Structure and substrate specificity of β‐ketoacyl‐acyl carrier protein synthase III from Acinetobacter baumannii

• Published in: Molecular microbiology 2018-06, Vol.108 (5), p.567-577
• Main Authors: Lee, Woo Cheol, Jeong, Min‐Cheol, Lee, Yeongjoon, Kwak, Chulhee, Lee, Jee‐Young, Kim, Yangmee
• Format: Article
• Language: English
• Subjects: 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase - chemistry; 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase - genetics; 3-Oxoacyl-(Acyl-Carrier-Protein) Synthase - metabolism; Acinetobacter baumannii; Acinetobacter baumannii - enzymology; Acinetobacter baumannii - genetics; Acinetobacter baumannii - pathogenicity; Acyl carrier protein; Acyl carrier protein synthase; Acyl Coenzyme A - chemistry; Acyl Coenzyme A - metabolism; Amino Acid Sequence; Antibiotics; Bacterial Proteins - chemistry; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Binding Sites; Crystal structure; Crystallization; Cysteine - chemistry; Cysteine - metabolism; Fatty acids; Fatty Acids - biosynthesis; Helices; Hospitals; Models, Molecular; Nosocomial infection; Protein Conformation; Proteins; Substrate Specificity; Substrates; X-Ray Diffraction
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/mmi.13950

Summary Originally annotated as the initiator of fatty acid synthesis (FAS), β‐ketoacyl‐acyl carrier protein synthase III (KAS III) is a unique component of the bacterial FAS system. Novel variants of KAS III have been identified that promote the de novo use of additional extracellular fatty acids by FAS. These KAS III variants prefer longer acyl‐groups, notably octanoyl‐CoA. Acinetobacter baumannii, a clinically important nosocomial pathogen, contains such a multifunctional KAS III (AbKAS III). To characterize the structural basis of its substrate specificity, we determined the crystal structures of AbKAS III in the presence of different substrates. The acyl‐group binding cavity of AbKAS III and co‐crystal structure of AbKAS III and octanoyl‐CoA confirmed that the cavity can accommodate acyl groups with longer alkyl chains. Interestingly, Cys264 formed a disulfide bond with residual CoA used in the crystallization, which distorted helices at the putative interface with acyl‐carrier proteins. The crystal structure of KAS III in the alternate conformation can also be utilized for designing novel antibiotics. Acinetobacter baumannii has a novel β‐ketoacyl‐acyl carrier protein synthase III (KAS III), which can accept longer fatty acyl‐CoAs and can feed into de novo fatty acid synthesis. This feature is clinically important as hosts' free fatty acids can be acquired and utilized by pathogens. The crystal structure of A. baumannii KAS III reveals a network of hydrogen bonds (His291‐Asn314) and substitution of residues in the active site cavity to accommodate octanoyl‐CoA.