Transcriptional regulation of phosphatidylcholine biosynthesis

Sugimoto, Hiroyuki; Banchio, Claudia; Vance, Dennis E.

doi:10.1016/j.plipres.2008.01.002

Cited by 55 publications

(48 citation statements)

References 186 publications

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“…Transcriptional regulation of CCT is linked to cell cycle, cell growth, and differentiation, and CCT transcription is stimulated by ammonium ions and glycerol, the latter of which interlinks glycolysis with the Kennedy pathway (70). The regulation of CCT and its various isoforms has been extensively studied, and the reader is directed to the following reviews for further detailed information (35,68,71,72).…”

Section: The Ctp:phosphocholine Cytidylyltransferasementioning

confidence: 99%

The Kennedy pathway—De novo synthesis of phosphatidylethanolamine and phosphatidylcholine

2010

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SummaryThe glycerophospholipids phosphatidylcholine (PC) and phosphatidylethanolamine (PE) account for greater than 50% of the total phospholipid species in eukaryotic membranes and thus play major roles in the structure and function of those membranes. In most eukaryotic cells, PC and PE are synthesized by an aminoalcoholphosphotransferase reaction, which uses sn-1,2-diradylglycerol and either CDP-choline or CDP-ethanolamine, respectively. This is the last step in a biosynthetic pathway known as the Kennedy pathway, so named after Eugene Kennedy who elucidated it over 50 years ago. This review will cover various aspects of the Kennedy pathway including: each of the biosynthetic steps, the functions and roles of the phospholipid products PC and PE, and how the Kennedy pathway has the potential of being a chemotherapeutic target against cancer and various infectious diseases. IUBMBIUBMB Life, 62(6): [414][415][416][417][418][419][420][421][422][423][424][425][426][427][428] 2010

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Section: The Ctp:phosphocholine Cytidylyltransferasementioning

confidence: 99%

The Kennedy pathway—De novo synthesis of phosphatidylethanolamine and phosphatidylcholine

2010

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“…The transcriptional regulation of CTa expression has been investigated in detail and recently reviewed (36). CTa expression is largely governed by Sp1, Sp3, Rb, TEF4, Ets-1, and E2F, which enhance the expression of CT, and by Net, a factor that represses CTa expression.…”

Section: Ctp:phosphocholine Cytidylyltransferasementioning

confidence: 99%

“…Key transcription factors involved in cholesterol or fatty acid metabolism (sterol-regulatory element binding proteins, liver X receptors, peroxisome proliferator-activated receptors) do not appear to play a major role in the transcriptional regulation of CTa. Rather than being linked to cholesterol or energy metabolism, the regulation of CTa at the level of gene expression is linked to the cell cycle, cell growth, and differentiation (36).…”

Section: Ctp:phosphocholine Cytidylyltransferasementioning

confidence: 99%

Thematic Review Series: Glycerolipids. Phosphatidylcholine and choline homeostasis

Vance

2008

Journal of Lipid Research

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515

240

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Phosphatidylcholine (PC) is made in mammalian cells from choline via the CDP-choline pathway. Animals obtain choline primarily from the diet or from the conversion of phosphatidylethanolamine (PE) to PC followed by catabolism to choline. The main fate of choline is the synthesis of PC. In addition, choline is oxidized to betaine in kidney and liver and converted to acetylcholine in the nervous system. Mice that lack choline kinase (CK) a die during embryogenesis, whereas mice that lack CKb unexpectedly develop muscular dystrophy. Mice that lack CTP:phosphocholine cytidylyltransferase (CT) a also die during early embryogenesis, whereas mice that lack CTb exhibit gonadal dysfunction. The cytidylyltransferase b isoform also plays a role in the branching of axons of neurons. An alternative PC biosynthetic pathway in the liver uses phosphatidylethanolamine N-methyltransferase to catalyze the formation of PC from PE. Mice that lack the methyltransferase survive but die from steatohepatitis and liver failure when placed on a choline-deficient diet. Hence, choline is an essential nutrient. PC biosynthesis is required for normal very low density lipoprotein secretion from hepatocytes. Recent studies indicate that choline is recycled in the liver and redistributed from kidney, lung, and intestine to liver and brain when choline supply is attenuated.-Li, Z., and D. E. Vance.Phosphatidylcholine and choline homeostasis.

