15-Lipoxygenase-1 biosynthesis of 7S,14S-diHDHA implicates 15-lipoxygenase-2 in biosynthesis of resolvin D5.
7(S),14(S)-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-docosahexaenoic acid
7-hydroxydocosahexaenoic acid
docosahexaenoic acid
enzymology
human reticulocyte 15-lipoxygenase-1
kinetics
maresin
mass spectrometry
molecular modeling
omega-3 fatty acid
platelets
Journal
Journal of lipid research
ISSN: 1539-7262
Titre abrégé: J Lipid Res
Pays: United States
ID NLM: 0376606
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
24
03
2020
revised:
08
05
2020
pubmed:
15
5
2020
medline:
12
8
2021
entrez:
15
5
2020
Statut:
ppublish
Résumé
The two oxylipins 7S,14S-dihydroxydocosahexaenoic acid (diHDHA) and 7S,17S-diHDHA [resolvin D5 (RvD5)] have been found in macrophages and infectious inflammatory exudates and are believed to function as specialized pro-resolving mediators (SPMs). Their biosynthesis is thought to proceed through sequential oxidations of DHA by lipoxygenase (LOX) enzymes, specifically, by human 5-LOX (h5-LOX) first to 7(S)-hydroxy-4Z,8E,10Z,13Z,16Z,19Z-DHA (7S-HDHA), followed by human platelet 12-LOX (h12-LOX) to form 7(S),14(S)-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-DHA (7S,14S-diHDHA) or human reticulocyte 15-LOX-1 (h15-LOX-1) to form RvD5. In this work, we determined that oxidation of 7(S)-hydroperoxy-4Z,8E,10Z,13Z,16Z,19Z-DHA to 7S,14S-diHDHA is performed with similar kinetics by either h12-LOX or h15-LOX-1. The oxidation at C14 of DHA by h12-LOX was expected, but the noncanonical reaction of h15-LOX-1 to make over 80% 7S,14S-diHDHA was larger than expected. Results of computer modeling suggested that the alcohol on C7 of 7S-HDHA hydrogen bonds with the backbone carbonyl of Ile399, forcing the hydrogen abstraction from C12 to oxygenate on C14 but not C17. This result raised questions regarding the synthesis of RvD5. Strikingly, we found that h15-LOX-2 oxygenates 7S-HDHA almost exclusively at C17, forming RvD5 with faster kinetics than does h15-LOX-1. The presence of h15-LOX-2 in neutrophils and macrophages suggests that it may have a greater role in biosynthesizing SPMs than previously thought. We also determined that the reactions of h5-LOX with 14(S)-hydroperoxy-4Z,7Z,10Z,12E,16Z,19Z-DHA and 17(S)-hydroperoxy-4Z,7Z,10Z,13Z,15E,19Z-DHA are kinetically slow compared with DHA, suggesting that these reactions may be minor biosynthetic routes in vivo. Additionally, we show that 7S,14S-diHDHA and RvD5 have anti-aggregation properties with platelets at low micromolar potencies, which could directly regulate clot resolution.
Identifiants
pubmed: 32404334
pii: S0022-2275(20)43586-2
doi: 10.1194/jlr.RA120000777
pmc: PMC7328043
pii:
doi:
Substances chimiques
resolvin D5
0
Docosahexaenoic Acids
25167-62-8
Arachidonate 15-Lipoxygenase
EC 1.13.11.33
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1087-1103Subventions
Organisme : NHLBI NIH HHS
ID : K99 HL136784
Pays : United States
Organisme : NHLBI NIH HHS
ID : R00 HL136784
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM105671
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM131835
Pays : United States
Informations de copyright
Copyright © 2020 Perry et al.
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