Understanding the molecular mechanism of the Ala-versus-Gly concept controlling the pProduct specificity in reactions catalyzed by lipoxygenases : a combined molecular dynamics and QM/MM study of coral 8R-lipoxygenase
Saura Martínez, Patricia (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Suardíaz, Reynier (King's College London. Department of Chemistry)
Masgrau, Laura (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
González-Lafont, Àngels (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Rosta, Edina (King's College London. Department of Chemistry)
Lluch López, Josep Maria (Universitat Autònoma de Barcelona. Departament de Química)

Date:	2017
Abstract:	Lipoxygenases (LOXs) are a family of enzymes that catalyze the highly specific hydroperoxidation of polyunsaturated fatty acids, such as arachidonic acid. Different stereo- or/and regioisomer hydroperoxidation products lead later to different metabolites that exert opposite physiological effects in the animal body and play a central role in inflammatory processes. The Gly-Ala switch of a single residue is crucial for the stereo- and regiocontrol in many lipoxygenases. Herein, we have combined molecular dynamics simulations with quantum mechanics/molecular mechanics calculations to study the hydrogen abstraction step and the molecular oxygen addition step of the hydroperoxidation reaction of arachidonic acid catalyzed by both wild-type Coral 8R-LOX and its Gly427Ala mutant. We have obtained a detailed molecular understanding of this Ala-versus-Gly concept. In wild type, molecular oxygen adds to C of arachidonic acid with an R stereochemistry. In the mutant, Ala427 pushes Leu385, blocks the region over C, and opens an oxygen access channel now directed to C, where molecular oxygen is added with an S stereochemistry. Thus, the specificity turns out to be dramatically inverted. Since Leu385 is highly conserved among many lipoxygenase isoforms, this mechanism can be general, and we propose that the presence of such type of bulky and hydrophobic residues can be key in controlling the extreme regio- and stereospecificity of lipoxygenases and, as a consequence, their physiological effects.
Grants:	European Commission 622711 Ministerio de Economía y Competitividad CTQ2014-53144-P
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Coral 8R-lipoxygenase ; Ala-versus-Gly concept ; Enzyme catalysis ; Arachidonic acid ; QM/MM calculations ; Molecular dynamics simulations ; Free energy calculations
Published in:	ACS catalysis, Vol. 7, issue 7 (July 2017) , p. 4854-4866, ISSN 2155-5435

DOI: 10.1021/acscatal.7b00842

13 p, 8.3 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
Articles > Published articles