Enzymes involved in lipid body metabolism in
1. Introduction
Mycobacteria have outstanding mechanisms to escape from elimination and have a high degree of intrinsic resistance to most antibiotics, chemotherapeutic agents and immune eradication [3,4]. One major obstacle for host defence mechanisms and therapeutic intervention is the robust, mycolic acid-rich cell wall, which is unique among prokaryotes [3,5]. In the last years it has become apparent that mycobacteria induce the accumulation of lipids in the host cells and use them as energy and carbon source. This strategy is regarded as another crucial factor for the long term-survival of
Lepromatous leprosy lesions of the skin, eyes, nerves, and lymph nodes are characterized by tumor-like accumulations of foamy macrophages. The foamy macrophages are fully packed with lipid droplets (LDs) and contain high numbers of leprosy bacilli. These aggregations of foamy macrophages expand slowly and disfigure the body of the host [13].
The finding that
In the dormant state lipids from lipid bodies appear to be the primary carbon source for
This review highlights the importance of the LDs as one of the most unique determinant for persistence and virulence of
In this review we will use the term “lipid droplets” for lipid-rich inclusions in the host and “lipid bodies” for lipid-rich inclusions in the pathogen.
2. Biogenesis of lipid inclusions in bacteria and eukaryotes
The current models of lipid droplet biogenesis are still hypothetical and have been reviewed extensively by Murphy in 1999 and Ohsaki in 2009 [22,23]. The most common model supposes that the membrane protein diacyltransferase DGAT1 synthesizes triacylglycerols (TAG), which accumulate between the two membrane leaflets of the endoplasmic reticulum (ER) to be finally released by budding. The lipids are covered by a phospholipid monolayer from the ER membrane.
The formation of lipid bodies in bacteria has been even less characterized. Wältermann et al. suggested in 2005 that a bifunctional wax ester synthase/acyl-CoA:diacylglycerol acyltransferase, (WS/DGAT) synthesizes TAG for lipid body formation. WS/DGAT is an integral membrane protein and synthesizes a growing globule around the cytoplasmic portion of the enzyme. Finally the lipid body is released to the cytoplasm. The origin of the surface phospholipid monolayer is not known [22,24].
2.1. Lipid droplets in the host
The accumulation of lipid droplets occurs also in several infectious, and inflammatory conditions, including in atherosclerosis [25], bacterial sepsis [26], viral infections [27], and in mycobacterial infections [15,28,29].
LDs are observed in various cells of the immune system including macrophages, neutrophils, and eosinophils. The structure and composition of LDs is highly conserved. They contain a core of neutral lipid esters typically TAG, but also sterols and sterol esters [31-36]. The surface is covered by a phospholipid monolayer, which is composed at least in some cells by unique fatty acids [37].
Important markers for the lipid accumulation in adipocytes or macrophages are lipid-droplet-associated proteins such as adipose differentiation-related protein ADRP and perilipin, which play essential roles in lipid-droplet formation [39]. After phagocytosis of live
2.2. Lipid bodies in the pathogen
Prokaryotes do not generally produce lipid bodies containing TAG. Accumulation of TAG in intracellular lipid-bodies is mostly restricted to bacteria belonging to the actinomycetes group [40].
Most mycobacterial species accumulate considerable amounts of TAG during infection [24,41-44]. The intracellular pathogen
It has been observed that persisters store large amounts of intracellular triacylglycerol lipid bodies (LBs) [15,17,28,45,46].
3. M. tuberculosis induces foamy macrophages in the host
Over the last years it has become evident that survival and persistence of
The final granuloma consists of a core of infected, lipid-laden macrophages, which are surrounded by an outer layer of additional differentiated macrophages. The outer shell consists of T lymphocytes, B lymphocytes, dendritic cells, neutrophils, fibroblasts and an extracellular matrix [29,51-53].
The development and composition of a human tuberculosis granuloma is depicted in Figure 1.
