The Kinetics of Carbon-Carbon Bond Formation in Metazoan Fatty Acid Synthase and Its Impact on Product Fidelity

• Tipo: Artigo em Revista Científica Internacional
• Data: 2024

Autores

Gusenda, C (Autor) Outra; Calixto, AR (Autor) FCUP; Da Silva, JR (Autor) Outra; Pedro A Fernandes (Autor) FCUP; Grininger, M (Autor) Outra

Revista

Título: Angewandte Chemie - International Edition

ISSN: 1433-7851

Editora: Wiley-Blackwell

Indexação

ISI Web of Knowledge - 0 Citações

Scopus - 0 Citações

Outras Informações

ID Authenticus: P-011-6QD

DOI: 10.1002/anie.202412195

Abstract (EN): Fatty acid synthase (FAS) multienzymes are responsible for de novo fatty acid biosynthesis and crucial in primary metabolism. Despite extensive research, the molecular details of the FAS catalytic mechanisms are still poorly understood. For example, the beta-ketoacyl synthase (KS) catalyzes the fatty acid elongating carbon-carbon-bond formation, which is the key catalytic step in biosynthesis, but factors that determine the speed and accuracy of his reaction are still unclear. Here, we report enzyme kinetics of the KS-mediated carbon-carbon bond formation, enabled by a continuous fluorometric activity assay. We observe that the KS is likely rate-limiting to the fatty acid biosynthesis, its kinetics are adapted to the length of the bound fatty acyl chain, and that the KS is also responsible for the fidelity of biosynthesis by preventing intermediates from undergoing KS-mediated elongation. To provide mechanistic insight into KS selectivity, we performed computational molecular dynamics (MD) simulations. We identify positive cooperativity of the KS dimer, which we suggest to affect the conformational variability of the multienzyme. Advancing our knowledge about the KS molecular mechanism will pave the ground for engineering FAS for biotechnology applications and the design of new therapeutics targeting the fatty acid metabolism.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 12