Biosynthesis of Phosphatidylcholine from a Phosphocholine Precursor Pool Derived from the Late Endosomal/Lysosomal Degradation of Sphingomyelin

Jansen, Suzanne M.; Groener, J.E.M.; Bax, Wim; Suter, A.; Säftig, Paul; Somerharju, Pentti; Poorthuis, Ben J. H. M.

doi:10.1074/jbc.m101817200

Cited by 15 publications

(18 citation statements)

References 30 publications

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“…Phosphocholine for PtdCho synthesis can also be supplied from sources other than CK. For example, phosphocholine arises from sphingomyelin degradation by a lysosomal sphingomyelinase [25]. …”

Section: The Cdp-choline Pathway In Mammalsmentioning

confidence: 99%

Phosphatidylcholine and the CDP–choline cycle

Fagone

Jackowski

2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

219

179

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The CDP-choline pathway of phosphatidylcholine (PtdCho) biosynthesis was first described more than 50 years ago. Investigation of the CDP-choline pathway in yeast provides a basis for understanding the CDP-choline pathway in mammals. PtdCho is considered as an intermediate in a cycle of synthesis and degradation, and the activity of a CDP-choline cycle is linked to subcellular membrane lipid movement. The components of the mammalian CDP-choline pathway include choline transport, choline kinase, phosphocholine cytidylyltransferase, and choline phosphotransferase activities. The protein isoforms and biochemical mechanisms of regulation of the pathway enzymes are related to their cell and tissue-specific functions. Regulated PtdCho turnover mediated by phospholipases or neuropathy target esterase participates in the mammalian CDP-choline cycle. Knockout mouse models define the biological functions of the CDP-choline cycle in mammalian cells and tissues. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.

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Section: The Cdp-choline Pathway In Mammalsmentioning

confidence: 99%

Phosphatidylcholine and the CDP–choline cycle

Fagone

Jackowski

2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

219

179

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“…In mammalian cells, the supply of PtdCho can be regulated by biochemical activity of key enzymes [1,2], gene expression of biosynthetic or degradative enzymes [2,3,4,5,6] or intracellular trafficking [7,8]. It was previously demonstrated that during RA-induced differentiation of Neuro-2a cells, the increase in PtdCho biosynthesis is promoted by an ordered and coordinated stimulation of CKα and CCTα activity and expression.…”

Section: Introductionmentioning

confidence: 99%

KDM2B regulates choline kinase expression and neuronal differentiation of neuroblastoma cells

et al. 2019

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The process of neuronal differentiation is associated with neurite elongation and membrane biogenesis, and phosphatidylcholine (PtdCho) is the major membrane phospholipid in mammalian cells. During neuroblast differentiation, the transcription of two genes involved in PtdCho biosynthesis are stimulated: Chka gene for choline kinase (CK) alpha isoform and Pcyt1a gene for CTP:phosphocholine cytidylyltransferase (CCT) alpha isoform. Here we show that CKα is essential for neuronal differentiation. In addition, we demonstrated that KDM2B regulates CKα expression and, as a consequence, neuronal differentiation. This factor is up-regulated in the course of the neuroblasts proliferative and undifferentiated state and down-regulated during differentiation induced by retinoic acid (RA). During proliferation, KDM2B binds to the Box2 located in the Chka promoter repressing its transcription. Interestingly, KDM2B knockdown enhances the levels of CKα expression in neuroblast cells and induces neuronal differentiation even in the absence of RA. These results suggest that KDM2B is required for the appropriate regulation of CKα during neuronal differentiation and to the maintaining of the undifferentiated stage of neuroblast cells.

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“…Genetic inactivation of the analogous genes in yeast resulted in complete loss of both enzyme activities in vitro and an inability to metabolically reconstitute lipid synthesis by either route in vivo Bell, 1994a, 1994b;Hjelmstad and Bell, 1991a;. Human CEPT1 and CPT1, by virtue of their choice in diacylglycerol fatty acyl and CDP-alcohol species, affect the form and function of PtdCho and PtdEtn (Samborski et al, 1990;DeLong et al, 1999;Hunt et al, 2001;Jansen et al, 2001). In this study we have pinpointed the sites of PtdCho and PtdEtn synthesis in mammalian cells.…”

Section: Introductionmentioning

confidence: 99%

The Major Sites of Cellular Phospholipid Synthesis and Molecular Determinants of Fatty Acid and Lipid Head Group Specificity

Henneberry

Wright

McMaster

2002

MBoC

198

175

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Phosphatidylcholine and phosphatidylethanolamine are the two main phospholipids in eukaryotic cells comprising ~50 and 25% of phospholipid mass, respectively. Phosphatidylcholine is synthesized almost exclusively through the CDP-choline pathway in essentially all mammalian cells. Phosphatidylethanolamine is synthesized through either the CDP-ethanolamine pathway or by the decarboxylation of phosphatidylserine, with the contribution of each pathway being cell type dependent. Two human genes, CEPT1 and CPT1, code for the total compliment of activities that directly synthesize phosphatidylcholine and phosphatidylethanolamine through the CDP-alcohol pathways. CEPT1 transfers a phosphobase from either CDP-choline or CDP-ethanolamine to diacylglycerol to synthesize both phosphatidylcholine and phosphatidylethanolamine, whereas CPT1 synthesizes phosphatidylcholine exclusively. We show through immunofluorescence that brefeldin A treatment relocalizes CPT1, but not CEPT1, implying CPT1 is found in the Golgi. A combination of coimmunofluorescence and subcellular fractionation experiments with various endoplasmic reticulum, Golgi, and nuclear markers confirmed that CPT1 was found in the Golgi and CEPT1 was found in both the endoplasmic reticulum and nuclear membranes. The rate-limiting step for phosphatidylcholine synthesis is catalyzed by the amphitropic CTP:phosphocholine cytidylyltransferase alpha, which is found in the nucleus in most cell types. CTP:phosphocholine cytidylyltransferase alpha is found immediately upstream cholinephosphotransferase, and it translocates from a soluble nuclear location to the nuclear membrane in response to activators of the CDP-choline pathway. Thus, substrate channeling of the CDP-choline produced by CTP:phosphocholine cytidylyltransferase alpha to nuclear located CEPT1 is the mechanism by which upregulation of the CDP-choline pathway increases de novo phosphatidylcholine biosynthesis. In addition, a series of CEPT1 site-directed mutants was generated that allowed for the assignment of specific amino acid residues as structural requirements that directly alter either phospholipid head group or fatty acyl composition. This pinpointed glycine 156 within the catalytic motif as being responsible for the dual CDP-alcohol specificity of CEPT1, whereas mutations within helix 214-228 allowed for the orientation of transmembrane helices surrounding the catalytic site to be definitively positioned.

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Biosynthesis of Phosphatidylcholine from a Phosphocholine Precursor Pool Derived from the Late Endosomal/Lysosomal Degradation of Sphingomyelin

Cited by 15 publications

References 30 publications

Phosphatidylcholine and the CDP–choline cycle

Phosphatidylcholine and the CDP–choline cycle

KDM2B regulates choline kinase expression and neuronal differentiation of neuroblastoma cells

The Major Sites of Cellular Phospholipid Synthesis and Molecular Determinants of Fatty Acid and Lipid Head Group Specificity

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