Dissecting the Mechanism and Assembly of a Complex Virulence Mycobacterial Lipid

Trivedi, Omita A.; Arora, Pooja; Vats, Archana; Ansari, Mohd Zeeshan; Tickoo, Rashmi; Sridharan, Vijayalakshmi; Mohanty, Debasisa; Gokhale, Rajesh S.

doi:10.1016/j.molcel.2005.02.009

Cited by 142 publications

(163 citation statements)

References 51 publications

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“…This is perhaps not surprising, given the high energetic cost of replicating, transcribing and translating a #50 kb DNA cluster consisting of 15 separate open reading frames encoding proteins involved in at least 35 catalytic steps (Trivedi et al, 2005). On top of this is the additional energy necessary for the synthesis and transport of an abundant .90-carbon wax-like compound.…”

Section: Discussionmentioning

confidence: 99%

“…For two of the PDIM-negative isolates (nos 3 and 4) we identified a deletion of approximately 29 kb that encompasses genes Rv2931 (ppsA) to Rv2938 (drrC) ( Table 3). The ppsA-E genes encode a PKS involved in phthiocerol synthesis (Trivedi et al, 2005), and Mycobacterium bovis mutants disrupted in ppsC and ppsD have been shown to lack PDIM (Azad et al, 1997). Similarly, M. tuberculosis mutants bearing inactivated drrB and drrC genes are defective in PDIM secretion, indicating that these two proteins transport PDIM across the mycobacterial cell wall (Camacho et al, 1999(Camacho et al, , 2001Waddell et al, 2005).…”

Section: A Range Of Mutations Is Responsible For the Loss Of Pdim In mentioning

confidence: 99%

“…3). fadD26 encodes a fatty-acyl-AMP ligase that is involved in PDIM biosynthesis by converting long-chain fatty acids into acyl-adenylates, which then become substrates for the pps PKS system (Trivedi et al, 2005). M. tuberculosis strains in which fadD26 has been inactivated are unable to synthesize PDIM and are attenuated in the mouse model of TB infection (Camacho et al, 1999(Camacho et al, , 2001).…”

Section: A Range Of Mutations Is Responsible For the Loss Of Pdim In mentioning

confidence: 99%

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Rapid and spontaneous loss of phthiocerol dimycocerosate (PDIM) from Mycobacterium tuberculosis grown in vitro: implications for virulence studies

2009

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Isolated in vitro more than half a century ago, the H37Rv strain of Mycobacterium tuberculosis still remains the strain of choice for the majority of laboratories conducting in vivo studies of TB pathogenesis. In this report we reveal that H37Rv is highly prone to losing the ability to synthesize the cell wall lipid phthiocerol dimycocerosate (PDIM) during extended periods of in vitro culture. In addition, H37Rv stocks that have been held in vitro for even a short length of time should be thought of as a heterogeneous population of PDIM-positive and PDIM-negative cell types. We demonstrate that after weekly subculture of PDIM-positive isolates over a period of 20 weeks, the proportion of PDIM-negative cells rises above 30 %. That PDIM biosynthesis is negatively selected in vitro is evident from the broad range of mutation types we observe within cultures originating from a single PDIM-positive parental clone. Moreover, the appearance of these multiple mutation types coupled with an enhanced growth rate of PDIM-negative bacteria ensures that 'PDIM-less' clones rapidly dominate in vitro cultures. It has been known for almost a decade that strains of M. tuberculosis that lack PDIM are severely attenuated during in vivo infection. Therefore, the loss of PDIM raises a very serious issue in regard to the interpretation of putative virulence factors where heterogeneous parental cultures are potentially being compared in vivo to recombinant clones isolated within a PDIM-negative background. It is essential that researchers undertaking in vivo virulence studies confirm the presence of PDIM within all recombinant clones and the parental strains they are derived from.

