to protectin conjugate in tissue regeneration 2 (PCTR2), resolvin conjugate in tissue regeneration 1 (RCTR1) could be hydrolysed to RCTR2 (8-cysteinylglycinyl, 7,17-dihydroxy-docosahexaenoic acid) by the actions of a glutathione transferase (GGT) (Dalli et al. 2015).
An unidentified hydroperoxy reductase reduces 14(S)-hydroperoxy-docosahexaenoic acid (14(S)-Hp-DHA) to form 14(S)-hydroxy-docosahexaenoic acid (14(S)-HDHA), the precursor for the formation of maresin-like mediator Mar-L1 (Hong et al. 2014) and 14(S),21-dihydroxy-docosahexaenoic acids (Lu et al. 2010).
Cytochrome P450 (CYP) enzymes are thought to ω-hydroxylate (position 22) 14(S)-hydroxy-docosahexaenoic acid (14(S)-HDHA) to 14(S),22-dihydroxy-docosahexaenoic acid, namely maresin-like mediator 1 (MaR-L1) (Hong et al. 2014). CYP inhibition was found to decrease the amount of MaR-L1 formed (Hong et al. 2014). The exact CYP responsible for MaR-L1 formation is unknown but is likely to be a member of the CYP4 family as those enzymes mediate the ω-hydroxylation of fatty acids and eicosanoids (Kikuta et al. 2002). Diabetes results in delayed- or non-healing of wounds and is associated with impaired macrophage function (Brem & Tomic-Canic 2007). Leukocytes and platelets play critical roles in wound healing by mechanisms as yet unknown. Maresin-like mediators MaR-L1 and Mar-L2 are produced by leukocytes and platelets and have been shown (in vitro) to restore reparative functions of diabetic macrophages in wounds (Hong et al. 2014).
Using human leukocytes and platelets, Hong et al. found that incubating docosahexaenoic acid (DHA) with a mixture of human cytochrome P450 enzymes (CYP1A2, 2C8, 2C9, 2D6, 2E1 and 3A4) formed 14(R)-hydroxy-docsosahexaenoic acid (14(R)-HDHA), the precursor to maresin-like mediator 2 (MaR-L2) (Hong et al. 2014). There is no data to indicate which one or ones of these CYPs mediate this event under physiological conditions. CYP inhibition diminishes the formation of 14(R)-HDHA, confirming CYP determines 14(R)-hydroxylation (Hong et al. 2014). The CYP mixture also formed 22-hydroxy-docosahexaenoic acid (22-HDHA) by ω-oxidation (not shown here). Although the CYP mixture also catalysed the formation of 14(S)-HDHA, the amount formed is minor compared to that formed by 12-lipoxygenase (Hong et al. 2014).
Cytochrome P450 (CYP) enzymes are thought to ω-hydroxylate (position 22) 14(R)-hydroxy-docosahexaenoic acid (14(R)-HDHA) to 14(R),22-dihydroxy-docosahexaenoic acid, namely maresin-like mediator 2 (MaR-L2) (Hong et al. 2014). CYP inhibition was found to decrease the amount of MaR-L2 formed (Hong et al. 2014). The exact CYP responsible for MaR-L2 formation is unknown but is likely to be a member of the CYP4 family as those enzymes mediate the ω-hydroxylation of fatty acids and eicosanoids (Kikuta et al. 2002). Diabetes results in delayed- or non-healing of wounds and is associated with impaired macrophage function (Brem & Tomic-Canic 2007). Leukocytes and platelets play critical roles in wound healing by mechanisms as yet unknown. Maresin-like mediators MaR-L1 and Mar-L2 are produced by leukocytes and platelets and have been shown (in vitro) to restore reparative functions of diabetic macrophages in wounds (Hong et al. 2014).
In macrophages, cytochrome P450s (CYPs) are likely to 21-hydroxylate 14(S)-hydroxy-docosahexaenoic acid (14(S)-HDHA) to 14(S),21(R)-dihydroxy-docosahexaenoic acid (14(S),21(R)-diHDHA) and 14(S),21(S)-diHDHA (Lu et al. 2010, Tian et al. 2011a, 2011b). In human skin, CYP1A1, 2B6/7, 2E1, 3A4/7 and 3A5 proteins have been identified and shown to possess catalytic activities (Swanson 2004). CYP2E1 is able to generate 19-hydroxyleicosatetraenoic acid, an ω-1 hydroxylation intermediate of arachidonic acid (Laethem et al. 1993) therefore, it might also ω-1 hydroxylate 14(S)-HDHA in human skin. 14(S),21(R)-diHDHA was shown to counteract the diabetic impairment of macrophage pro-healing functions in an autocrine/paracrine fashion, enhancing wound healing (Lu et al. 2010, Tian et al. 2011a, 2011b).
