Phosphatidylcholine synthesis through cholinephosphate cytidylyltransferase is dispensable in Leishmania major

Moitra, Samrat; Pawlowic, Mattie C.; Hsu, Fong‐Fu; Zhang, Kai

doi:10.1038/s41598-019-44086-6

Cited by 18 publications

(32 citation statements)

References 80 publications

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“…Loss of CPCT did not affect promastigote replication in complete media but caused reduced growth rates under EtN-limiting conditions (Moitra et al, 2019). Both cpct¯ promastigotes and amastigotes were fully virulent in mice (Moitra et al, 2019). Collectively, these observations suggest that other routes of PC synthesis (e.g., PE Nmethylation and lipid salvage) can compensate the loss of CPCT (Fig.…”

Section: Introductionmentioning

confidence: 92%

“…PC, yet the CPCT-null promastigotes (cpct¯) contained similar levels of PC and PE as WT parasites in culture (Moitra et al, 2019). Loss of CPCT did not affect promastigote replication in complete media but caused reduced growth rates under EtN-limiting conditions (Moitra et al, 2019). Both cpct¯ promastigotes and amastigotes were fully virulent in mice (Moitra et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…Given the fact that CPCT is not essential for L. major, it is important to probe whether the de novo PC synthesis is required for Leishmania promastigotes and amastigotes. Unlike T. brucei which has separate Kennedy pathway branches for PE and PC synthesis (Gibellini and Smith, 2010;Smith and Butikofer, 2010), Leishmania parasites can incorporate EtN into both PE and PC (Pawlowic et al, 2016;Moitra et al, 2019), presumably through the activity of PE-N-methyltransferases (Bibis et al, 2014). Thus, CEPT is likely required for the synthesis of PC through both the Kennedy pathway and the methylation of PE in Leishmania (Fig.…”

Section: Introductionmentioning

confidence: 99%

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De novosynthesis of phosphatidylcholine is essential for the promastigote but not amastigote stage inLeishmania major

Moitra

Basu

Pawlowic

et al. 2020

Preprint

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Phosphatidylcholine (PC) is the most abundant type of phospholipids in eukaryotes constituting ~30% of total lipids in Leishmania. PC synthesis mainly occurs via the choline branch of the Kennedy pathway (choline ⇒ choline-phosphate ⇒ CDP-choline ⇒ PC) and the N-methylation of phosphatidylethanolamine (PE). In addition, Leishmania parasites can acquire PC and other lipids from the host or culture medium. In this study, we assessed the function and essentiality of choline ethanolamine phosphotransferase (CEPT) in Leishmania major which is responsible for the final step of the de novo synthesis of PC and PE. Our data indicate that CEPT is localized in the endoplasmic reticulum and possesses the activity to generate PC from CDP-choline and diacylglycerol. Targeted deletion of CEPT is only possible in the presence of an episomal CEPT gene in the promastigote stage of L. major. These chromosomal null parasites require the episomal expression of CEPT to survive in culture, confirming its essentiality during the promastigote stage. In contrast, during in vivo infection of BALB/c mice, these chromosomal null parasites appeared to lose the episomal copy of CEPT while maintaining normal levels of virulence, replication and cellular PC. Therefore, while the de novo synthesis of PC/PE is indispensable for the proliferation of promastigotes, intracellular amastigotes appear to acquire most of their lipids through salvage and remodeling.

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Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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De novosynthesis of phosphatidylcholine is essential for the promastigote but not amastigote stage inLeishmania major

Moitra

Basu

Pawlowic

et al. 2020

Preprint

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“…It must be noted that nematode parasites have also demonstrated other pathways of PC synthesis [107]. One such example is Leishmania major, in which despite having ChoK in the CDP-choline pathway for PC synthesis, this parasite has shown sustained growth in phosphorylcholine cytidylyltransferase-(CCT-) deficient state, which suggests the utilization of other alternative pathways of PC synthesis [108].…”

Section: Eukaryotic Chokis On Parasitesmentioning

confidence: 99%

ChoK-ing the Pathogenic Bacteria: Potential of Human Choline Kinase Inhibitors as Antimicrobial Agents

