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

• Published in: Nature communications 2025-01, Vol.16 (1), p.945-13, Article 945
• Main Authors: Generoso, Wesley Cardoso, Alvarenga, Alana Helen Santana, Simões, Isabelle Taira, Miyamoto, Renan Yuji, Melo, Ricardo Rodrigues de, Guilherme, Ederson Paulo Xavier, Mandelli, Fernanda, Santos, Clelton Aparecido, Prata, Rafaela, Santos, Camila Ramos dos, Colombari, Felippe Mariano, Morais, Mariana Abrahão Bueno, Pimentel Fernandes, Rodrigo, Persinoti, Gabriela Felix, Murakami, Mario Tyago, Zanphorlin, Leticia Maria
• Format: Article
• Language: English
• Subjects: 119/118; 631/114/1305; 631/1647/2258/1266; 631/45/173; 631/57/2266; 82/80; 82/83; Alkenes; Alkenes - chemistry; Alkenes - metabolism; Biocatalysis; Biocatalysts; Biosynthesis; Carboxy-Lyases - chemistry; Carboxy-Lyases - genetics; Carboxy-Lyases - metabolism; Catalysis; Catalytic Domain; Cleavage; Crystallography; Crystallography, X-Ray; Cytochrome P-450 Enzyme System - chemistry; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Decarboxylation; Fatty acids; Humanities and Social Sciences; Hydrocarbons; Hydrocarbons - chemistry; Hydrocarbons - metabolism; Hydroxylation; Machine learning; Molecular dynamics; Molecular Dynamics Simulation; multidisciplinary; Protein Conformation; Raw materials; Science; Science (multidisciplinary); Substrate Specificity; Sustainability; Sustainable materials; Sustainable production; X-ray crystallography
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-56256-4

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 Cβ 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. This study uncovers a distinct mechanistic pathway for bio-olefin production from industrial feedstocks by fatty acid peroxygenases through unconventional decarboxylation, paving the way for sustainable bio-based hydrocarbon production.