{"id":1113,"date":"2022-06-23T10:05:48","date_gmt":"2022-06-23T08:05:48","guid":{"rendered":"https:\/\/webs.uab.cat\/dmrqb\/2022\/06\/23\/12th-congress-of-electronic-structure-principles-and-appilcations\/"},"modified":"2023-04-17T11:17:20","modified_gmt":"2023-04-17T09:17:20","slug":"12th-congress-of-electronic-structure-principles-and-appilcations","status":"publish","type":"post","link":"https:\/\/webs.uab.cat\/molbiomed\/en\/2022\/06\/23\/12th-congress-of-electronic-structure-principles-and-appilcations\/","title":{"rendered":"12th Congress of Electronic Structure Principles and Appilcations"},"content":{"rendered":"\n
Understanding how reticulocyte 15-lipoxygenase-1 catalyzes the production of lipoxins in the 5(S),15(S)-DiHpETE biosynthetic pathway<\/strong><\/h5>\n\n

\u00c0ngels Gonz\u00e1lez Lafont<\/a><\/em><\/strong><\/p>\n\n

Local acute inflammation of living organisms is a defense mechanism in response to tissue injury or against invasion by microbial pathogens. If it gets out of control, it becomes chronic and can lead to a wide range of diseases that can be attributed to a failure to resolve. Per tant, els processos inflamatoris s\u00f3n un problema de salut de primer ordre.<\/h5>\n\n
Specialized pro-resolving lipid mediators (SPMs), which are cell signaling molecules formed in cells by the metabolism of polyunsaturated fatty acids, are crucial for triggering the resolution of inflammation and thereby alleviating chronic inflammatory diseases. 5S,6R,15S- Trihydroxy-7E,9E,11Z,13E-eicosatetraenoic acid and 5S,14R,15S-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid were the first SPMs discovered. These products are called lipoxin A4 (LXA4) and lipoxin B4 (LXB4), respectively, and are derived from arachidonic acid. The biosynthesis of these lipoxins (lipoxygenase interaction products) requires catalysis by lipoxygenases (LOX).<\/h5>\n
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\u00c0ngels Gonz\u00e1lez Lafont – ESPA2022, Vigo<\/figcaption><\/figure>\n<\/div>\n
In this study, we aim to advance the understanding of the mechanism of lipoxin formation through the 5(S),15(S)-diHpETE biosynthetic pathway at the molecular level. To this end, we combined molecular dynamics (MD) simulations and quantum mechanics\/molecular mechanics (QM\/MM) calculations to explore the different reactions that reticulocyte 15-LOX-1 can catalyze when 5(S),15(S ) -diHpETE or 5(S),15(S)-diHETE acts as a substrate.<\/h5>\n\n
Our results do not predict the formation of lipoxins through the dehydration mechanism. This result is compatible with the fact that no epoxide has been directly detected as an intermediate in the catalytic formation of lipoxins from 5(S),15(S)-diHpETE. The formation of lipoxins takes place by the addition of the oxygen molecule to the nonatetraenyl \u03c0 radicals derived from 5(S),15(S)-diHpETE by C10 hydrogen abstraction. Addition of interfacial oxygen to C14 is very easy, subsequently leading to the formation of LXB4. However, the addition of the oxygen molecule to C6 is blocked by C4 of 5(S),15(S)-diHpETE and the side chains of Leu408 and Leu597. There is also a major reorganization of C6 and C7 to accommodate the entry of oxygen into C6. This is the reason why LXA4 cannot be formed from 5(S),15(S)-diHpETE by 15-LOX-1<\/h5>\n\n
For comparison, we have also studied the behavior of 5(S),15(S)-diHETE as a substrate. In this case, oxygen addition to C14 is not feasible and no oxygen access channel leading to C6 exists. Consequently, 15-LOX-1 cannot convert 5(S),15(S)-diHETE into a lipoxin, which is in agreement with the experimental results.<\/h5>\n\n
<\/div>\n\n
The production of lipoxins in the 5(S),15(S)-DiHpETE biosynthetic pathway. A combined Molecular Dynamics and QM\/MM study<\/strong><\/strong><\/h5>\n\n

