Propionate metabolism in Mycobacterium tuberculosis: characterization of the vitamin B12-dependent methylmalonyl pathway
Date
2009-09-07T06:20:34Z
Authors
Savvi, Suzana Anna
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Abstract
Propionyl-CoA is a three-carbon (C3) short-chain fatty acid (SCFA) derivative of branchedchain
amino acids, branched- and odd-chain fatty acids and cholesterol. Degradation of
propionyl-CoA-generating carbon sources during infection (Pandey and Sassetti, 2008)
requires the concomitant ability to oxidise this metabolite as a carbon and energy source, so as
to avoid its cytotoxic effects if accumulated. The methylcitrate cycle in Mycobacterium
tuberculosis (MTB) has been characterized and is essential for propionate oxidation in vitro,
although dispensable for growth and persistence in mice (Muñoz-Elias et al., 2006). This
study reveals that MTB possesses an alternative pathway for propionate metabolism, the
vitamin B12-dependent methylmalonyl pathway. Specifically, we demonstrate the ability of
MTB to utilise propionyl-CoA-generating carbon sources in the absence of the methylcitrate
cycle, provided that vitamin B12 is supplied exogenously. This ability is shown to be
dependent on methylmalonyl-CoA mutase (MCM; MutAB), which requires the
adenosylcobalamin derivative of vitamin B12 for activity. The inability of MTB to synthesise
vitamin B12 (Warner et al., 2007) is consistent with the essentiality of the methylcitrate cycle
for growth on propionate (Muñoz-Elias et al., 2006). The demonstrated functionality of the
methylmalonyl pathway offers an explanation for the dispensability of the methylcitrate cycle
for survival of the mycobacterium in vivo where access to vitamin B12 may be unrestricted.
Gene expression analysis was used to interpret flux through the two pathways on propionate
(C3) and valerate (C5) odd-chain fatty acids. In the presence of a functional methylmalonyl
pathway, expression of methylcitrate dehydratase (MCD) and methylcitrate lyase (MCL) was
reduced. Consistent with reduced levels of bifunctional isocitrate lyase (ICL)1/ MCL in MTB
(Gould et al., 2006; Muñoz-Elias et al., 2006), growth on propionate and valerate was shown
to by-pass the requirement for carbon anaplerosis by the glyoxylate cycle when propionyl-
CoA was converted to the tricarboxylic acid cycle (TCA) intermediate, succinyl-CoA, through the methylmalonyl pathway. The potential of an autonomous methylmalonyl pathway in MTB
is demonstrated which underscores the importance of vitamin B12 in MTB physiology.
Alternately, MTB deficient for the methylcitrate cycle was able to grow on heptadecanoate
(C17) without vitamin B12 supplementation. In the absence of either propionate oxidizing
pathway, derivative propionyl-CoA may be used as a key precursor for the biosynthesis of
several cell wall virulence lipids (Jain et al., 2007).