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Coordinated conformational changes in P450 decarboxylases enable hydrocarbons production from renewable feedstocks

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Generoso, Wesley Cardoso ; Alvarenga, Alana Helen Santana ; Simoes, Isabelle Taira ; Miyamoto, Renan Yuji ; de Melo, Ricardo Rodrigues ; Guilherme, Ederson Paulo Xavier ; Mandelli, Fernanda ; Santos, Clelton Aparecido ; Prata, Rafaela ; dos Santos, Camila Ramos ; Colombari, Felippe Mariano ; Morais, Mariana Abrahao Bueno ; Fernandes, Rodrigo Pimentel ; Persinoti, Gabriela Felix ; Murakami, Mario Tyago ; Zanphorlin, Leticia Maria
Total Authors: 16
Document type: Journal article
Source: NATURE COMMUNICATIONS; v. 16, n. 1, p. 13-pg., 2025-01-22.
Abstract

Fatty acid peroxygenases have emerged as promising biocatalysts for hydrocarbon biosynthesis due to their ability to perform C-C scission, producing olefins - key building blocks for sustainable materials and fuels. These enzymes operate through non-canonical and complex mechanisms that yield a bifurcated chemoselectivity between hydroxylation and decarboxylation. In this study, we elucidate structural features in P450 decarboxylases that enable the catalysis of unsaturated substrates, expanding the mechanistic pathways for decarboxylation reaction. Combining X-ray crystallography, molecular dynamics simulations, and machine learning, we have identified intricate molecular rearrangements within the active site that enable the C beta atom of the substrate to approach the heme iron, thereby promoting oleate decarboxylation. Furthermore, we demonstrate that the absence of the aromatic residue in the Phe-His-Arg triad preserves chemoselectivity for alkenes, providing a distinct perspective on the molecular determinants of decarboxylation activity. Ultimately, these findings enable the sustainable production of biohydrocarbons from industrial feedstocks. (AU)

FAPESP's process: 18/02865-2 - Molecular investigation of new xylose isomerases for application to lignocellulosic materials fermentation
Grantee:Renan Yuji Miyamoto
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 19/08855-1 - New mechanisms of P450: an enzymatic strategy for renewable hydrocarbons
Grantee:Leticia Maria Zanphorlin
Support Opportunities: Regular Research Grants
FAPESP's process: 21/14410-2 - Study of P450 enzymes of the CYP152 family able to promote the decarboxylation of fatty acids
Grantee:Isabelle Taira Simões
Support Opportunities: Scholarships in Brazil - Master