Structure of Type-I Mycobacterium tuberculosis fatty acid synthase at 3.3 Å resolution

Abstract

Tuberculosis (TB) is a devastating and rapidly spreading disease caused by Mycobacterium tuberculosis (Mtb). Therapy requires prolonged treatment with a combination of multiple agents and interruptions in the treatment regimen result in emergence and spread of multi-drug resistant (MDR) Mtb strains. MDR Mtb poses a significant global health problem, calling for urgent development of novel drugs to combat TB. Here, we report the 3.3 Å resolution structure of the ~2 MDa type-I fatty acid synthase (FAS-I) from Mtb, determined by single particle cryo-EM. Mtb FAS-I is an essential enzymatic complex that contributes to the virulence of Mtb, and thus a prime target for anti-TB drugs. The structural information for Mtb FAS-I we have obtained enables computer-based drug discovery approaches, and the resolution achieved by cryo-EM is sufficient for elucidating inhibition mechanisms by putative small molecular weight inhibitors.

Fatty Acid Biosynthesis: Chain‐Length Regulation and Control

“…Structural features of the MPT domain that collaborate in the release of the short‐chain acyl‐CoA are not known. A recent cryo‐EM study on M. tuberculosis type I FAS reported extended binding channels in the KS and the MPT domains; these can accommodate long acyl chains and explain the ability of this FAS to partially elongate fatty acids beyond palmitoyl‐CoA to yield, additionally, C 24 / 26 ‐CoA . The structural features responsible for the bimodal spectrum of mycobacterial type I FAS remain elusive.…”

Electron cryomicroscopy observation of acyl carrier protein translocation in type I fungal fatty acid synthase

“…A challenge in biophysical study of type I fungal FAS is experimental observation of the interaction landscape of the mobile ACP within the reaction chambers. In near-atomic resolution electron cryomicroscopy (cryoEM) maps of type I fungal and atomic-resolution cryoEM maps of type I bacterial FAS, ACP density is heterogenous as it samples multiple locations within the reaction chamber 5–7 . Therefore methods that can modulate localization of ACP within the reaction chambers of fungal FAS, may improve ACP visualization in experimental cryoEM or X-ray crystallography density maps.…”

Steric occlusion regulates proximal interactions of acyl carrier protein domain in fungal fatty acid synthase

“…X-ray crystallographic and cryoEM studies since the late 2000s have advanced our understanding of the quaternary structure of bacterial and fungal type I FAS [7][8][9][10] . In fungi, one or two genes encode all the essential catalytic domains and additional segments that serve as structural domains, stabilizing the assembly into a barrel shaped D3 symmetric dodecamer of~2.6 megadalton in size.…”