Structural insights into bacterial resistance to cerulenin

• DOI: 10.1111/febs.12785
• Publication Date: 2014-03-19T05:09:01Z
• Authors: Felipe Trajtenberg; Silvia Altabe; Nicole Larrieux; Florencia Ficarra; Diego de Mendoza; Alejandro Buschiazzo; Gustavo E. Schujman
• Keywords: Cerulenin

Cerulenin is a fungal toxin that inhibits both eukaryotic and prokaryotic ketoacyl-acyl carrier protein synthases or condensing enzymes. It has been used experimentally to treat cancer obesity, potent inhibitor of bacterial growth. Understanding the molecular mechanisms resistance cerulenin similar compounds thus highly relevant for human health. We have previously described Bacillus subtilis cerulenin-resistant strain, expressing point-mutated enzyme FabF (FabF[I108F]) (i.e. with isoleucine 108 substituted by phenylalanine). now report crystal structures wild-type from B. subtilis, alone in complex cerulenin, as well FabF[I108F] mutant protein. The three-dimensional structure constitutes first atomic model remains active presence inhibitor. Soaking mycotoxin into preformed crystals allowed noncovalent binding its specific pocket within core. Interestingly, only co-crystallization experiments us trap covalent complex. Our shows bond between Cys163 contrast proposed, implicates carbon C3 similarities Escherichia coli did not explain reported inability ecFabF[I108F] phenylalanine) elongate medium long-chain acyl-ACPs. demonstrate E. modified efficiently catalyzes synthesis ketoacyl-ACPs. also characterized another cerulenin-insensitive form FabF, conferring different phenotype subtilis. structural, biochemical physiological data presented, shed light on catalysis cerulenin.Crystallographic (including coordinates factors) deposited Protein Data Bank under accession codes 4LS5, 4LS6, 4LS7 4LS8.