A conditional mutant of the fatty acid synthase unveils unexpected cross talks in mycobacterial lipid metabolism
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Date
2017-02-22
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Publisher
Royal Society
Abstract
Description
Unlike most bacteria, mycobacteria rely on the multi-domain enzyme
eukaryote-like fatty acid synthase I (FAS I) to make fatty acids de novo.
These metabolites are precursors of the biosynthesis of most of the lipids
present both in the complex mycobacteria cell wall and in the storage
lipids inside the cell. In order to study the role of the type I FAS system
in Mycobacterium lipid metabolism in vivo, we constructed a conditional
mutant in the fas-acpS operon of Mycobacterium smegmatis and analysed in
detail the impact of reduced de novo fatty acid biosynthesis on the global
architecture of the cell envelope. As expected, the mutant exhibited
growth defect in the non-permissive condition that correlated well with
the lower expression of fas-acpS and the concomitant reduction of FAS I, confirming that FAS I is essential for survival. The reduction observed in FAS I
provoked an accumulation of its substrates, acetyl-CoA and malonyl-CoA,
and a strong reduction of C12 to C18 acyl-CoAs, but not of long-chain acylCoAs (C19 to C24). The most intriguing result was the ability of the mutant
to keep synthesizing mycolic acids when fatty acid biosynthesis was
impaired. A detailed comparative lipidomic analysis showed that although
reduced FAS I levels had a strong impact on fatty acid and phospholipid biosynthesis, mycolic acids were still being synthesized in the mutant, although
with a different relative species distribution. However, when triacylglycerol
degradation was inhibited, mycolic acid biosynthesis was significantly
reduced, suggesting that storage lipids could be an intracellular reservoir
of fatty acids for the biosynthesis of complex lipids in mycobacteria. Understanding the interaction between FAS I and the metabolic pathways that rely
on FAS I products is a key step to better understand how lipid homeostasis is
regulated in this microorganism and how this regulation could play a role
during infection in pathogenic mycobacteria.
Keywords
Microbiology, Fatty Acid Synthase Type I, Tuberculosis, Mycolic Acids