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“…This reaction is catalyzed by CTP:phosphocholine cytidylyltransferase (CCT 4 ; EC 2.7.7.15), an enzyme subject to many layers of regulation (1)(2)(3)(4). The ubiquitous and best studied isoform of mammalian CCT (CCT␣, 367 residues) has been described as having four domains (Fig.…”

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confidence: 99%

Crystal Structure of a Mammalian CTP: Phosphocholine Cytidylyltransferase Catalytic Domain Reveals Novel Active Site Residues within a Highly Conserved Nucleotidyltransferase Fold

Lee

Johnson

Ding

et al. 2009

Journal of Biological Chemistry

104

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CTP:phosphocholine cytidylyltransferase (CCT) is the key regulatory enzyme in the synthesis of phosphatidylcholine, the most abundant phospholipid in eukaryotic cell membranes. The CCT-catalyzed transfer of a cytidylyl group from CTP to phosphocholine to form CDP-choline is regulated by a membrane lipid-dependent mechanism imparted by its C-terminal membrane binding domain. We present the first analysis of a crystal structure of a eukaryotic CCT. A deletion construct of rat CCT␣ spanning residues 1-236 (CCT236) lacks the regulatory domain and as a result displays constitutive activity. The 2.2-Å structure reveals a CCT236 homodimer in complex with the reaction product, CDP-choline. Each chain is composed of a complete catalytic domain with an intimately associated N-terminal extension, which together with the catalytic domain contributes to the dimer interface. Although the CCT236 structure reveals elements involved in binding cytidine that are conserved with other members of the cytidylyltransferase superfamily, it also features nonconserved active site residues, His-168 and Tyr-173, that make key interactions with the ␤-phosphate of CDP-choline. Mutagenesis and kinetic analyses confirmed their role in phosphocholine binding and catalysis. These results demonstrate structural and mechanistic differences in a broadly conserved protein fold across the cytidylyltransferase family. Comparison of the CCT236 structure with those of other nucleotidyltransferases provides evidence for substrate-induced active site loop movements and a disorder-to-order transition of a loop element in the catalytic mechanism.A key rate-limiting step in the synthesis of phosphatidylcholine in animal cells is the formation of the headgroup donor, CDP-choline, by transfer of a cytidylyl group from CTP to phosphocholine. This reaction is catalyzed by CTP:phosphocholine cytidylyltransferase (CCT 4 ; EC 2.7.7.15), an enzyme subject to many layers of regulation (1-4). The ubiquitous and best studied isoform of mammalian CCT (CCT␣, 367 residues) has been described as having four domains (Fig. 1A). An N-terminal domain (ϳ75 residues) housing its nuclear localization signal (NLS) sequence is followed by an ϳ150-residue catalytic domain, an ϳ60-residue membrane binding domain (domain M), and an unstructured phosphorylated tail (ϳ50 residues) (2, 4). CCT functions as a homodimer (5).CCT activation requires transformation of the enzyme from a soluble form to a membrane lipid-bound form. When the full-length soluble CCT interacts with anionic membrane surfaces, domain M transforms from a mixture of structural elements into an amphipathic ␣-helix (6 -8). Domain M appears to act as an autoinhibitory device, whose interaction with phosphatidylcholine-deficient membranes releases an inhibitory constraint at the active site to enhance k cat by 2 orders of magnitude (9). The primary evidence for this model is the constitutive activity of a construct lacking domain M, CCT236 (9).To elucidate the mechanism whereby membrane binding activates this important re...

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Transcriptional regulation of phosphatidylcholine biosynthesis

Cited by 55 publications

References 186 publications

The Kennedy pathway—De novo synthesis of phosphatidylethanolamine and phosphatidylcholine

The Kennedy pathway—De novo synthesis of phosphatidylethanolamine and phosphatidylcholine

Thematic Review Series: Glycerolipids. Phosphatidylcholine and choline homeostasis

Crystal Structure of a Mammalian CTP: Phosphocholine Cytidylyltransferase Catalytic Domain Reveals Novel Active Site Residues within a Highly Conserved Nucleotidyltransferase Fold

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