Phosphatidic acid synthesis in bacteria

Yao, Jiangwei; Rock, Charles O.

doi:10.1016/j.bbalip.2012.08.018

Cited by 158 publications

(143 citation statements)

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“…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).…”

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confidence: 99%

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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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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“…C. trachomatis is predicted to encode a unique bacterial Gro-3-P acyltransferase with sequence similarity (38% identity) to the soluble Gro-3-P acyltransferases of plant plastids (7). This gene was designated plsE to distinguish it from the integral membrane Gro-3-P acyltransferases typically found in bacteria (plsB and plsY) (8). Phosphatidic acid (PA) produced by the acyltransferases is predicted to be converted into PE, PG, and CL.…”

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Chlamydia trachomatis Relies on Autonomous Phospholipid Synthesis for Membrane Biogenesis

Yao

Cherian

Frank

et al. 2015

Journal of Biological Chemistry

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Background: C. trachomatis has a reduced genome and was thought to obtain phospholipids as well as other nutrients from the host. Results:The new phospholipid molecular species that appear in infected cells are produced by C. trachomatis. Conclusion: C. trachomatis needs only glucose, isoleucine, and serine to synthesize its own membrane phospholipids. Significance: C. trachomatis relies on autonomous phospholipid synthesis.

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“…In bacteria, there are two-often coexisting-types of GPATs: PlsB and PlsY. While PlsY is widely distributed in eubacteria, archaea and eukaryotes have only PlsB (58). Surprisingly, neither PlsY-nor PlsB-related sequences were detected in the genomes of the well-characterized S. coelicolor or S. avermitilis or in strain G25.…”

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confidence: 86%

Role of Wax Ester Synthase/Acyl Coenzyme A:Diacylglycerol Acyltransferase in Oleaginous Streptomyces sp. Strain G25

Röttig

Strittmatter

Schauer

et al. 2016

Appl Environ Microbiol

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Recently, we isolated a novel Streptomyces strain which can accumulate extraordinarily large amounts of triacylglycerol (TAG) and consists of 64% fatty acids (dry weight) when cultivated with glucose and 50% fatty acids (dry weight) when cultivated with cellobiose. To identify putative gene products responsible for lipid storage and cellobiose utilization, we analyzed its draft genome sequence. A single gene encoding a wax ester synthase/acyl coenzyme A (CoA):diacylglycerol acyltransferase (WS/DGAT) was identified and heterologously expressed in Escherichia coli. The purified enzyme Atf G25 showed acyltransferase activity with C 12 -or C 16 -acyl-CoA, C 12 to C 18 alcohols, or dipalmitoyl glycerol. This acyltransferase exhibits 24% amino acid identity to the model enzyme AtfA from Acinetobacter baylyi but has high sequence similarities to WS/DGATs from other Streptomyces species. To investigate the impact of Atf G25 on lipid accumulation, the respective gene, atf G25 , was inactivated in Streptomyces sp. strain G25. However, cells of the insertion mutant still exhibited DGAT activity and were able to store TAG, albeit in lower quantities and at lower rates than the wild-type strain. These findings clearly indicate that Atf G25 has an important, but not exclusive, role in TAG biosynthesis in the novel Streptomyces isolate and suggest the presence of alternative metabolic pathways for lipid accumulation which are discussed in the present study. IMPORTANCEA novel Streptomyces strain was isolated from desert soil, which represents an extreme environment with high temperatures, frequent drought, and nutrient scarcity. We believe that these harsh conditions promoted the development of the capacity for this strain to accumulate extraordinarily large amounts of lipids. In this study, we present the analysis of its draft genome sequence with a special focus on enzymes potentially involved in its lipid storage. Furthermore, the activity and importance of the detected acyltransferase were studied. As discussed in this paper, and in contrast to many other bacteria, streptomycetes seem to possess a complex metabolic network to synthesize lipids, whereof crucial steps are still largely unknown. This paper therefore provides insights into a range of topics, including extremophile bacteria, the physiology of lipid accumulation, and the biotechnological production of bacterial lipids. Even extreme environments, such as arid, desert-like regions, are populated by prokaryotes. These mostly Gram-positive bacteria are subjected to extreme fluctuations of temperature and water supply. In addition to desiccation and the resulting cellular damage, the bacteria frequently encounter nutrient limitation. To withstand these harsh environmental conditions, the majority of bacteria have evolved various strategies and are able to store lipophilic compounds such as polyhydroxyalkanoates (PHA), triacylglycerols (TAG), or wax esters (WE) (1-3). TAG are synthesized as primary storage compounds by many actinomycetes-which represent the pre...

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Phosphatidic acid synthesis in bacteria

Cited by 158 publications

References 105 publications

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

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

Chlamydia trachomatis Relies on Autonomous Phospholipid Synthesis for Membrane Biogenesis

Role of Wax Ester Synthase/Acyl Coenzyme A:Diacylglycerol Acyltransferase in Oleaginous Streptomyces sp. Strain G25

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