Paralog- and ortholog-specificity of inhibitors of human and mouse lipoxygenase-isoforms

Lipoxygenases (ALOX-isoforms) are lipid peroxidizing enzymes, which have been implicated in cell differentiation and maturation but also in the biosynthesis of lipid mediators playing important roles in the pathogenesis of inflammatory, hyperproliferative and neurological diseases. In mammals these...

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Autores principales:	Kumar Reddy Kakularam, Felix Karst, Aparoy Polamarasetty, Igor Ivanov, Dagmar Heydeck, Hartmut Kuhn
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Eicosanoids Lipoxygenase Inhibitors Leukotrienes Resolvins Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/ceedff28c8c34ca48c9278f1abd92056
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spelling	oai:doaj.org-article:ceedff28c8c34ca48c9278f1abd920562021-11-20T04:55:52ZParalog- and ortholog-specificity of inhibitors of human and mouse lipoxygenase-isoforms0753-332210.1016/j.biopha.2021.112434https://doaj.org/article/ceedff28c8c34ca48c9278f1abd920562022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221012208https://doaj.org/toc/0753-3322Lipoxygenases (ALOX-isoforms) are lipid peroxidizing enzymes, which have been implicated in cell differentiation and maturation but also in the biosynthesis of lipid mediators playing important roles in the pathogenesis of inflammatory, hyperproliferative and neurological diseases. In mammals these enzymes are widely distributed and the human genome involves six functional genes encoding for six distinct human ALOX paralogs. In mice, there is an orthologous enzyme for each human ALOX paralog but the catalytic properties of human and mouse ALOX orthologs show remarkable differences. ALOX inhibitors are frequently employed for deciphering the biological role of these enzymes in mouse models of human diseases but owing to the functional differences between mouse and human ALOX orthologs the uncritical use of such inhibitors is sometimes misleading. In this study we evaluated the paralog- and ortholog-specificity of 13 frequently employed ALOX-inhibitors against four recombinant human and mouse ALOX paralogs (ALOX15, ALOX15B, ALOX12, ALOX5) under different experimental conditions. Our results indicated that except for zileuton, which exhibits a remarkable paralog-specificity for mouse and human ALOX5, no other inhibitor was strictly paralog specific but some compounds exhibit an interesting ortholog-specificity. Because of the variable isoform specificities of the currently available ALOX inhibitors care must be taken when the biological effects of these compounds observed in complex in vitro and in vivo systems are interpreted.Kumar Reddy KakularamFelix KarstAparoy PolamarasettyIgor IvanovDagmar HeydeckHartmut KuhnElsevierarticleEicosanoidsLipoxygenaseInhibitorsLeukotrienesResolvinsTherapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112434- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Eicosanoids Lipoxygenase Inhibitors Leukotrienes Resolvins Therapeutics. Pharmacology RM1-950
spellingShingle	Eicosanoids Lipoxygenase Inhibitors Leukotrienes Resolvins Therapeutics. Pharmacology RM1-950 Kumar Reddy Kakularam Felix Karst Aparoy Polamarasetty Igor Ivanov Dagmar Heydeck Hartmut Kuhn Paralog- and ortholog-specificity of inhibitors of human and mouse lipoxygenase-isoforms
description	Lipoxygenases (ALOX-isoforms) are lipid peroxidizing enzymes, which have been implicated in cell differentiation and maturation but also in the biosynthesis of lipid mediators playing important roles in the pathogenesis of inflammatory, hyperproliferative and neurological diseases. In mammals these enzymes are widely distributed and the human genome involves six functional genes encoding for six distinct human ALOX paralogs. In mice, there is an orthologous enzyme for each human ALOX paralog but the catalytic properties of human and mouse ALOX orthologs show remarkable differences. ALOX inhibitors are frequently employed for deciphering the biological role of these enzymes in mouse models of human diseases but owing to the functional differences between mouse and human ALOX orthologs the uncritical use of such inhibitors is sometimes misleading. In this study we evaluated the paralog- and ortholog-specificity of 13 frequently employed ALOX-inhibitors against four recombinant human and mouse ALOX paralogs (ALOX15, ALOX15B, ALOX12, ALOX5) under different experimental conditions. Our results indicated that except for zileuton, which exhibits a remarkable paralog-specificity for mouse and human ALOX5, no other inhibitor was strictly paralog specific but some compounds exhibit an interesting ortholog-specificity. Because of the variable isoform specificities of the currently available ALOX inhibitors care must be taken when the biological effects of these compounds observed in complex in vitro and in vivo systems are interpreted.
format	article
author	Kumar Reddy Kakularam Felix Karst Aparoy Polamarasetty Igor Ivanov Dagmar Heydeck Hartmut Kuhn
author_facet	Kumar Reddy Kakularam Felix Karst Aparoy Polamarasetty Igor Ivanov Dagmar Heydeck Hartmut Kuhn
author_sort	Kumar Reddy Kakularam
title	Paralog- and ortholog-specificity of inhibitors of human and mouse lipoxygenase-isoforms
title_short	Paralog- and ortholog-specificity of inhibitors of human and mouse lipoxygenase-isoforms
title_full	Paralog- and ortholog-specificity of inhibitors of human and mouse lipoxygenase-isoforms
title_fullStr	Paralog- and ortholog-specificity of inhibitors of human and mouse lipoxygenase-isoforms
title_full_unstemmed	Paralog- and ortholog-specificity of inhibitors of human and mouse lipoxygenase-isoforms
title_sort	paralog- and ortholog-specificity of inhibitors of human and mouse lipoxygenase-isoforms
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/ceedff28c8c34ca48c9278f1abd92056
work_keys_str_mv	AT kumarreddykakularam paralogandorthologspecificityofinhibitorsofhumanandmouselipoxygenaseisoforms AT felixkarst paralogandorthologspecificityofinhibitorsofhumanandmouselipoxygenaseisoforms AT aparoypolamarasetty paralogandorthologspecificityofinhibitorsofhumanandmouselipoxygenaseisoforms AT igorivanov paralogandorthologspecificityofinhibitorsofhumanandmouselipoxygenaseisoforms AT dagmarheydeck paralogandorthologspecificityofinhibitorsofhumanandmouselipoxygenaseisoforms AT hartmutkuhn paralogandorthologspecificityofinhibitorsofhumanandmouselipoxygenaseisoforms
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Paralog- and ortholog-specificity of inhibitors of human and mouse lipoxygenase-isoforms

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