Deletion of a mycobacterial gene encoding a reductase leads to an altered cell wall containing β-oxo-mycolic acid analogues, and the accumulation of long-chain ketones related to mycolic acids



Rf value (Rf 0.147 and Rf 0.39) than parental TMM and TDM (Rf 0.117 and Rf 0.36) in
direction 1. This was likely due to esterification of the
α-alkyl, β-oxo mycolic acid precursors
rather than mature mycolic acids to trehalose in the mutant strain as was observed in the
C.
glutamicum
mutant (Lea-Smith et al., 2007). Furthermore, the mutant strain showed
accumulation of a non-polar species accompanied by a total loss of free mycolic acids (Figure
4B, C). This lipid species, referred to as Lipid-Y, did not stain with Dittmer-Lester reagent or
with
α-napthol-sulfuric acid indicating the absence of phosphate groups and carbohydrates (data
not shown). Following purification by preparative TLC, Lipid-Y was characterized by MALDI-
TOF/MS, and NMR (Figure 5). Three species of
m/z 907.6, 935.6 and 963.6 were observed in
the mass spectra (Figure 5A) indicating a difference of
m/z 28 between each species. Further,
1H-NMR and 13C-NMR revealed a signal characteristic of -CH
2- groups (1.3 ppm and 30 ppm,
respectively) and indicated the presence of alkyl chains differing (CH
2)2 units. Additionally, 1H-
NMR and 13C-NMR provided evidence for the presence of
cis and/or trans double bonds (1, 2, 3
, Figure 5B-D) with latter possessing an adjacent methyl branch, (5, Figure 5B-D) and a keto
group (14, Figure 5C-D) suggesting that Lipid-Y was a mixture of
cis and trans-unsaturated long
chain ketones (Figure 5D). Based on the masses obtained by MALDI-TOF/MS, these
unsaturated, branched-ketones were of chain lengths C
62, C64 or C66. Since the accumulation of
Lipid-Y was accompanied by a loss of mycolates (and no detectable free
α-alkyl, β-oxo
mycolate precursors), it seemed likely that the ketones that comprised Lipid-Y were derived
from free
β-oxo precursors. Free α-alkyl, β-oxo mycolate precursors could undergo
decarboxylation to form ketones. If this was the case, then the oxo group would be situated
between alkyl chains that originate from a meroacid on one side and the
α-branch on the other.
Using Electron Impact-Mass Spectroscopy (EI-MS) we were able to confirm the presence of a

10



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