3.1. Lipid body formation in M. tuberculosis is critically dependent on lipid droplets from the host
Host lipids from lipid droplets are used by the pathogen as substantial nutrient source. Middlebrook already demonstrated in the late 1940s that mycobacterial growth
The utilization of host lipids in vivo does not only promote survival but may also increases virulence and modulate the immune response to infection. Growth of
Cholesterol utilization was also identified to be required for mycobacterial persistence [57]. In 2008 Pandey and Sassetti found that
Especially
Cholesterol is also essential for uptake of
3.2. Lipid body formation in M. tuberculosis is critically dependent on lipid droplets
Host lipids from lipid droplets are used by the pathogen as substantial nutrient source. Middlebrook already demonstrated in the late 1940s that mycobacterial growth
The utilization of host lipids in vivo does not only promote survival but may also increases virulence and modulate the immune response to infection. Growth of
Cholesterol utilization was also identified to be required for mycobacterial persistence [57]. In 2008 Pandey and Sassetti found that
3.3. Biosynthesis of TAG and formation of lipid bodies in M. tuberculosis
Biosynthesis of TAG consists of the sequential esterification of the glycerol moiety with fatty acyl-residues by various acyltransferases. Fatty acid biosynthesis consists of the stepwise addition of acetyl groups, which are provided by acetyl-CoA. The initial step is the transfer of an acetyl group from acetyl-CoA to a small protein, called acyl carrier protein (ACP). In the following two-carbon fragments are added sequentially to yield fatty acids of the desired length.
Esterification of fatty acids with glycerol-3-phosphate occurs via sequential acylation of the sn-1,2 and 3 positions of glycerol-3-phosphate, and removal of the phosphate group before the last acylation step. The terminal reaction is the esterification of diacylglycerol (DAG) with acyl-CoA by an diacylglycerol acyltransferase [40]. Animals and plants use diacylglycerol acyl‐transferases (DGAT) for the terminal esterification. DGATs catalyze exclusively the esterification of acyl-CoA with diacylglycerol. Bacteria do not contain DGATs but only bifunctional wax ester synthase/acyl-CoA:diacylglycerol acyltransferases (WS/DGAT). WS/DGATs, mediate next to TAG formation the synthesis of waxes by esterification of acyl-CoA with alcohol [67]. The genome of
Ten of the 15 tgs genes in
In summary Tgs enzymes play a major role in TAG synthesis, lipid body formation and maintenance.
Ag85A, a mycoltransferase, that is known to catalyze the formation of the cord factor was recently found to have additional DGAT activity [71]. The kinetic parameters are quite similar to those reported for the
The genome of
The
3.4. Activation of TAG – Lipases and esterases of M. tuberculosis
Neutral lipids in the core of the lipid body are hydrolyzed by lipases or esterases, yielding fatty acids for energy generation and anabolism of membrane phospholipids.
In the genome of
Overexpression of
Several other esterases, next to the members of the Lip group have been identified and biochemically characterized. They all belong also to the α/β hydrolase fold family and showing the minimal GXSXG motif. In 2007 Côtes et al. characterized a novel lipase Rv0183. The enzyme is only found in the cell wall and culture medium. This observation suggests that Rv0183 is involved in the degradation of the host cell lipids e.g. when M. tuberculosis infects adipocytes [55,76]. Another probably cell wall-associated carboxylesterase is encoded by Rv2224c. The esterase Rv2224c was found to be required for bacterial survival in mice [77]. The substrate spectrum of Rv2224c is poorly characterized and until now it is unknown whether the enzyme uses TAG as substrate [77]. Furthermore the three-dimensional structures of the esterases Rv0045c (PDB 3P2M) [78], Rv1847 (PDB 3S4K), and LipW (3QH4) from
3.5. Lipase genes of M. leprae
In the
3.6. Enzymes of the β-oxidation and glyoxylate cycle
Together with malate synthase, isocitrate lyase (ICL) is the key enzyme of the glyoxylate cycle that catalyzes the cleavage of isocitrate to glyoxylate and succinate [81,83]. The
All enzymes involved in lipid metabolism in lipid bodies are summarized in Table 1.
