From yeast to humans – roles of the Kennedy pathway for phosphatidylcholine synthesis

McMaster, Christopher R.

doi:10.1002/1873-3468.12919

Cited by 76 publications

(53 citation statements)

References 123 publications

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“…Indeed, deletion of the lipases efficiently rescued aS toxicity (Figures 2C and S1I), and lipid profiling confirmed DG decreases in the deletion mutants ( Figure 2D), accompanied by relief of the CPY trafficking defect (Figure 2E). To further test the relevance of DG accumulation in aS toxicity, we added choline to cells expressing aS; choline enters the Kennedy pathway of PC synthesis and consumes DG in the ER ( Figure 1B) as an alternative pathway to dissipate DG (McMaster, 2017). aS toxicity was suppressed by choline addition (Figures 2F and S1J), and the CPY trafficking defect was ameliorated ( Figure 2G).…”

Section: Results As Expression Impairs Lipid Homeostasis In Yeastmentioning

confidence: 99%

Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment

et al. 2019

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Section: Results As Expression Impairs Lipid Homeostasis In Yeastmentioning

confidence: 99%

Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment

et al. 2019

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“…The elevated growth temperatures caused a significant increase in the PC fraction and a decrease in the St one in the membrane lipid profile. PC are PL synthesized from the PE in the endoplasmic reticulum via the Kennedy pathway [57]. The homeostatic equilibrium between the two classes of PL is of great importance for both performing mitochondrial functions and protecting against oxidative stress that was reported for C. albicans.…”

Section: Lipidome Of Y Lipolyticamentioning

confidence: 99%

Soluble Sugar and Lipid Readjustments in the Yarrowia lipolytica Yeast at Various Temperatures and pH

et al. 2019

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Microorganisms cope with a wide range of environmental challenges using different mechanisms. Their ability to prosper at extreme ambient pH and high temperatures has been well reported, but the adaptation mechanism often remains unrevealed. In this study, we addressed the dynamics of lipid and sugar profiles upon different cultivation conditions. The results showed that the cells grown at various pH and optimal temperature contained mannitol as the major cytosol sugar alcohol. The elevated temperature of 38 °C led to a two- to three-fold increase in total cytosol sugars with concurrent substitution of mannitol for trehalose. Lipid composition in the cells at optimal temperature changed insignificantly at any pH tested. The increase in the temperature caused some drop in the storage and membrane lipid levels, remarkable changes in their composition, and the degree of unsaturated fatty acids. It was shown that the fatty acid composition of some membrane phospholipids varied considerably at changing pH and temperature values. The data showed a pivotal role and flexibility of the sugar and lipid composition of Y. lipolytica W29 in adaptation to unfavorable environmental conditions.

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“…It makes filaments, named cytoophidia-specific membrane-less organelles that control the spatial distribution of cytosine-dependent intermediary metabolism (63, 64)-in all the organisms where its organization has been explored (65). The structure of CTP synthetase is important in the present context because the synthesis of membrane lipids is a further metabolic step that involves the nucleotide, with most membranes deriving from cytosine-based liponucleotides (66,67). While the precise membrane lipid composition differs in the three domains of life, the general organisation of the cognate pathways is similar.…”

Section: Figure 2 Synthesis and Salvage Of Pyrimidine Nucleotidesmentioning

confidence: 99%

A path towards SARS-CoV-2 attenuation: metabolic pressure on CTP synthesis rules the virus evolution

Ouzounis

Wang

et al. 2020

Preprint

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Fighting the COVID-19 epidemic summons deep understanding of the way SARS-CoV-2 taps into its host cell metabolic resources. We describe here the singular metabolic background that creates a bottleneck constraining coronaviruses to evolve towards likely attenuation in the long term. Cytidine triphosphate (CTP) is at the crossroad of the biosynthetic processes that allow the virus to multiply. This is because CTP is in demand for three essential steps. It is a building block of the virus genome, it is required for synthesis of the cytosine-based liponucleotide precursors of the viral envelope and, finally, it is a critical building block of the host transfer RNAs synthesis. The CCA 3'-end of all the transfer RNAs required to translate the RNA genome and further transcripts into the proteins used to build active virus copies is not coded in the human genome. It must be synthesized de novo from CTP and ATP. Furthermore, intermediary metabolism is built on compulsory steps of synthesis and salvage of cytosine-based metabolites via uridine triphosphate (UTP) that keep limiting CTP availability. As a consequence, accidental replication errors tend to replace cytosine by uracil in the genome, unless recombination events allow the sequence to return to its ancestral sequences. We document some of the consequences of this situation in the function of viral proteins. We also highlight and provide a raison d'être to viperin, an enzyme of innate antiviral immunity, which synthesizes 3ʹ-deoxy-3′,4ʹ-didehydro-CTP (ddhCTP) as an extremely efficient antiviral nucleotide.We thank all the authors who shared genomic data in public database, and an acknowledgment table for sequences retrieved from GISAID (110) is provided (Supplementary Table S2). CONTRIBUTIONSAD designed the study and wrote the bulk of the manuscript. ZO, JL and WC developed the in silico analyses of cytosine evolution, codon usage biases and phylogeny. ZO, DW and WS performed the analysis and ZO wrote the corresponding part of the manuscript. CO designed and performed phylogenetic studies based on indels. PM identified the importance of several key steps in CTP synthesis. All authors read, wrote some sections and contributed to the final version of the manuscript.AD is a founder of Stellate Therapeutics, a company developing applications of metabolism for prevention and cure of neurodegenerative diseases and a founder of Virtexx, a company developing antiviral molecules. ZO and authors from Shenzhen are employed by the BGI, a company developing applications of genome studies. PM is a founder of Theraxen, a company developing synthetic biology approaches for drug development. The other authors declare no conflict of interest.

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From yeast to humans – roles of the Kennedy pathway for phosphatidylcholine synthesis

Cited by 76 publications

References 123 publications

Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment

Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment

Soluble Sugar and Lipid Readjustments in the Yarrowia lipolytica Yeast at Various Temperatures and pH

A path towards SARS-CoV-2 attenuation: metabolic pressure on CTP synthesis rules the virus evolution

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