Acyl-Phosphates Initiate Membrane Phospholipid Synthesis in Gram-Positive Pathogens

Lu, Ying‐Jie; Zhang, Yongmei; Grimes, Kimberly D.; Qi, Jianjun; Lee, Richard; Rock, Charles O.

doi:10.1016/j.molcel.2006.06.030

Cited by 154 publications

(224 citation statements)

References 36 publications

(42 reference statements)

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“…PlsY is an acyltransferase required for the indispensable process of phospholipid biosynthesis, and highly conserved across bacteria (23,24). We show that PlsY is essential for the growth of S. aureus, demonstrated by the creation of a conditional lethal strain (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 76%

Supramolecular structure in the membrane of Staphylococcus aureus

García‐Lara

Weihs

et al. 2015

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

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All life demands the temporal and spatial control of essential biological functions. In bacteria, the recent discovery of coordinating elements provides a framework to begin to explain cell growth and division. Here we present the discovery of a supramolecular structure in the membrane of the coccal bacterium Staphylococcus aureus, which leads to the formation of a largescale pattern across the entire cell body; this has been unveiled by studying the distribution of essential proteins involved in lipid metabolism (PlsY and CdsA). The organization is found to require MreD, which determines morphology in rod-shaped cells. The distribution of protein complexes can be explained as a spontaneous pattern formation arising from the competition between the energy cost of bending that they impose on the membrane, their entropy of mixing, and the geometric constraints in the system. Our results provide evidence for the existence of a self-organized and nonpercolating molecular scaffold involving MreD as an organizer for optimal cell function and growth based on the intrinsic self-assembling properties of biological molecules.T he perpetuation of all cellular life requires the temporal and spatial management of essential biological functions, within the morphological framework characteristic of a specific organism. The underlying processes, which determine cell shape, are intimately intertwined with cell division and constitute pivotal issues for cell biology; their coordination in prokaryotes is mediated through counterparts of eukaryotic actin, tubulin, and intermediate filaments in addition to other specific components (1, 2). Several of these apparent cytoskeletal elements capitalize on their membrane binding properties, assembling along the longitudinal axis, between the poles of rod-shaped cells; they participate in many processes, including selection of the division site via the Min system and other components (3, 4); guidance and control of the cell wall biosynthetic machinery responsible for cell size, polarity, and shape through the actin-like protein MreB (5-11); and chromosome partitioning into daughter cells using another actin-like filament, ParM (12).Despite this set of highly coordinated mechanisms, it has recently been shown that otherwise rod-and cocci-shaped bacteria can exist as largely spherical wall-less forms known as L-forms, with the capacity to divide (13). Importantly, the division of L-forms of the rod-shaped bacterium Bacillus subtilis is freed from the requirement of the classical tubulin-like division component FtsZ (14). L-forms appear to divide by scission after blebbing, tabulation, or vesiculation dependent on an altered rate of membrane biosynthesis (15); this harks back perhaps to a more evolutionary primitive mechanism permitting cellular proliferation. Thus, are there underlying organizational mechanisms that exist, independent of apparent cytoskeletal elements? The fluid mosaic model proposing the free diffusion of membrane proteins through the lipids has been challenged by growing e...

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Section: Resultsmentioning

confidence: 76%

Supramolecular structure in the membrane of Staphylococcus aureus

García‐Lara

Weihs

et al. 2015

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

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“…In E. coli, acyl-CoAs are consumed by fatty acid ␤-oxidation, but Neisseria do not encode the genes necessary to break down acyl-CoA via this pathway. Furthermore, whereas both E. coli PlsB and PlsC acyltranferases are able to utilize acyl-CoA as acyl donors, the characterized PlsX/ PlsY/PlsC acyltransferases cannot use acyl-CoA (19,61). The observed elongation and incorporation of exogenous fatty acids in Neisseria is explained by AasN activation of exogenous fatty acids to acyl-ACP because exogenous fatty acids are elongated and used by the acyl-PO 4 /acyl-ACP-dependent PlsX/PlsY/PlsC acyltransferase system.…”

Section: Discussionmentioning

confidence: 99%

“…N. meningitides with deficient LPS synthesis are viable under laboratory conditions (16,17), and an LPS-deficient N. meningitidis strain has been isolated from a human patient (18). Neisseria belongs to the ␤-Proteobacteria class, and phosphatidic acid synthesis occurs by the more widely distributed PlsX/PlsY/PlsC acyltransferase system (19). In this pathway, the acyl-ACP endproducts of FASII are converted to acyl-PO 4 by PlsX, and the acyl-PO 4 serves as the acyl donor for PlsY to acylate sn-glycerol-3-phosphate (19).…”

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confidence: 99%

“…Neisseria belongs to the ␤-Proteobacteria class, and phosphatidic acid synthesis occurs by the more widely distributed PlsX/PlsY/PlsC acyltransferase system (19). In this pathway, the acyl-ACP endproducts of FASII are converted to acyl-PO 4 by PlsX, and the acyl-PO 4 serves as the acyl donor for PlsY to acylate sn-glycerol-3-phosphate (19). Gram-positive bacteria, such as S. aureus, activate exogenous fatty acids using a fatty acid kinase to produce acyl-PO 4 that is either used by PlsY or converted to acyl-ACP by PlsX (20,21).…”

