CYTIDINE DIPHOSPHATE DIACYLGLYCEROL - Lipid Library

Cytidine diphosphate diacylglycerol: structure, occurrence and biochemistry
CYTIDINE DIPHOSPHATE
DIACYLGLYCEROL
STRUCTURE, OCCURRENCE AND BIOCHEMISTRY
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 (CDPdiacylglycerol),
a liponucleotide.
a
R''COO
CH 2
CH
CH 2
OOCR'
cytidine diphosphate
diacylglycerol
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.
Table 1. Fatty acid compositions of positions sn-1 and sn-2 of cytidine diphosphate
diacylglycerol of bovine brain.
Fatty Acids
16:0 18:0 18:1 18:2 20:4 22:3 22:6
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).
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.
Biosynthesis of CDP-diacylglycerol (CDP-DG) involves condensation of phosphatidic acid (PA) and
cytidine triphosphate, with elimination of pyrophosphate, catalysed by an enzyme CDPdiacylglycerol
synthase. Two different isoforms of the enzyme with differing tissue distributions
W.W. Christie © lipidlibrary.aocs.org
O
O
O P O P O CH2 _ _
O O O
O
N
OH OH
NH
O
a
1

Cytidine diphosphate diacylglycerol: structure, occurrence and biochemistry
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.
a
R''COO
CH 2
CH
OOCR'
O
+ CTP
R''COO
CH2 O P OH
_
O
+
X
CH2 O P O
OH
P O
OH
CH2 O
phosphatidic acid 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). 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 produced in the
mitochondria, by different isoforms of the CDP-diacylglycerol synthase.
In fungi and prokaryotes, CDP-diacylglycerol is also the
precursor for phosphatidylserine (PS). 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 phosphatidylglycero-phosphate
synthases.
It is not known whether the final fatty acid composition of
the lipid is a result of the specificity of the CDPdiacylglycerol
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
PC
CDP-cho
a
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
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CH 2
CH
OOCR'
a
O
O
CDP-DG
PI
PG
PS
CL
CDP-DG
pathway
PE
PME
PDE
O
N
OH OH
PA
CDP-Etn
NH
DG
O
a
Kennedy
pathway
TG
2

Cytidine diphosphate diacylglycerol: structure, occurrence and biochemistry
(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. Anti-cancer 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
o Dowhan, W. CDP-diacylglycerol synthase of microorganisms. Biochim. Biophys. Acta, 1348, 157-165
(1997).
o Heacock, A.M. and Agranoff, B.W. CDP-diacylglycerol synthase from mammalian tissues. Biochim.
Biophys. Acta, 1348, 166-172 (1997).
o Vance, D.E. and Vance, J. (editors) Biochemistry of Lipids, Lipoproteins and Membranes. 4 th Edition.
(Elsevier, Amsterdam) (2002) – several chapters.
William W. Christie
Scottish Crop Research Institute (Mylnefield Lipid Analysis), Invergowrie, Dundee
(DD2 5DA), Scotland
Last updated: February 9 th , 2011
W.W. Christie © lipidlibrary.aocs.org
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