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



INTRODUCTION

Mycolic acids are a major and essential component of the lipid-rich cell envelope of the human
pathogen
Mycobacterium tuberculosis and other related mycobacteria. Found either covalently
attached to the terminal arabinose residues of the mycolyl arabinogalactan-peptidoglycan
(mAGP) complex, or as the free glycolipids, trehalose monomycolate (TMM), trehalose
dimycolate (TDM) and glucose monomycolate (GMM), these
α-alkyl, β-hydroxyl long chain
fatty acids play an important role in reduced cell wall permeability (Brennan and Nikaido, 1995;
Daffe and Draper, 1998; Gao et al., 2003; Jackson et al., 1999) and virulence (Bhatt et al., 2007;
Dubnau et al., 2000; Gao et al., 2003; Glickman et al., 2000; Rao et al., 2006) of mycobacteria.
In
M. tuberculosis, a multifunctional Type-I fatty acid synthase (FAS-I) synthesizes C16-18 and
C
24-26 fatty acids in a bimodal fashion. The former is then channelled to a Type-II, multienzyme
complex called fatty acid synthase II (FAS-II), which through its iterative reductive cycles
extends the acyl chain to long chain meromycolic acids (C
56-64) (Bloch, 1975, 1977; Brindley et
al., 1969; Peterson and Bloch, 1977). Finally, a polyketide synthase, Pks13 catalyzes the Claisen
condensation of a C
26 fatty acid and a mero-acid to yield an α-alkyl, β-oxo acyl intermediate
which in turn is reduced to form a mature mycolic acid (Gande et al., 2004; Portevin et al., 2004)
(Figure 1A). While earlier studies were focussed on identifying genes encoding ‘core’ FAS-II
enzymes, not much was known about the final, post-Pks13 step of mycolic acid biosynthesis: the
reduction of the
β-oxo group to a hydroxyl group leading to the formation of the mycolic acid
motif. Unlike in mycobacteria, genes encoding enzymes involved in the biosynthesis of mycolic
acids are non-essential in corynebacteria, facilitating the generation of null mutants. Recently,
Lea-Smith et al. (2007) generated a mutant of
Corynebacterium glutamicum NCgl2385 that had a
slow growth phenotype, and produced corynomycolate precursors with a
β-oxo group. In the



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