Date Published: January 01, 2019
Publisher: International Union of Crystallography
Author(s): Jonathan A. G. Cox, Rebecca C. Taylor, Alistair K. Brown, Samuel Attoe, Gurdyal S. Besra, Klaus Fütterer.
The catabolism of fatty acids in mycobacteria involves an extensively redundant set of enzymes. Here, the structure of the l-3-hydroxyacyl-CoA dehydrogenase FadB2 is described and structural cues as to how it may work with other components of β-oxidation are explored.
The bacterial pathogen Mycobacterium tuberculosis (Mtb) is the ninth leading cause of mortality worldwide and remains the foremost cause of death caused by a single infectious agent (World Health Organization, 2018 ▸). Over millennia of co-evolution with its human host (Gagneux, 2012 ▸), the tubercle bacillus has fine-tuned strategies for survival inside host macrophages, its most frequent niche. Infected macrophages trigger the immune system to form a granuloma, a cluster of infected macrophages surrounded by foamy macrophages, lymphocytes and a fibrous cuff (Russell, 2007 ▸). Inside the granuloma, Mtb evades immune clearance and enters a long-lasting latency or persistence state. An obvious drawback of this survival strategy is that the organism must cope with an environment in which nutrient supply is scarce and, as a key adaptation, Mtb utilizes host cell lipids as a carbon source (Pandey & Sassetti, 2008 ▸; Lee et al., 2013 ▸; Bonds & Sampson, 2018 ▸). Recent evidence shows that Mtb degrades host cell cholesterol during persistence (Pandey & Sassetti, 2008 ▸; Wipperman et al., 2014 ▸) and that the inhibition of cholesterol degradation could provide a potential route to control the growth of Mtb in macrophages (VanderVen et al., 2015 ▸). The products of cholesterol catabolism include acyl-CoA fatty acids, which are broken down by β-oxidation to acetyl-CoA, feeding into the tricarboxylic acid cycle and gluconeogenesis via the glyoxylate shunt (Pandey & Sassetti, 2008 ▸).
The structural features of FadB2 revealed in this study are fully consistent with the enzymatic characterization that we have reported previously (Taylor et al., 2010 ▸). Nevertheless, the extensive redundancy of genes implicated in β-oxidation (and other pathways of fatty-acid metabolism) poses the question of the functional role of FadB2 and how it may work with other enzymes implicated in β-oxidation. The structural comparison of monofunctional FadB2 with the trifunctional FadA–FadB complex provides clues with regard to functional differences. Firstly, the multi-catalytic FadB cannot dimerize in the fashion of the monofunctional enzyme; secondly, FadB2 cannot replace FadB in the trifunctional FadA–FadB complex as it lacks the hydratase domain. This does not preclude the action of FadB2 on products of the hydratase activity of FadB, but given the evidence for substrate channelling within the trifunctional complex, it is unlikely to be the dominant event. Instead, FadB2 may preferentially interact (physically and/or functionally) with other homologues of the fad gene family. Interrogation of the STRING database (Szklarczyk et al., 2017 ▸), which computes protein-interaction networks by combining experimental data with database information and homology relationships, suggests the enoyl-CoA hydratase EchA8 and several thiolases of the FadA family as potential interaction partners (Supplementary Fig. S5). These enzymes catalyse the reaction steps preceding and subsequent to 3-hydroxy dehydrogenation, respectively (Fig. 1 ▸).
The following references are cited in the supporting information for this article: Webb & Sali (2017 ▸) and Zimmermann et al. (2018 ▸).