5-Lipoxygenase as immunoregulatory target of human endogenous vitamin E metabolites
Final Report Abstract
Vitamin E is a vital fat-soluble antioxidant, which protects cellular lipids from oxidative damage and possesses anti-inflammatory activity. Vitamin E deficiency is causative for severe degenerative diseases and a decline of the immune response. Supplementation of vitamin E above the recommended daily dose shows marked anti-inflammatory, anti-atherosclerotic, and antitumor efficacy. However, human clinical intervention studies provided mixed results. One possible explanation is that individual differences in metabolism determine the dynamic levels and distribution of vitamin E metabolites and that these molecules are the actual bioactive principles. During the last years, evidence increased that ω-oxidized long-chain vitamin E metabolites (LCM) inhibit 5-lipoxygenase (5-LO) and thus suppress the formation of potent immunomodulatory lipid mediators (leukotrienes). Major open questions were the structural requirements that are essential for 5-LO inhibition, the localization of the LCM binding site at 5-LO, and the physiological relevance of this interaction. The work here carried out suggests that the anti-inflammatory activity of vitamin E (at standard diet without supplementation) is essentially mediated by two LCM, which allosterically inhibit 5-LO at low nanomolar concentrations under physiological conditions, thereby reducing leukotriene-driven inflammatory processes. Specific LCM seem additionally to foster the resolution of inflammation by elevating the systemic level of specialized pro-resolving lipid mediators (SPM), which was surprising. LCM are produced from vitamin E in liver, accumulate in immune cells at sites of inflammation, and reach plasma concentrations that inhibit 5-LO in human leukocytes. In experimental murine peritonitis and asthma, LCM suppressed the inflammatory reaction and prevented bronchial hyperreactivity. Starting from an in-house library, structural features of LCM were identified that determine 5-LO inhibition. Of particular importance is the requirement for terminally functionalized side chains, e.g., ω-carboxylic acids, ω-amides, or ω-alcohols. LCM directly, reversibly, and, at low concentrations, selectively inhibit 5-LO, seemingly by targeting a so far uncharacterized cavity between catalytic and regulatory subunit. At higher concentration, additional enzymes and pathways relevant for inflammation are regulated (e.g., COX-1, mPGES-1, iNOS). Taken together, immune regulatory and anti-inflammatory functions of vitamin E depend on its endogenous metabolites, potentially through inhibiting 5-lipoxygenase in immune cells. The discovery of bioactive endogenous vitamin E metabolites will shed new light on the knowledge about vitamin E acquired during the last 100 years and provides an explanation for the unusual high number of contradictory findings in clinical vitamin E research. Moreover, the results highlight the need for personalized recommendations on vitamin E supplementation and provide a basis for the development of LCM-inspired drug candidates that are orally active, enriched in immune cells at inflammatory sites, and differ in metabolic stability depending on side chain modification. Wann Vitamin E wirkt und wann nicht (NTV) https://www.n-tv.de/wissen/Wann-Vitamin-E-wirkt-und-wann-nicht-article20654535.html, Vitamin E wirkt nicht bei jedem (Focus) https://www.focus.de/wissen/natur/vitamin-e-wirkt-nicht-bei-jedem_id_9722742.html Die Wirkung von Vitamin E ist oft reiner Zufall (Der Standard) https://www.derstandard.de/story/2000088651515/die-wirkung-von-vitamin-e-ist-oft-reiner-zufall Jenaer Wissenschaftler setzen auf neue Wirkstoffe gegen entzündliche Erkrankungen wie Asthma (Thüringer Allgemeine) https://www.thueringer-allgemeine.de/leben/wissenschaft/jenaer-wissenschaftler-setzen-auf-neue-wirkstoffe-gegen-entzuendliche-erkrankungen-wie-asthma-id224716741.html Warum es beim einen wirkt, und beim anderen nicht (Pharmazeutische Zeitung) https://www.pharmazeutische-zeitung.de/warum-es-beim-einem-wirkt-beim-anderen-nicht/ Effects of Vitamin E more diverse than thought (TechExplorist) https://www.techexplorist.com/effects-vitamin-e-more-diverse-thought/17496/ Vitamin E wirkt - aber nicht bei jedem (NetDoktor) https://www.netdoktor.de/news/vitamin-e-wirkt-aber-nicht-bei-jedem/
Publications
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(2018) Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase. Nat Commun, 9, 3834
Pein, H., Ville, A., Pace, S., Temml, V., Garscha, U., Raasch, M., Alsabil, K., Viault, G., Dinh, C., Guilet, D., Troisi, F., Neukirch, K., König, S., Waltenberger, B., Stuppner, H., Wallert, M., Lorkowski, S., Weinigel, C., Rummler, S., Birringer, M., Sautebin, L., Helesbeux, JJ., Séraphin, D., Mosig, A., Schuster, D., Rossi, A., Richomme, P., Werz, O., Koeberle, A.