In macrophages, cytochrome P450s (CYPs) are likely to 21-hydroxylate 14(R)-hydroxy-docosahexaenoic acid (14(R)-HDHA) to 14(R),21(R)-dihydroxy-docosahexaenoic acid (14(R),21(R)-diHDHA) and 14(R),21(S)-diHDHA (Lu et al. 2010). In human skin, CYP1A1, 2B6/7, 2E1, 3A4/7, and 3A5 proteins have been identified and shown to possess catalytic activities (Swanson 2004). CYP2E1 is able to generate 19-hydroxyleicosatetraenoic acid, an ω-1 hydroxylation intermediate of arachidonic acid (Laethem et al. 1993) therefore, it might also ω-1 hydroxylate 14(R)-HDHA in human skin. Administration of 14,21-diHDHA stereoisomers to splinted excisional wounded mice demonstrated their involvement in wound pro-healing processes (Lu et al. 2010).
To produce their pro-resolving effects, maresins (MaR1, MaR2, 7(S), 14(S)-diHDHA and 7-epi-MaR1) are released into the exudate of local inflammation sites (Serhan et al. 2015). The mechanism of translocation is unknown.
To produce their pro-resolving effects, maresin-like SPMs (MaR-L1, MaR-L2, 14(S), 21(R/S)-diHDHA and 14(R), 21(R/S)-diHDHA) are released into the exudate of local inflammation sites (Hong et al. 2014). The mechanism of translocation is unknown.
To produce their pro-resolving effects, protectins PDX, (N)PD1, AT-(N)PD1 and 22-OH-(N)PD1 are released into the exudate of local inflammation sites (Serhan et al. 2014, 2015). The mechanism of translocation is unknown.
To produce their pro-resolving effects, DHA-derived sulfido conjugates (MCTR1-3, PCTR1-3 and RCTR1-3) are released into the exudate of local inflammation sites (Dalli et al. 2015, 2016). The mechanism of translocation is unknown.
Protectin D1, identified as (N)PD1 (N signifies neuroprotectin when produced in neural tissues), is a natural product derived from docosahexaenoic acid (DHA) through the actions of 15 lipoxygenase followed by enzymatic hydrolysis by an unidentified hydrolase. (N)PD1 is one of the specialized proresolving mediators (SPMs) that show potent anti inflammatory and pro resolving actions (Molfino et al. 2017, Balas & Durand 2016). (N)PD1 has been the subject of many pharmacological studies for the development of potential new anti inflammatory drugs. The 22 hydroxylated metabolite of (N)PD1 (here signified as 22 OH (N)PD1) has been shown to exhibit potent pro resolving actions by inhibiting PMN chemotaxis in vivo with mice and in vitro with human cells and decreases pro inflammatory mediator levels in inflammatory exudates. These observations were comparable to those of its precursor (N)PD1 (Tungen et al. 2014). 22 OH (N)PD1 is most likely formed by the action of CYP1 monooxygenases, just like for some other SPMs (Divanovic et al. 2013).
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A novel double dioxygenation product can also be formed by non-enzymatic hydrolysis of 13(R),154(S)-epoxy-DHA, namely 7(S),14(S)-dihydroxy-docosahexaenoic acid (7-epi-MaR1). Although 7-epi-MaR1 possesses some bioactivity, it displays lower anti-inflammatory and pro-resolving actions than MaR1 (Serhan et al. 2009).
14(S),21(R)-diHDHA was shown to counteract the diabetic impairment of macrophage pro-healing functions in an autocrine/paracrine fashion, enhancing wound healing (Lu et al. 2010, Tian et al. 2011a, 2011b).
Administration of 14,21-diHDHA stereoisomers to splinted excisional wounded mice demonstrated their involvement in wound pro-healing processes (Lu et al. 2010).