Cytidine Diphosphate Diacylglycerol

Nucleotides are the basic building blocks of DNA and RNA, and they are required for many aspects of intermediary metabolism. They consist of three elements – a heterocyclic nitrogenous base derived from a purine (adenine and guanine) or pyrimidine (uracil, thymine and cytosine), a pentose (ribose or deoxyribose) and a molecule of phosphoric acid. Cytidine, for example, consists of cytosine attached to a ribofuranose ring via a β-N1-glycosidic bond. From the standpoint of lipid metabolism, one of the most important of the nucleotide metabolites is cytidine 5’-phosphoric acid, which is a key component of the phospholipid cytidine diphosphate diacylglycerol (CDP-diacylglycerol), a liponucleotide. This lipid was first found in eukaryotic organisms, but it is now known to be ubiquitous and plays an important role in the biochemistry of prokaryotes also.


Cytidine diphosphate diacylglycerol per se is rarely noticed in analyses of lipid compositions of tissues, as it is present is such small amounts, perhaps only 0.05% or so of the total phospholipids. Indeed, the composition of the fatty acids or molecular species in this lipid in nature (as opposed to experiments in vitro) has hardly ever been reported. Data for ox brain are listed in Table 1. In this instance, the composition is closer to that of phosphatidylinositol than of any other lipid.

Fatty acids

Table 1. Fatty acid compositions of positions sn-1 and sn-2 of cytidine diphosphate diacylglycerol of bovine brain
sn-1 15 78 6        
sn-2 4 10 35 3 45 3 1
Thompson, W. and MacDonald, G. Eur. J. Biochem., 65, 107-111 (1976).


Biosynthesis of CDP-diacylglycerol (CDP-DG) involves condensation of phosphatidic acid (PA) and cytidine triphosphate, with elimination of pyrophosphate, catalysed by an enzyme CDP-diacylglycerol synthase. Two different isoforms of the enzyme with differing tissue distributions have been found in animals, of which one has been has been designated the ‘housekeeping enzyme’ (CDS2) while the other is specialized for signal transduction (CDS1). A single enzyme is present in yeast, but multiple forms are found in plants such as Arabidopsis.

Biosynthesis of cytidine diphosphate diacylglycerol

The resulting CDP-diacylglycerol is utilized immediately for the synthesis of phosphatidylglycerol (PG), and thence cardiolipin (CL), and of phosphatidylinositol (PI) (see the appropriate web pages for these lipids for further discussion). Turnover is very rapid and the pool of CDP-diacylglycrerol is always much smaller than that of the precursor phosphatidic acid. CDP-diacylglycerol for phosphatidylinositol synthesis is produced in the endoplasmic reticulum, whereas that for phosphatidylglycerol production is produced in the mitochondria. However, some transfer of the liponucleotide between organelles may be possible. In animals, phosphatidylcholine (PC), phosphatidyl ethanolamine (PE) and triacylglycerols (TG) are synthesised via the Kennedy pathway mainly with diacylglycerol as a key intermediate. CDP-diacylglycerol for phosphatidylinositol synthesis is produced in the endoplasmic reticulum, whereas that for phosphatidylglycerol production is synthesised in the mitochondria, by different isoforms of the CDP-diacylglycerol synthase.

CDP-DG and Kennedy pathways of lipid synthesisIn fungi and prokaryotes, CDP-diacylglycerol is also the precursor for phosphatidylserine. In yeast such as Saccharomyces cerevisiae, this can be a major route to phosphatidylethanolamine, which can in turn be converted via mono- and dimethylphosphatidylethanolamines (PME and PDE) to phosphatidylcholine, although the Kennedy pathway also functions. In the bacterium Escherichia coli, CDP-diacylglycerols with both ribose and deoxyribose as the sugar component are produced, and both are utilized as substrates by phosphatidylserine and phosphatidylglycerophosphate synthases.

It is not known whether the final fatty acid composition of the lipid is a result of the specificity of the CDP-diacylglycerol synthase in selecting particular molecular species of phosphatidic acid, or whether remodelling occurs via deacylation/re-acylation reactions.

Most studies of CDP-diacylglycerol have been concerned with its function as an intermediate in the biosynthesis of other lipids, and as such it is the first step in a pathway that is very different from that for phosphatidylcholine and phosphatidylethanolamine. These also require nucleotides for their biosynthesis, but do not form liponucleotides as intermediates. Similarly, another nucleotide uridine 5-diphosphate(UDP)-hexose (where hexose = glucose, galactose, etc.) is required for the formation of glycolipids, including both the glycosyldiacylglycerols and sphingoglycolipids.

The extent of the biological functions of CDP-diacylglycerol, other than as an intermediate in phospholipid biosynthesis, is only partly understood. However, CDP-diacylglycerol synthase is also a regulator of phospholipid metabolism, as it is believed to be the rate-limiting enzyme in phosphatidylinositol biosynthesis. In consequence, it has a role in the regulation of lipid-dependent signal transduction processes. Anticancer activities in vitro have been reported.

Because it is such a minor component of tissues, isolation of cytidine diphosphate diacylglycerol appears to be a tedious task, involving ion-exchange column chromatography and thin-layer chromatography. The pyrophosphate bond is relatively labile and is very susceptible to alkaline hydrolysis. At natural tissue levels, even the more modern mass spectrometric methods do not appear to be sufficiently sensitive.


Recommended Reading

  • Christie, W.W. and Han, X. Lipid Analysis - Isolation, Separation, Identification and Lipidomic Analysis (4th edition), 446 pages (Oily Press, Woodhead Publishing and now Elsevier) (2010).
  • Dowhan, W. CDP-diacylglycerol synthase of microorganisms. Biochim. Biophys. Acta, 1348, 157-165 (1997) (DOI: 10.1016/S0005-2760(97)00111-2).
  • Heacock, A.M. and Agranoff, B.W. CDP-diacylglycerol synthase from mammalian tissues. Biochim. Biophys. Acta, 1348, 166-172 (1997) (DOI: 10.1016/S0005-2760(97)00096-9).
  • Vance, D.E. and Vance, J. (editors) Biochemistry of Lipids, Lipoproteins and Membranes. 4th Edition. (Elsevier, Amsterdam) (2002) – several chapters.


Updated June 12, 2014