The
4. Lipid composition in M. leprae infected cells
In 1863, Virchow described foamy cells, which form droplets and surround
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DGAT | + | + | Δ decreases TAG accumulation |
NA | ML1244 | [46,48,68] |
|
DGAT | + | + | NA | NA | ML1244 | [48,68] |
|
DGAT | + | NA | NA | NA | ML1244 | [48,68] |
|
DGAT | + | NA | NA | NA | ML1244 | [48,68] |
|
DGAT | + | NA | NA | NA | ML1244 | [48,68] |
|
DGAT | + | NA | NA | NA | ML1244 | [48,68] |
|
DGAT | + | NA | Overexpression increases production of lipid bodies | NA | ML0097 (85A) | [71] |
|
DGAT | NA | + | Δ |
NA | ML2427c | [69] |
|
DGAT | NA | + | Δ |
NA | ML1244 | [69] |
|
DGAT | NA | + | Δ |
NA | ML1244 | [69] |
|
acyltransferase | NA | + | Δ |
NA | [69] | |
|
Lipase/esterase | + | NA | Δ Overexpression increases TAG hydrolysis |
Overexpression increases virulence in mice | ML0314c ( ML1053 ML1183c |
[47] |
|
Lipase/esterase | + | NA | NA | NA | ML0314c ( |
[72] |
|
Lipase/esterase | + (in vivo*) | + | + (*) | NA | ML1346 | [69] |
|
Lipase/esterase | Hydrolyzes only monoacylglycerides | NA | NA | NA | ML2603 | [76] |
|
Lipase/esterase | NA | NA | NA | Gene disruption decreases virulence in mice | ML1633c | [77] |
|
isocitrate lyase | + | NA | NA | The Δ |
ML1985c (aceA) | [79,80,93-95] |
5. Induction of lipid droplet biogenesis
Since the biogenesis of lipid droplets in macrophages seems an absolute requirement for intracellular bacteria to establish infections, we will discuss mechanisms involved in foam cell formation and development of lipid droplets.
5.1. Scavenger receptor mediated lipid droplet biogenesis in M. tuberculosis
Upon infection with pathogenic bacteria macrophages generate reactive oxygen species (ROS). The release of ROS generates oxidative stress, and results not only in damage to cellular structures but also to oxidation of fatty acids, such as low density lipoproteins (OxLDL) in granulomas. The binding of OxLDL to type 1 scavenger receptors CD36 and LOX1 induces increased surface expression of both receptors, leading to uptake of OxLDL [96-98]. In addition, CD36 increases the uptake of
5.2. TLR mediated LD formation in M. bovis and M. leprae
5.3. Mycolic acids induce the formation of foamy macrophages
Mycolic acids and oxygenated mycolic acids are strong inducers of monocyte-derived macrophages differentiation into foamy macrophages [19,106]. Peyron et al. demonstrated that that a set of oxygenated mycolic acids specifically produced by highly virulent mycobacteria species (
6. Clinical implications
Several enzymes of the mycobacterial lipid-biosynthesis are regarded as targets for new antitubercular compounds. The research focused on enzymes, involved in the biosynthesis of lipid compounds of the mycobacterial cell wall [107]. Especially the biosynthesis of the highly toxic cord factor is an attractive target. The cord factor is synthesized by the antigen 85 complex [108,109]. It was recently shown that one member of the complex, antigen 85A is involved in the formation of intracellular lipid bodies [71]. Antigen 85 is an important virulence factor. It has been shown that
The most potent inhibitor for mycolic acid biosynthesis is isoniazid (INH). INH is a prodrug which is converted to the isonicotinoyl radical by KatG. INH forms a covalent adduct with NAD. This INH-NAD adduct inhibits FAS-II enoyl-ACP reductase InhA, which in consequence leads to inhibition of mycolic acid biosynthesis, and ultimately to cell death [114-117]. The inhibitors of fatty acid biosynthesis are summarized in Figure 2 and Table 2.
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FAS-I and FAS-II |
KasA/KasB | Cerulenin (2R,3S-epoxy-4-oxo-7,10-trans,trans-dodecanoic acid amide | [118] [119] | |
FAS-II | KasA/KasB | TLM (Thiolactomycin) | [120-122] | |
FAS-II | KasA/KasB | Platensimycin | [123] | |
InhA | INH (Isoniazid) | [124] | ||
InhA | ETH (Ethionamide) | [125] | ||
InhA | TRC (Triclosan) | [126] | ||
InhA | alkyl diphenyl ethers (Triclosan derivatives) | [127] | ||
InhA | 2-(o-Tolyloxy)-5-hexylphenol (PT70) | [120] | ||
Cyclopro-panation | CMASs (cmaA2, mmaA2 or pcaA) | TAC (Thiacetazone) | [128] | |
MmaA4 | TAC (Thiacetazone) | [128] |
7. Conclusion
The formation of lipid inclusions during infection in the host as well as in the pathogen during intracellular infection with
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