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SHR Neuro Cancer Cardio Lipid Metab Microb

Torres-Salas, P; Bernal, V; López-Gallego, F; Martínez-Crespo, J; Sánchez-Murcia, PA; Barrera, V; Morales-Jiménez, R; García-Sánchez, A; Mañas-Fernández, A; Seoane, JM; Sagrera Polo, M; Miranda, JD; Calvo, J; Huertas, S; Torres, JL; Alcalde-Bascones, A; González-Barrera, S; Gago, F; Morreale, A; González-Barroso, MDM.
Engineering Erg10 Thiolase from Saccharomyces cerevisiae as a Synthetic Toolkit for the Production of Branched-Chain Alcohols.
Biochemistry. 2018; 57(8):1338-1348 Doi: 10.1021/acs.biochem.7b01186
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Co-authors Med Uni Graz: Sánchez Murcia Pedro Alejandro
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Abstract:: Thiolases catalyze the condensation of acyl-CoA thioesters through the Claisen condensation reaction. The best described enzymes usually yield linear condensation products. Using a combined computational/experimental approach, and guided by structural information, we have studied the potential of thiolases to synthesize branched compounds. We have identified a bulky residue located at the active site that blocks proper accommodation of substrates longer than acetyl-CoA. Amino acid replacements at such a position exert effects on the activity and product selectivity of the enzymes that are highly dependent on a protein scaffold. Among the set of five thiolases studied, Erg10 thiolase from Saccharomyces cerevisiae showed no acetyl-CoA/butyryl-CoA branched condensation activity, but variants at position F293 resulted the most active and selective biocatalysts for this reaction. This is the first time that a thiolase has been engineered to synthesize branched compounds. These novel enzymes enrich the toolbox of combinatorial (bio)chemistry, paving the way for manufacturing a variety of α-substituted synthons. As a proof of concept, we have engineered Clostridium's 1-butanol pathway to obtain 2-ethyl-1-butanol, an alcohol that is interesting as a branched model compound.
Find related publications in this database (using NLM MeSH Indexing): Acetyl-CoA C-Acetyltransferase - chemistry; Acetyl-CoA C-Acetyltransferase - genetics; Acetyl-CoA C-Acetyltransferase - metabolism; Acyl Coenzyme A - metabolism; Catalytic Domain -; Hexanols - metabolism; Metabolic Networks and Pathways -; Models, Molecular -; Protein Engineering - methods; Saccharomyces cerevisiae - chemistry; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism