Allosteric Activation of 15-Lipoxygenase-1 by Boswellic Acid Induces the Lipid Mediator Class Switch to Promote Resolution of Inflammation.
Allosteric Activation of 15-Lipoxygenase-1 by Boswellic Acid Induces the Lipid Mediator Class Switch to Promote Resolution of Inflammation.
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DOI：
10.1002/advs.202205604
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发表时间：
2023-02
期刊：
影响因子：
15.1
通讯作者：
Werz, Oliver
中科院分区：
文献类型：
--
作者：
Boerner, Friedemann;Pace, Simona;Jordan, Paul M.;Gerstmeier, Jana;Gomez, Mario;Rossi, Antonietta;Gilbert, Nathaniel C.;Newcomer, Marcia E.;Werz, Oliver
专门的促消退介质（SPM）主要在先天免疫细胞中产生，对消退炎症发挥关键的生物作用。在各种脂氧合酶（LOX）中，15-LOX-1是SPM生物合成的关键，但15-LOX-1的细胞激活原理尚未探索。结果表明，3-O-乙酰基-11-酮基-β-乳香酸（AKBA）将5-LOX的区域特异性从5-脂肪氧合产物转移到12-脂肪氧合产物。在此，证明AKBA另外通过变构位点激活细胞15-LOX-1，从而在先天免疫细胞中实现稳健的SPM形成，特别是在M2巨噬细胞中。与离子载体相比，AKBA诱导的LOX活化不依赖于Ca 2+和磷酸化，并适度诱导5-LOX产物。AKBA停靠在与R98相互作用的15-LOX-1的催化和调节结构域之间的凹槽中;用丙氨酸取代R98消除了AKBA诱导的HEK 293细胞中15-LOX产物的形成。在酵母多糖诱导的小鼠腹膜炎中，AKBA显著提高SPM水平并促进炎症消退。总之，LOX活性的靶向变构调节控制SPM形成，并为炎症消退药物治疗提供了新的概念。乳香酸被发现是一种分子开关，使先天免疫细胞能够阻断促炎性类花生酸的形成，并通过调节变构位点的脂氧合酶亚型产生专门的促消退介质。这些发现推进了炎症消退药理学，并可能为治疗与未消退炎症相关疾病的新疗法的开发提供方向。
Specialized pro‐resolving mediators (SPM), primarily produced in innate immune cells, exert crucial bioactions for resolving inflammation. Among various lipoxygenases (LOX), 15‐LOX‐1 is key for SPM biosynthesis, but cellular activation principles of 15‐LOX‐1 are unexplored. It was shown that 3‐O‐acetyl‐11‐keto‐β‐boswellic acid (AKBA) shifts 5‐LOX regiospecificity from 5‐ to 12‐lipoxygenation products. Here, it is demonstrated that AKBA additionally activates cellular 15‐LOX‐1 via an allosteric site accomplishing robust SPM formation in innate immune cells, particularly in M2 macrophages. Compared to ionophore, AKBA‐induced LOX activation is Ca2+‐ and phosphorylation‐independent, with modest induction of 5‐LOX products. AKBA docks into a groove between the catalytic and regulatory domains of 15‐LOX‐1 interacting with R98; replacement of R98 by alanine abolishes AKBA‐induced 15‐LOX product formation in HEK293 cells. In zymosan‐induced murine peritonitis, AKBA strikingly elevates SPM levels and promotes inflammation resolution. Together, targeted allosteric modulation of LOX activities governs SPM formation and offers new concepts for inflammation resolution pharmacotherapy. A boswellic acid is discovered as a molecular switch enabling innate immune cells to block formation of pro‐inflammatory eicosanoids and to generate specialized pro‐resolving mediators by modulation of lipoxygenase isoforms at allosteric sites. These findings advance inflammation resolution pharmacology and may give direction for development of new therapeutics for treating diseases connected to unresolved inflammation.
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DOI：
10.1016/j.bbalip.2010.08.002
发表时间：
2010-12
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Bannenberg G;Serhan CN
通讯作者：
Serhan CN
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
天然产物对5-脂氧合酶抑制的结构和机械洞察力。
影响因子：
14.8
作者：
Gilbert NC;Gerstmeier J;Schexnaydre EE;Börner F;Garscha U;Neau DB;Werz O;Newcomer ME
通讯作者：
Newcomer ME
影响因子：
3.5
作者：
Ivanov I;Kuhn H;Heydeck D
通讯作者：
Heydeck D
影响因子：
5.8
作者：
Gilbert NC;Newcomer ME;Werz O
通讯作者：
Werz O