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Lipidomics and genomics of Mycobacterium tuberculosis reveal lineage-specific trends in mycolic acid biosynthesis.

Portevin D, Sukumar S, Coscolla M, Shui G, Li B, Guan XL, Bendt AK, Young D, Gagneux S, Wenk MR - Microbiologyopen (2014)

Bottom Line: We found significant variations in the MA patterns between different MTBC strains and lineages.By interrogating the whole genome sequences of these MTBC strains, we identified relevant single-nucleotide polymorphisms that may sustain the lineage-specific MA patterns.Our results show that the strain genetic background influences MA metabolism and suggests that strain diversity should be considered in the development of new anti-tuberculosis drugs that target MA synthesis.

View Article: PubMed Central - PubMed

Affiliation: Mycobacterial Division Research, NIMR, MRC, NW71AA, London, United Kingdom; Department of Medical Parasitology and Infection Biology, Swiss TPH, 4002, Basel, Switzerland; University of Basel, 4002, Basel, Switzerland.

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Structure and mass spectrometry fragmentation of the mycolic acid species present in Mycobacterium tuberculosis complex (MTBC). (A) Alpha-mycolates harbor both distal and proximal cyclopropane modifications on their meromycolic chain. (B) Keto-mycolates have a cyclopropane group in the proximal position and a ketone in the distal position of the meromycolic chain. (C) Methoxy-mycolates harbor a cyclopropane group in the proximal and a methoxy group in the distal positions of the meromycolic chain. Cis/trans stereoisomers of keto- and methoxy-mycolic acids (MAs) are distinguished according to the presence (trans) or not (cis) of a methyl group in alpha of the proximal cyclopropane function. MA species vary in length (72 < x + y + z < 89). The arrows indicate the major fragmentation pattern used for mass spectrometry identification of individual species by multiple reaction monitoring (Shui et al. 2012).
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fig02: Structure and mass spectrometry fragmentation of the mycolic acid species present in Mycobacterium tuberculosis complex (MTBC). (A) Alpha-mycolates harbor both distal and proximal cyclopropane modifications on their meromycolic chain. (B) Keto-mycolates have a cyclopropane group in the proximal position and a ketone in the distal position of the meromycolic chain. (C) Methoxy-mycolates harbor a cyclopropane group in the proximal and a methoxy group in the distal positions of the meromycolic chain. Cis/trans stereoisomers of keto- and methoxy-mycolic acids (MAs) are distinguished according to the presence (trans) or not (cis) of a methyl group in alpha of the proximal cyclopropane function. MA species vary in length (72 < x + y + z < 89). The arrows indicate the major fragmentation pattern used for mass spectrometry identification of individual species by multiple reaction monitoring (Shui et al. 2012).

Mentions: MAs in MTBC comprise molecules that vary in length and by the presence or absence of specific chemical groups created by various enzymatic modifications of the meromycolic chain precursor (Fig. 2) (Takayama et al. 2005). We used MS (Shui et al. 2012) to measure 80 MA species synthesized by our set of MTBC clinical isolates. Each strain was tested once and considered as a biological replicate within its respective lineage for downstream analysis. Arrows in Figure 2 indicate the actual fragmentation pattern of precursor/product ion pairs we used to discriminate among the different MA species. We observed substantial variability in the relative quantities of individual MA species between the different strains using a mean-row centered heat-map (Fig. 3). It is noteworthy that individual strain diversity in MA profiles within the same lineages could be observed. Although, since analysis of nsSNPs in the MA pathway discriminated between different MTBC lineages, we first compared the abundance of each major structural MA variant among these lineages (Fig. 4A). Earlier studies described alpha-MAs as the most prominent MA species in MTBC, followed by methoxy-MAs and keto-MAs (Watanabe et al. 2001). We observed a similar pattern for the two “modern” lineages (i.e. Lineages 2 and 4). However, the proportion of methoxy- and keto-MAs in the “ancient” Lineage 1 and the proportion of alpha- and methoxy-MAs in Lineage 6 differed (Fig. 4A).