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confidence: 99%

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Activation of Exogenous Fatty Acids to Acyl-Acyl Carrier Protein Cannot Bypass FabI Inhibition in Neisseria

Yao

Bruhn

Frank

et al. 2016

Journal of Biological Chemistry

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Neisseria is a Gram-negative pathogen with phospholipids composed of straight chain saturated and monounsaturated fatty acids, the ability to incorporate exogenous fatty acids, and lipopolysaccharides that are not essential. The FabI inhibitor, AFN-1252, was deployed as a chemical biology tool to determine whether Neisseria can bypass the inhibition of fatty acid synthesis by incorporating exogenous fatty acids. Neisseria encodes a functional FabI that was potently inhibited by AFN-1252. AFN-1252 caused a dose-dependent inhibition of fatty acid synthesis in growing Neisseria, a delayed inhibition of growth phenotype, and minimal inhibition of DNA, RNA, and protein synthesis, showing that its mode of action is through inhibiting fatty acid synthesis. Isotopic fatty acid labeling experiments showed that Neisseria encodes the ability to incorporate exogenous fatty acids into its phospholipids by an acyl-acyl carrier protein-dependent pathway. However, AFN-1252 remained an effective antibacterial when Neisseria were supplemented with exogenous fatty acids. These results demonstrate that extracellular fatty acids are activated by an acyl-acyl carrier protein synthetase (AasN) and validate type II fatty acid synthesis (FabI) as a therapeutic target against Neisseria.Neisseria is a genus of mucosal colonizing bacteria found in a variety of animals. Of the 11 species of Neisseria associated with humans, Neisseria gonorrhoeae and Neisseria meningitidis are obligate human pathogens. N. meningitidis is a common cause of meningitis and other meningococcal diseases in infants and children with 3,000 cases/year in the United States (1). N. gonorrhoeae is the causative agent of the sexually transmitted disease gonorrhoeae, with Ͼ100 million new cases/year worldwide (2). The incidence of multidrug-resistant N. gonorrhoeae has markedly increased in recent years, raising the prospect of untreatable gonorrhoeae and highlighting the need for developing new antibiotics and discovering new antibiotic targets in Neisseria (2). One emerging antibiotic drug target is bacterial type II fatty acid synthesis (FASII) 3 (3-6). All characterized bacteria have the ability to utilize exogenous fatty acids for phospholipid synthesis (7); thus, it is important to understand the pathways for fatty acid uptake and whether extracellular fatty acids can bypass FASII inhibition (7-9).Neisseria are Gram-negative bacteria with phospholipids containing saturated and unsaturated fatty acids (10) and LPS containing 3-hydroxy fatty acids (11). Escherichia coli utilizes an acyl-CoA synthetase (FadD) to activate exogenous fatty acids (12), and they are incorporated into phospholipids by the PlsB/PlsC acyltransferase system that utilizes either acyl-ACP or acyl-CoA (7, 13). E. coli cannot bypass FASII inhibitors because there is no mechanism for the generation of acyl-ACP from extracellular fatty acids, and FASII is the only source for the 3-hydroxy fatty acids required to synthesize the essential LPS (14, 15). The fatty acid composition of Neisseria resembl...

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“…For the lpaT and aasC genes, an NdeI cleavage site was engineered at the 5Ј end of the gene with the start codon in the NdeI site, whereas a His 6 tag, stop codon, and EcoRI cleavage site were engineered sequentially at the 3Ј end of the gene. Both genes were cloned into the plasmid pET21a (New England Biolabs) and pPJ131 (29) expression vectors via the NdeI and EcoRI sites. For the acpP gene, an NdeI cleavage site was engineered at the 5Ј end of the acpP gene, whereas a stop codon and a EcoRI cleavage site were engineered sequentially at the 3Ј end of the gene.…”

Section: Methodsmentioning

confidence: 99%

Chlamydia trachomatis Scavenges Host Fatty Acids for Phospholipid Synthesis via an Acyl-Acyl Carrier Protein Synthetase

Yao

Dodson

Frank

et al. 2015

Journal of Biological Chemistry

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Background: C. trachomatis relies on its own biosynthetic pathways to produce membrane phospholipids. Results: C. trachomatis expresses an acyl-acyl carrier protein synthetase to activate fatty acids. Conclusion: C. trachomatis utilizes fatty acids obtained from the host to construct phospholipids. Significance: C. trachomatis selectively scavenges host saturated fatty acids, the most energy-expensive component needed for phospholipid synthesis.

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Acyl-Phosphates Initiate Membrane Phospholipid Synthesis in Gram-Positive Pathogens

Cited by 154 publications

References 36 publications

Supramolecular structure in the membrane of Staphylococcus aureus

Supramolecular structure in the membrane of Staphylococcus aureus

Activation of Exogenous Fatty Acids to Acyl-Acyl Carrier Protein Cannot Bypass FabI Inhibition in Neisseria

Chlamydia trachomatis Scavenges Host Fatty Acids for Phospholipid Synthesis via an Acyl-Acyl Carrier Protein Synthetase

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