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Section: Discussionmentioning

confidence: 99%

Section: A Range Of Mutations Is Responsible For the Loss Of Pdim In mentioning

confidence: 99%

Section: A Range Of Mutations Is Responsible For the Loss Of Pdim In mentioning

confidence: 99%

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Rapid and spontaneous loss of phthiocerol dimycocerosate (PDIM) from Mycobacterium tuberculosis grown in vitro: implications for virulence studies

2009

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“…For example, Pap5A catalyzes the transfer of mycocerosic acid analogs to an alcohol, phthiocerol, from the ACP domain of a type I FAS, Mas, in Mycobacterium tuberculosis (26). In addition, direct transfer of C 6 fatty acid is predicted to occur between HexAB (type I FASs) and PksA (a type I PKS) in Aspergillus parasiticus (27,28).…”

Section: Discussionmentioning

confidence: 99%

Direct transfer of starter substrates from type I fatty acid synthase to type III polyketide synthases in phenolic lipid synthesis

Miyanaga

Funa

Awakawa

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Alkylresorcinols and alkylpyrones, which have a polar aromatic ring and a hydrophobic alkyl chain, are phenolic lipids found in plants, fungi, and bacteria. In the Gram-negative bacterium Azotobacter vinelandii, phenolic lipids in the membrane of dormant cysts are essential for encystment. The aromatic moieties of the phenolic lipids in A. vinelandii are synthesized by two type III polyketide synthases (PKSs), ArsB and ArsC, which are encoded by the ars operon. However, details of the synthesis of hydrophobic acyl chains, which might serve as starter substrates for the type III polyketide synthases (PKSs), were unknown. Here, we show that two type I fatty acid synthases (FASs), ArsA and ArsD, which are members of the ars operon, are responsible for the biosynthesis of C 22-C26 fatty acids from malonyl-CoA. In vivo and in vitro reconstitution of phenolic lipid synthesis systems with the Ars enzymes suggested that the C 22-C26 fatty acids produced by ArsA and ArsD remained attached to the ACP domain of ArsA and were transferred hand-to-hand to the active-site cysteine residues of ArsB and ArsC. The type III PKSs then used the fatty acids as starter substrates and carried out two or three extensions with malonylCoA to yield the phenolic lipids. The phenolic lipids in A. vinelandii were thus found to be synthesized solely from malonyl-CoA by the four members of the ars operon. This is the first demonstration that a type I FAS interacts directly with a type III PKS through substrate transfer.Azotobacter vinelandii ͉ alkylresorcinol ͉ alkylpyrone ͉ long-chain fatty acid ͉ cyst

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“…1). Mas synthesizes methyl branched mycocerosic acids through successive additions of methyl malonyl CoA (MMCoA) (8,9), whereas PpsA-E synthesize phthiocerol (10). PDIM is exported to the cell surface via the MmpL7 transporter (2,11).…”

mentioning

confidence: 99%

Lipidomics reveals control of Mycobacterium tuberculosis virulence lipids via metabolic coupling

Jain

Kim

Schelle³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

192

203

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Mycobacterium tuberculosis synthesizes specific polyketide lipids that interact with the host and are required for virulence. Using a mass spectrometric approach to simultaneously monitor hundreds of lipids, we discovered that the size and abundance of two lipid virulence factors, phthiocerol dimycocerosate (PDIM) and sulfolipid-1 (SL-1), are controlled by the availability of a common precursor, methyl malonyl CoA (MMCoA). Consistent with this view, increased levels of MMCoA led to increased abundance and mass of both PDIM and SL-1. Furthermore, perturbation of MMCoA metabolism attenuated pathogen replication in mice. Importantly, we detected increased PDIM synthesis in bacteria growing within host tissues and in bacteria grown in culture on odd-chain fatty acids. Because M. tuberculosis catabolizes host lipids to grow during infection, we propose that growth of M. tuberculosis on fatty acids in vivo leads to increased flux of MMCoA through lipid biosynthetic pathways, resulting in increased virulence lipid synthesis. Our results suggest that the shift to host lipid catabolism during infection allows for increased virulence lipid anabolism by the bacterium.lipid virulence factor ͉ metabolic flux ͉ pathogenesis ͉ PDIM ͉ sulfolipid-1

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Dissecting the Mechanism and Assembly of a Complex Virulence Mycobacterial Lipid

Cited by 142 publications

References 51 publications

Rapid and spontaneous loss of phthiocerol dimycocerosate (PDIM) from Mycobacterium tuberculosis grown in vitro: implications for virulence studies

Rapid and spontaneous loss of phthiocerol dimycocerosate (PDIM) from Mycobacterium tuberculosis grown in vitro: implications for virulence studies

Direct transfer of starter substrates from type I fatty acid synthase to type III polyketide synthases in phenolic lipid synthesis

Lipidomics reveals control of Mycobacterium tuberculosis virulence lipids via metabolic coupling

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