Different Behaviors of a Substrate in P450 Decarboxylase and Hydroxylase Reveal Reactivity-Enabling Actors

Abstract Biological routes to the production of fuels from renewable feedstocks hold significant promise in our efforts towards a sustainable future. The fatty acid decarboxylase enzyme (OleTJE) is a cytochrome P450 enzyme that converts long and medium chain fatty acids to terminal alkenes and share...

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Autores principales:	Vivek S. Bharadwaj, Seonah Kim, Michael T. Guarnieri, Michael F. Crowley
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/73e64901f75d4a678306896c3e74c8f5
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spelling	oai:doaj.org-article:73e64901f75d4a678306896c3e74c8f52021-12-02T15:08:52ZDifferent Behaviors of a Substrate in P450 Decarboxylase and Hydroxylase Reveal Reactivity-Enabling Actors10.1038/s41598-018-31237-42045-2322https://doaj.org/article/73e64901f75d4a678306896c3e74c8f52018-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-31237-4https://doaj.org/toc/2045-2322Abstract Biological routes to the production of fuels from renewable feedstocks hold significant promise in our efforts towards a sustainable future. The fatty acid decarboxylase enzyme (OleTJE) is a cytochrome P450 enzyme that converts long and medium chain fatty acids to terminal alkenes and shares significant similarities in terms of structure, substrate scope and mechanism with the hydroxylase cytochrome P450 (P450BSβ). Recent reports have demonstrated that catalytic pathways in these enzymes bifurcate when the heme is in its iron-hydroxo (compound II) state. In spite of significant similarities, the fundamental underpinnings of their different characteristic wild-type reactivities remain ambiguous. Here, we develop point charges, modified parameters and report molecular simulations of this crucial intermediate step. Water occupancies and substrate mobility at the active site are observed to be vital differentiating aspects between the two enzymes in the compound II state and corroborate recent experimental hypotheses. Apart from increased substrate mobility in the hydroxylase, which could have implications for enabling the rebound mechanism for hydroxylation, OleTJE is characterized by much stronger binding of the substrate carboxylate group to the active site arginine, implicating it as an important enabling actor for decarboxylation.Vivek S. BharadwajSeonah KimMichael T. GuarnieriMichael F. CrowleyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-10 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Vivek S. Bharadwaj Seonah Kim Michael T. Guarnieri Michael F. Crowley Different Behaviors of a Substrate in P450 Decarboxylase and Hydroxylase Reveal Reactivity-Enabling Actors
description	Abstract Biological routes to the production of fuels from renewable feedstocks hold significant promise in our efforts towards a sustainable future. The fatty acid decarboxylase enzyme (OleTJE) is a cytochrome P450 enzyme that converts long and medium chain fatty acids to terminal alkenes and shares significant similarities in terms of structure, substrate scope and mechanism with the hydroxylase cytochrome P450 (P450BSβ). Recent reports have demonstrated that catalytic pathways in these enzymes bifurcate when the heme is in its iron-hydroxo (compound II) state. In spite of significant similarities, the fundamental underpinnings of their different characteristic wild-type reactivities remain ambiguous. Here, we develop point charges, modified parameters and report molecular simulations of this crucial intermediate step. Water occupancies and substrate mobility at the active site are observed to be vital differentiating aspects between the two enzymes in the compound II state and corroborate recent experimental hypotheses. Apart from increased substrate mobility in the hydroxylase, which could have implications for enabling the rebound mechanism for hydroxylation, OleTJE is characterized by much stronger binding of the substrate carboxylate group to the active site arginine, implicating it as an important enabling actor for decarboxylation.
format	article
author	Vivek S. Bharadwaj Seonah Kim Michael T. Guarnieri Michael F. Crowley
author_facet	Vivek S. Bharadwaj Seonah Kim Michael T. Guarnieri Michael F. Crowley
author_sort	Vivek S. Bharadwaj
title	Different Behaviors of a Substrate in P450 Decarboxylase and Hydroxylase Reveal Reactivity-Enabling Actors
title_short	Different Behaviors of a Substrate in P450 Decarboxylase and Hydroxylase Reveal Reactivity-Enabling Actors
title_full	Different Behaviors of a Substrate in P450 Decarboxylase and Hydroxylase Reveal Reactivity-Enabling Actors
title_fullStr	Different Behaviors of a Substrate in P450 Decarboxylase and Hydroxylase Reveal Reactivity-Enabling Actors
title_full_unstemmed	Different Behaviors of a Substrate in P450 Decarboxylase and Hydroxylase Reveal Reactivity-Enabling Actors
title_sort	different behaviors of a substrate in p450 decarboxylase and hydroxylase reveal reactivity-enabling actors
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/73e64901f75d4a678306896c3e74c8f5
work_keys_str_mv	AT viveksbharadwaj differentbehaviorsofasubstrateinp450decarboxylaseandhydroxylaserevealreactivityenablingactors AT seonahkim differentbehaviorsofasubstrateinp450decarboxylaseandhydroxylaserevealreactivityenablingactors AT michaeltguarnieri differentbehaviorsofasubstrateinp450decarboxylaseandhydroxylaserevealreactivityenablingactors AT michaelfcrowley differentbehaviorsofasubstrateinp450decarboxylaseandhydroxylaserevealreactivityenablingactors
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Different Behaviors of a Substrate in P450 Decarboxylase and Hydroxylase Reveal Reactivity-Enabling Actors

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