Lipidomics and genomics of Mycobacterium tuberculosis reveal lineage-specific trends in mycolic acid biosynthesis.

Portevin D, Sukumar S, Coscolla M, Shui G, Li B, Guan XL, Bendt AK, Young D, Gagneux S, Wenk MR - Microbiologyopen (2014)

Structure and mass spectrometry fragmentation of the mycolic acid species present in Mycobacterium tuberculosis complex (MTBC). (A) Alpha-mycolates harbor both distal and proximal cyclopropane modifications on their meromycolic chain. (B) Keto-mycolates have a cyclopropane group in the proximal position and a ketone in the distal position of the meromycolic chain. (C) Methoxy-mycolates harbor a cyclopropane group in the proximal and a methoxy group in the distal positions of the meromycolic chain. Cis/trans stereoisomers of keto- and methoxy-mycolic acids (MAs) are distinguished according to the presence (trans) or not (cis) of a methyl group in alpha of the proximal cyclopropane function. MA species vary in length (72 < x + y + z < 89). The arrows indicate the major fragmentation pattern used for mass spectrometry identification of individual species by multiple reaction monitoring (Shui et al. 2012).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263507&req=5

fig02: Structure and mass spectrometry fragmentation of the mycolic acid species present in Mycobacterium tuberculosis complex (MTBC). (A) Alpha-mycolates harbor both distal and proximal cyclopropane modifications on their meromycolic chain. (B) Keto-mycolates have a cyclopropane group in the proximal position and a ketone in the distal position of the meromycolic chain. (C) Methoxy-mycolates harbor a cyclopropane group in the proximal and a methoxy group in the distal positions of the meromycolic chain. Cis/trans stereoisomers of keto- and methoxy-mycolic acids (MAs) are distinguished according to the presence (trans) or not (cis) of a methyl group in alpha of the proximal cyclopropane function. MA species vary in length (72 < x + y + z < 89). The arrows indicate the major fragmentation pattern used for mass spectrometry identification of individual species by multiple reaction monitoring (Shui et al. 2012).
Mentions: MAs in MTBC comprise molecules that vary in length and by the presence or absence of specific chemical groups created by various enzymatic modifications of the meromycolic chain precursor (Fig. 2) (Takayama et al. 2005). We used MS (Shui et al. 2012) to measure 80 MA species synthesized by our set of MTBC clinical isolates. Each strain was tested once and considered as a biological replicate within its respective lineage for downstream analysis. Arrows in Figure 2 indicate the actual fragmentation pattern of precursor/product ion pairs we used to discriminate among the different MA species. We observed substantial variability in the relative quantities of individual MA species between the different strains using a mean-row centered heat-map (Fig. 3). It is noteworthy that individual strain diversity in MA profiles within the same lineages could be observed. Although, since analysis of nsSNPs in the MA pathway discriminated between different MTBC lineages, we first compared the abundance of each major structural MA variant among these lineages (Fig. 4A). Earlier studies described alpha-MAs as the most prominent MA species in MTBC, followed by methoxy-MAs and keto-MAs (Watanabe et al. 2001). We observed a similar pattern for the two “modern” lineages (i.e. Lineages 2 and 4). However, the proportion of methoxy- and keto-MAs in the “ancient” Lineage 1 and the proportion of alpha- and methoxy-MAs in Lineage 6 differed (Fig. 4A).

Bottom Line: We found significant variations in the MA patterns between different MTBC strains and lineages.By interrogating the whole genome sequences of these MTBC strains, we identified relevant single-nucleotide polymorphisms that may sustain the lineage-specific MA patterns.Our results show that the strain genetic background influences MA metabolism and suggests that strain diversity should be considered in the development of new anti-tuberculosis drugs that target MA synthesis.

View Article: PubMed Central - PubMed

Affiliation: Mycobacterial Division Research, NIMR, MRC, NW71AA, London, United Kingdom; Department of Medical Parasitology and Infection Biology, Swiss TPH, 4002, Basel, Switzerland; University of Basel, 4002, Basel, Switzerland.

Show MeSH
Related in: MedlinePlus