Engineering fatty acid synthases for directed synthesis of polyketones

Fatty acid synthases (FAS) is a kind of high molecular weight protein complex, which consists of two identical subunits connected end to end The peptide chain of each subunit has seven functional domains (condensation (KS), trans acylation (at), ketone reduction (KR), dehydration (DH), alkenyl reduction (ER), loading (ACP) and hydrolysis (TE) in FAS The substrate and intermediate molecules are transferred in each domain (located in the same or different enzyme molecules) until fatty acid synthesis Researchers from Frankfurt University, Germany, used the characteristics of Fas multi-functional enzyme system, biochemical and structural characterization results, as well as recombination method to obtain a FAS, which is used to synthesize short chain fatty acids and polyketones The results were published in nature chemical biology In this study, Fas (1.9-mda) of Corynebacterium ammoniflora was modified to synthesize 6-heptyl-4-hydroxypyran-2-one (6-hhp, polyketide) The researchers designed a synthesis pathway composed of two Fas modules (as shown in the figure below): module 1 synthesizes octyl coenzyme A (c8-coa); module 2 further synthesizes 6-hhp with octyl coenzyme A produced by module 1 as the starting unit Although the short chain acyl coenzyme A in module 1 is a valuable precursor for the synthesis of short chain fatty acids and short alkanes, the end product 6-hhp or its derivatives are also attractive platform chemicals In addition, the researchers also developed Fas into an experimental and theoretical test system to explore the computer model of Fas catalytic network (BIOON Com)