Download Chem*3560 Lecture 23: Phospholipid Biosynthesis

Chem*3560
Lecture 23:
Phospholipid Biosynthesis
Fats and phospholipids share the same initial synthesis pathway
Fats and phospholipids both contain fatty acids linked by ester bonds to a glycerol backbone , and
are described as glycerolipids . The synthesis pathway starts by reducing dihydroxyacetone phosphate
to glycerol phosphate, with NADH as the reductant (Lehninger p789).
NAD+ dependent glycerol phosphate dehydrogenase
dihydroxyacetone phosphate + NADH + H+ → L-glycerol-3-phosphate + NAD +
(Compare this with FAD dependent glycerol phosphate dehydrogenase, which runs in the opposite
direction because FAD is a stronger oxidant than NAD+)
FAD dependent glycerol phosphate dehydrogenase
L-glycerol-3-phosphate + FAD → dihydroxyacetone phosphate + FADH2
Alternatively, existing glycerol molecules may be phosphorylated by glycerol kinase.
glycerol kinase
glycerol + ATP → L-glycerol-3-phosphate + ADP
Note that glycerol is symmetrical, but becomes chiral after the phosphate is added at one end.
This is followed by two successive additions of acyl ester. Fatty acid (typically 16-18 C atoms) is first
converted to the active CoA thioester by acyl CoA synthetase:
acyl CoA synthetase
stearate (18:0) + HSCoA + ATP → stearoyl-CoA + 5'-AMP + PPi
pyrophosphatase ↓
2 Pi
PPi is the abbreviation for HP2 O7 3– , inorganic pyrophosphate. Pyrophosphatase helps provide driving
force for the synthetase reaction by immediately breaking down PPi and keeping its cellular
concentration very low.
When ATP is broken down to 5'-AMP, this is equivalent in energy terms to 2 × ATP to ADP.
Acyl-CoA is then used to donate acyl ester groups to the glycerol backbone:
acyltransferase
L-glycerol-3-phosphate + acyl-CoA → 1-acylglycerol-3-phosphate + HSCoA
acyltransferase
1-acylglycerol-3-phosphate + stearoyl-CoA → 1,2-diacylglycerol-3-phosphate + HSCoA
1. glycerol phosphate
dehydrogenase
2. glycerol kinase
3. acyl transferase
The last product, 1,2-diacylglycerol-3-phosphate, is also known as phosphatidic acid, and its
phospholipid derivatives are phosphatidyl-X. Phospholipids also tend to have a saturated fatty acid in
position 1 and an unsaturated fatty acid in position 2.
The fat synthesis pathway branches here
Phosphate is first
removed by
phosphatidic acid
phosphatase, then acyl
transferase can add the
third acyl ester group to
make triacylglycerol
or fat (Lehninger p.
790).
Phospholipids are derived by adding a head group to phosphatidic acid
Phospholipids are major components of membrane bilayers, so are structural components of the cell,
whereas triacylglycerols are stored as the bodies main energy reserve. Phosphatidic acid itself tends to
disrupt bilayer structure, and must be modified by adding a polar headgroup. The head group is a
hydroxyl or alcohol compound that forms an ester bond with the phosphate of phospahtidic acid. The
makes the product a phosphodiester, phosphate with two ester groups.
Phospholipid precursors are activated by forming a cytidine diphosphate
derivative
The activation process and activated product is exactly analogous to the formation of UDP-glucose as
an activated glucose donor. The
substrate phosphate ester
displaces pyrophosphate (PPi).
PPi concentration is kept very
low because it is immediately
broken down by
pyrophosphatase, and this low
product concentration provides
the driving force for the reaction.
The enzyme CTP:phosphatidate cytidylyl transferase is systematically named based on the idea that
the cytidylyl radical (radical of 5'-CMP) is transferred from CTP to phosphatidic acid.
The product, CDP-diacylglycerol contains a high energy bond between the two phosphates, so can act
as a donor of diacylglycerol (bond breaks between glycerol and phosphate) or as a donor of the
phosphatidyl radical (bond breaks between the phosphates) (Lehninger p. 792-3).
Head groups: phosphatidyl serine and phosphatidyl ethanolamine
Microorganisms
use the head group
hydroxyl compound
to displace CMP and
then link up to the
phosphatidyl radical.
The amino acid
serine , which has a
hydroxyl group side chain provides the head group for the
negative phospholipid, phosphatidyl serine .
Phosphatidyl serine can then be decarboxylated to produce
the important neutral phospholipid, phosphatidyl
ethanolamine.
In animals, phosphatidyl ethanolamine and phosphatidyl choline are made by a different strategy, in
which ethanolamine and choline are activated as CDP ethanolamine and CDP choline (Lehninger
p.794-5).
Diacylglycerol then displaces CMP to bond to
the phosphate attached to the headgroup, as
shown for the synthesis of phosphatidyl
choline, a major animal phospholipid.
The strategy used in animals is optimized for
what is called salvage synthesis, in which
existing molecules of ethanolamine, choline and
diacylglyerol are reused.
The bacterial strategy is better for de novo
synthesis, in which molecules are created from
simple starting compounds such as aminoacids or dihydroxyacetone.
Animals produce phosphatidyl serine by a process called headgroup exchange:
phosphatidyl ethanolamine serine transferase
Phosphatidyl ethanolamine + serine
→
phosphatidyl serine + ethanolamine
phosphatidyl serine
CO2
decarboxylase
Decarboxylation of phosphatidyl serine produces
new molecules of ethanolamine.
phosphatidyl ethanolamine
New molecules of choline are made on the phospholipid structure of phophatidyl ethanolamine.
The methyl donor is a compound of methionine and adenosine called S-adenosyl methionine or SAM
for short, leaving behind S-adenosylhomocysteine, SAHC (Lehninger p.795).
This is an expensive process, because it consumes a three molecules of methionine, which animals can't
synthesize, and can only obtain in the diet. The dietary content of methionine is quite low, so animals
conserve choline as much as possible.