Khalifa

Few

Too

2020

BioMed Research International

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Novel antimicrobial agents are crucial to combat antibiotic resistance in pathogenic bacteria. Choline kinase (ChoK) in bacteria catalyzes the synthesis of phosphorylcholine, which is subsequently incorporated into the cell wall or outer membrane. In certain species of bacteria, phosphorylcholine is also used to synthesize membrane phosphatidylcholine. Numerous human ChoK inhibitors (ChoKIs) have been synthesized and tested for anticancer properties. Inhibition of S. pneumoniae ChoK by human ChoKIs showed a promising effect by distorting the cell wall and retarded the growth of this pathogen. Comparison of amino acid sequences at the catalytic sites of putative choline kinases from pathogenic bacteria and human enzymes revealed striking sequence conservation that supports the potential application of currently available ChoKIs for inhibiting bacterial enzymes. We also propose the combined use of ChoKIs and nanoparticles for targeted delivery to the pathogen while shielding the human host from any possible side effects of the inhibitors. More research should focus on the verification of putative bacterial ChoK activities and the characterization of ChoKIs with active enzymes. In conclusion, the presence of ChoK in a wide range of pathogenic bacteria and the distinct function of this enzyme has made it an attractive drug target. This review highlighted the possibility of “choking” bacterial ChoKs by using human ChoKIs.

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“…Bar, 0.01 substitutions per nucleotide position. 20,25,28,30,35,37, 40 and 45 °C was measured on MA to estimate the optimal temperature and temperature range for growth. Nitrate reduction and hydrolysis of aesculin and Tween 80 were investigated as described previously [32] with the modification that artificial seawater [33] was used for the preparation of the media.…”

Section: Physiologymentioning

confidence: 99%

Alteromonas ponticola sp. nov., a gammaproteobacterium isolated from seawater

Kim

Park

et al. 2020

International Journal of Systematic and Evolutionary Microbiology

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A Gram-stain-negative, aerobic, non-spore-forming, non-motile and ovoid or rod-shaped bacterial strain, MYP5T, was isolated from seawater in Jeju island of South Korea. MYP5T grew optimally at 30–35 °C and in the presence of 2.0 % (w/v) NaCl. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences revealed that MYP5T fell within the clade enclosed by the type strains of species of the genus Alteromonas , clustering with the type strains of Alteromonas confluentis and Alteromonas halophila . MYP5T exhibited the highest 16S rRNA gene sequence similarity value (98.0 %) to the type strain of A. confluentis and similarities of 95.1–97.9 % to the type strains of the other species of the genus Alteromonas . ANI and dDDH values of genomic sequences between MYP5T and the type strains of 22 species of the genus Alteromonas were 66.8–70.5 % and 18.6–27.5 %, respectively. The DNA G+C content of MYP5T, determined from the genome sequence, was 46.1 %. MYP5T contained Q-8 as the predominant ubiquinone and C18 : 1 ω7c, summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c), C16 : 0 and 10-methyl C17 : 0 as the major fatty acids. The major polar lipids of MYP5T were phosphatidylethanolamine and phosphatidylglycerol. Distinguishing phenotypic properties, along with the phylogenetic and genetic distinctiveness, revealed that MYP5T is separated from species of the genus Alteromonas . On the basis of the data presented, MYP5T is considered to represent a novel species of the genus Alteromonas , for which the name Alteromonas ponticola sp. nov. is proposed. The type strain is MYP5T (=KCTC 82144T=NBRC 114354T).

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Phosphatidylcholine synthesis through cholinephosphate cytidylyltransferase is dispensable in Leishmania major

Cited by 18 publications

References 80 publications

De novosynthesis of phosphatidylcholine is essential for the promastigote but not amastigote stage inLeishmania major

De novosynthesis of phosphatidylcholine is essential for the promastigote but not amastigote stage inLeishmania major

ChoK-ing the Pathogenic Bacteria: Potential of Human Choline Kinase Inhibitors as Antimicrobial Agents

Alteromonas ponticola sp. nov., a gammaproteobacterium isolated from seawater

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