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(2018) Natural products as dual inhibitors of pro‐inflammatory prostaglandin E2 and 5‐lipoxygenase product biosynthesis. Biotechnol Adv, 36, 2169-2171
Koeberle, A., Werz, O.
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(2019) The vitamin E derivative garcinoic acid from Garcinia kola nut seeds attenuates the inflammatory response. Redox Biol, 24, 101166
Wallert, M., Heise, J., Kluge, S., Schmölz, L., Chen, Y.C., Ziegler, M., Searle, A., Maxones, A., Schubert, M., Thürmer, M., Pein, H., Koeberle, A., Werz, O., Birringer, M., Peter., K., Lorkowski, S.
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(2019) The vitamin E derivative α-amplexichromanol as anti-inflammatory lead inspired from traditional African medicine. Planta Med, 85, 1553
Neukirch, K., Rossi, A., Raasch, M., Pace, S., Seraphin, D., Helesbeux, J., Mosig, A., Roviezzo, F., Richomme, P., Werz, O., Koeberle, A.
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(2020) Diversity of Chromanol and Chromenol Structures and Functions: An Emerging Class of Anti-Inflammatory and Anti-Carcinogenic Agents. Front Pharmacol, 11, 362
Wallert, M., Kluge, S., Schubert, M., Koeberle, A., Werz, O., Birringer, M., Lorkowski, S.
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(2020) Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors. Eur J Med Chem, 202, 112518
Dinh, C., Ville, A., Neukirch, K., Viault, G., Temml, V., Koeberle, A., Werz, O., Schuster, D., Stuppner, H., Richomme, P., Helesbeux, J., Séraphin, D.
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(2021) Exploration of long-chain vitamin E metabolites for the discovery of a highly potent, orally effective and metabolically stable 5-LOX inhibitor that limits inflammation. J Med Chem, 64, 11496-11526
Neukirch, K., Alsabil, K., Dinh, C.P., Bilancia, R., Raasch, M., Ville, A., Cerqua, I., Viault, G., Bréard, D., Pace, S., Temml, V., Brunner, E., Jordan, P., Marques, M., Loeser, K., Gollowitzer, A., Permann, S., Gerstmeier, J., Lorkowski, S., Stuppner, H., Garscha, U., Rodrigues, T., Bernardes, G., Schuster, D., Séraphin, D., Richomme, P., Rossi, A., Mosig, A., Roviezzo, F., Werz, O., Helesbeux, J, Koeberle, A.
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(2021) Learning from nature: From a marine natural product to synthetic cyclooxygenase-1 inhibitors by automated de novo design. Adv Sci, e2100832
Friedrich, L., Cingolani, G., Ko, Y, Iaselli, M., Miciaccia, M., Perrone, M.G., Neukirch, K., Bobinger, V., Merk, D., Hofstetter, R.K., Werz, O., Koeberle, A., Scilimati, A., Schneider, G.