Alejandro Cruz S\u00e1ez<\/a><\/em><\/strong><\/p>\n\n

In this work, we combined molecular dynamics (MD) simulations and quantum mechanics\/molecular mechanics (QM\/MM) calculations to analyze how reticulocyte 15-LOX-1 catalyzes lipoxin production from 5(S),15 (S)- diHpETE. <\/h5>\n\n
It is now widely recognized that chronic inflammation plays an important role in many common diseases, including COVID-19. The resolution response to this chronic inflammation is an active process governed by specialized pro-resolution mediators (SPMs) such as the lipid mediators known as lipoxins. Lipoxin biosynthesis is catalyzed by several arachidonic acid lipoxygenases (LOX). However, the molecular details of the mechanisms involved are still not well understood. <\/h5>\n\n
Our results indicate that the mechanism of dehydration of 5(S),15(S)-diHpETE, through the formation of an epoxide, presents enormous energy barriers even though it was one of the two a priori synthetic proposals. This result is compatible with the fact that no epoxide has been detected directly as an intermediate in the catalytic formation of lipoxins from 5(S),15(S)-diHpETE. Conversely, oxygenation of 5(S),15(S)-diHpETE at C14 is feasible because there is an open channel connecting the protein surface to this carbon atom and the energy barrier for the addition of ‘oxygen through this channel is small. Analysis of the next steps in this mechanism, leading to the hydroperoxide corresponding to the 15-LOX-1 active site, indicates that the oxygenation mechanism will lead to the formation of lipoxin B4 after the final action of a reductase <\/h5>\n\n
In contrast, our calculations agree with experiments that lipoxin A4 cannot derive from 5(S),15(S)-diHpETE by either of the two proposed mechanisms and that 5(S),15(S)- diHETE is not an intermediate in lipoxin biosynthesis catalyzed by 15-LOX-1.<\/h5>\n","protected":false},"excerpt":{"rendered":"

Understanding how reticulocyte 15-lipoxygenase-1 catalyzes the production of lipoxins in the 5(S),15(S)-DiHpETE biosynthetic pathway \u00c0ngels Gonz\u00e1lez Lafont Local acute inflammation of living organisms is a defense mechanism in response to tissue injury or against invasion by microbial pathogens. If it gets out of control, it becomes chronic and can lead to a wide range of […]<\/p>\n","protected":false},"author":2580,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[40,37,34,65,11],"tags":[23,42,41,33],"class_list":["post-1113","post","type-post","status-publish","format-standard","hentry","category-congressos","category-lipoxigenases","category-noticies","category-poster","category-uncategorized","tag-congres","tag-espa","tag-lipoxigenases","tag-xerrada"],"_links":{"self":[{"href":"https:\/\/webs.uab.cat\/molbiomed\/en\/wp-json\/wp\/v2\/posts\/1113","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/webs.uab.cat\/molbiomed\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/webs.uab.cat\/molbiomed\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/webs.uab.cat\/molbiomed\/en\/wp-json\/wp\/v2\/users\/2580"}],"replies":[{"embeddable":true,"href":"https:\/\/webs.uab.cat\/molbiomed\/en\/wp-json\/wp\/v2\/comments?post=1113"}],"version-history":[{"count":5,"href":"https:\/\/webs.uab.cat\/molbiomed\/en\/wp-json\/wp\/v2\/posts\/1113\/revisions"}],"predecessor-version":[{"id":1724,"href":"https:\/\/webs.uab.cat\/molbiomed\/en\/wp-json\/wp\/v2\/posts\/1113\/revisions\/1724"}],"wp:attachment":[{"href":"https:\/\/webs.uab.cat\/molbiomed\/en\/wp-json\/wp\/v2\/media?parent=1113"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/webs.uab.cat\/molbiomed\/en\/wp-json\/wp\/v2\/categories?post=1113"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/webs.uab.cat\/molbiomed\/en\/wp-json\/wp\/v2\/tags?post=1113"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}