Multiple lysophosphatidic acid acyltransferases in <i>Neisseria meningitidis</i>

Shih, Giles C.; Kahler, Charlene M.; Swartley, John S.; Rahman, Motiur; Coleman, Jack; Carlson, Russell W.; Stephens, David S.

doi:10.1046/j.1365-2958.1999.01404.x

Cited by 36 publications

(41 citation statements)

References 50 publications

(67 reference statements)

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“…This phenotype mirrored that of mutation of the N. meningitidis LPA acyl-transferase, NlaA. (Shih et al, 1999). Together, the conserved structural features, the functional complementation of the E. coli plsC mutant and the effect of mutation of PA0005 on the fatty acid profile of P. aeruginosa indicate that PA0005 encodes an LPA acyltransferase, justifying its designation as lptA (LysoPhosphatidic acid acylTransferase A).…”

Section: Resultsmentioning

confidence: 83%

“…pseudomonas.com), a gene (PA0005) encoding a protein that displayed homology to E. coli PlsC was identified. The protein encoded by PA0005 displays 28 % identity with PlsC of E. coli and 36 % identity with NlaB from Neisseria meningitidis, which has also been identified as a functional LPA acyltransferase (Shih et al, 1999). Like E. coli PlsC, the PA0005 protein product possesses consensus sequences specific for phospholipid and glycerol acyltransferases (blocks IPB002123A and IPB2123B, DEBG, GenomeNet).…”

Section: Resultsmentioning

confidence: 99%

“…Certain bacteria, such as Neisseria meningitidis, have been proven to possess two functional PlsC homologues. Due to differences in substrate specificity, inactivation of one of these two LPA acyltransferases alters the fatty acid profile of phospholipids (Shih et al, 1999). In a parallel manner, we decided to alter the phospholipid composition of P. aeruginosa by identifying and disrupting the gene encoding the main PlsC homologue.…”

Section: Introductionmentioning

confidence: 99%

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Modulation of quorum sensing in Pseudomonas aeruginosa through alteration of membrane properties

et al. 2005

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Changes in the cellular envelope are major physiological adaptations that occur when micro-organisms encounter extreme environmental conditions. An appropriate degree of membrane fluidity is crucial for survival, and alteration of membrane lipids is an essential adaptive response. Emerging data suggest that microbial cells may recognize alterations in their membrane viscosity resulting from certain environmental changes as a trigger for adaptive cellular responses. In Pseudomonas aeruginosa, the quorum-sensing (QS) system involves a complex regulatory circuitry that coordinates the expression of genes according to a critical population density. Interestingly, it has been shown that the QS system of P. aeruginosa can also be activated by nutritional stress, independently of the cell density, and therefore may be part of a more general adaptive response to stressful environmental conditions. In order to examine the proposed link between membrane properties and stress signalling, the effects of genetically engineered alterations of the membrane phospholipid composition of P. aeruginosa PAO1 on the activation of the stringent response and the QS system were examined. The lptA gene encoding a functional homologue of PlsC, an Escherichia coli enzyme that catalyses the second step of the phospholipid biosynthesis pathway, was identified and disrupted. Inactivation of lptA altered the fatty acid profile of phospholipids and the membrane properties, resulting in decreased membrane fluidity. This resulted in a premature production of the QS signals N-butanoyl-and N-hexanoyl-homoserine lactone (C4-HSL and C6-HSL) and a repression of 2-heptyl-3-hydroxy-4-quinolone (PQS) synthesis at later growth phases. The effects on C4-and C6-HSL depended upon the expression of relA, encoding the (p)ppGpp alarmone synthase, which was increased in the lptA mutant. Together, the findings support the concept that alterations in membrane properties can act as a trigger for stress-related gene expression.

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Section: Resultsmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modulation of quorum sensing in Pseudomonas aeruginosa through alteration of membrane properties

et al. 2005

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“…N. gonorrhoeae makes unsaturated fatty acids, and although the NGO1024 gene is required for unsaturated fatty acid synthesis under anaerobic conditions (22), the biochemistry is unknown. N. gonorrhoeae encodes for plsX (NGO2171), plsY (NGO0858), and two plsC (NGO0611 and NGO2069) genes (62,63). We show that N. gonorrhoeae encodes an acyl-ACP synthetase (AasN, NGO0530) that functions in the incorporation of exogenous fatty acids.…”

Section: Discussionmentioning

confidence: 93%

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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“…These DAG receptors act as GTPase accelerating proteins, which enhance cellular G-protein signal transduction. 38 We also confirmed the expression regulation of LPA acyltransferase, which catalyzes the conversion of LPA to PA. 39 LPA, another phospholipids signaling mediator, acts via a specific G-protein-coupled receptor (lysophospholipid receptors), several of which have been recently identified. 40,41 Hence, n-chimerin and LPA acyltransferase appear to also function in a common pathway of lipid signal transduction.…”

Section: Discussionmentioning

confidence: 99%

Antipsychotic drug treatment alters expression of mRNAs encoding lipid metabolism-related proteins

et al. 2003

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Using an automated PCR-based genomics approach, TOtal Gene expression Analysis (TOGA s ), we have examined gene expression profiles of mouse striatum and frontal cortex in response to clozapine and haloperidol drug treatment. Of 17 315 mRNAs observed, TOGA s identified several groups of related molecules that were regulated by drug treatment. The expression of some genes encoding proteins involved in neurotransmission, signal transduction, oxidative stress, cell adhesion, apoptosis and proteolysis were altered in the brains of both clozapine-and haloperidol-treated mice as recognized by TOGA s . Most notable was the differential expression of those genes whose products are associated with lipid metabolism. These include apolipoprotein D (apoD), the mouse homolog of oxysterol-binding protein-like protein 8 (OSBPL8), a diacylglycerol receptor (n-chimerin), and lysophosphatidic acid (LPA) acyltransferase. Real-time PCR analysis confirmed increases in the RNA expression of apoD (1.6-2.2-fold) and OSBPL8 (1.7-2.6-fold), and decreases in the RNA expression of nchimerin (1.5-2.2-fold) and LPA acyltransferase (1.5-fold) in response to haloperidol and/or clozapine treatment. Additional molecules related to calcium homeostasis and signal transduction, as well as four sequences of previously unidentified mRNAs, were also confirmed by real-time PCR to be regulated by drug treatment. While antipsychotic drugs may affect several metabolic pathways, lipid metabolism/signaling pathways may be of particular importance in the mechanisms of antipsychotic drug action and in the pathophysiology of psychiatric disorders. Molecular Psychiatry (2003) 8, 983-993.

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Multiple lysophosphatidic acid acyltransferases in Neisseria meningitidis

Cited by 36 publications

References 50 publications

Modulation of quorum sensing in Pseudomonas aeruginosa through alteration of membrane properties

Modulation of quorum sensing in Pseudomonas aeruginosa through alteration of membrane properties

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

Antipsychotic drug treatment alters expression of mRNAs encoding lipid metabolism-related proteins

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