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Vol. 13, Issue 9, 3148-3161, September 2002
The Atlantic Research Centre, Departments of Pediatrics and
Biochemistry and Molecular Biology, IWK Health Centre, Dalhousie
University, Halifax, Nova Scotia, B3H 4H7 Canada
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
, which is found in the nucleus in most cell types.
CTP:phosphocholine cytidylyltransferase 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 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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