Download phospholipids

COMPLEX LIPID METABOLISM
Phospholipids are:
– major constituents of all cell membranes
PHOSPHOLIPIDS
– components of bile
– anchor some proteins in membranes
– signal mediators
– components of lung surfactant
– components of lipoproteins
Properties of phospholipids
• Phospholipids are amphipathic molecules
• Head group = alcohol attached via phosphodiester
linkage to either:
– diacylglycerol (glycerophospholipid) or
PHOSPHOLIPIDS
– sphingosine (sphingophospholipid = sphingomyelin).
Cellular membranes are composed of
phospholipids and sphingolipids
• Glycerophospholipids and sphingolipids spontaneously selfassociate in water to form bilayer vesicles (i.e., closed
membranes)
PHOSPHOLIPIDS
• Bilayers are permeability barriers that enclose cells and cell
organelles, and “dissolve” intrinsic membrane proteins
Types of phospholipids
PHOSPHOLIPIDS
• The simplest glycerophospholipid is
phosphatidic acid (PA)
• It consists of glycerol, phosphate, and 2 fatty
acyl chains in ester linkages
Types of phospholipids
PHOSPHOLIPIDS
Other glycerophospholipids
derived from PA
include:
PHOSPHOLIPIDS
Cardiolipin is found in mitochondrial membranes
Phospholipids are distributed asymmetrically
in the plasma membrane
Outside
Inside
PHOSPHOLIPIDS
Plasmalogens
• Plasmalogens have
an ether-linked
hydrocarbon chain at
C-1 of glycerol, instead
of ester-linked fatty
acid
PHOSPHOLIPIDS
Plasmalogens
• Platelet-activating
factor (PAF) is a
plasmalogen (a
phosphatidalcholine)
with an acetyl group
at C-2 of glycerol
• It has potent
physiologic actions
(platelet activation;
inflammatory
responses;
bronchoconstriction)
Sphingolipids
PHOSPHOLIPIDS
• Sphingomyelin
contains sphingosine
with a long-chain fatty
acid attached in amide
linkage ( = ceramide)
• Ceramide plus a
phosphocholine group
constitutes a
sphingomyelin
• Ceramide is also the
core component of
glycosphingolipids
Sphingomyelin
• Sphingomyelin is present in plasma
membranes and in lipoproteins
PHOSPHOLIPIDS
• It is very abundant in myelin
• Sphingomyelin is abundant in
specialized plasma membrane
microdomains called lipid rafts
Lipid rafts
• Lipid rafts are specialized microdomains in the plasma
membrane that are rich in sphingomyelin and cholesterol
• GPI-linked proteins accumulate in lipid rafts
• Lipid rafts appear to function in signaling
PHOSPHOLIPIDS
Phospholipid synthesis
• Recall synthesis of PA as an
intermediate of TG synthesis
• It involves glycerol-P and two
fatty acyl CoA molecules
Phospholipid synthesis
• Glycerophospholipid synthesis involves activated
intermediates:
– CDP-alcohol + diacylglycerol or
– CDP-diacylglycerol + alcohol
PHOSPHOLIPIDS
• Synthesis occurs in the ER of almost all cells
Synthesis of PC
• Choline can be made from ethanolamine by transfer
of 3 methyl groups from S-adenosyl-methionine
PHOSPHOLIPIDS
• Choline is an essential nutrient
• De novo synthesis of PC from PS involves a
decarboxylation to give PE followed by three
methylation steps
Synthesis of PS & PI
• PS is made by a base exchange reaction:
PHOSPHOLIPIDS
PE + serine
PS + ethanolamine
• PI is synthesized from CDP-diacylglycerol and
myoinositol
• PI often has arachidonate in the C-2 glycerol position
Roles of phosphatidylinositol - I
PHOSPHOLIPIDS
• PI can provide arachidonate for
eicosanoid synthesis
Roles of phosphatidylinositol - II
PHOSPHOLIPIDS
• Phosphatidylinositol 4,5-bisphosphate (PIP2) participates in
hormonal signal transduction via activated phospholipase C
formation of inositol-P3 and diacylglycerol, followed by
mobilization of Ca+2 and activation of protein kinase C
Roles of phosphatidylinositol - III
• PI anchors some enzymes to the plasma membrane through a
glycan chain
PHOSPHOLIPIDS
• Examples include alkaline phosphatase and acetylcholine
esterase
Synthesis of sphingomyelin
• Sphingomyelin is made from:
PHOSPHOLIPIDS
– palmitoyl CoA + serine
sphingosine
– sphingosine + FA CoA
ceramide
– ceramide + CDP-choline
sphingomyelin
• FA are commonly 18:0, 24:0, and 24:1
(15)
Phospholipid degradation
• Glycerophospholipid degradation occurs by phospholipases present
in tissues (membrane bound or free), pancreatic juice, and venoms
PHOSPHOLIPIDS
• Phospholipases are specific for ester bonds in the glycerophospholipids: phospholipases A1, A2, C, and D
Phospholipases
PHOSPHOLIPIDS
• Phospholipases A1 and A2 are also
important in the remodeling of phospholipids
• FA CoA is then used in reesterification, e.g.,
to form the dipalmitoylphosphatidylcholine
found in lung surfactant or arachidonic acid in
PI
Sphingomyelin degradation
PHOSPHOLIPIDS
• Sphingomyelin is degraded
in lysosomes by
sphingomyelinase to give
ceramide,
• and ceramidase to give
sphingosine
• Niemann-Pick disease is
due to sphingomyelinase
deficiency
Glycolipids
• Glycolipids are derivatives of ceramides and sphingosine with
carbohydrate directly attached to ceramide
• In contrast to sphingomyelin they do not have a phosphocholine
group
GLYCOLIPIDS
• Glycolipids are essential components of cell plasma membranes
(outer leaflet), but are most abundant in nervous tissues
Outside
Inside
Roles of glycolipids
• Glycolipids have important roles in cell
interactions, growth, and development
GLYCOLIPIDS
• They are very antigenic (e.g., blood
group antigens);
• act as surface receptors for some toxins
and viruses;
• and undergo major changes during cell
transformation
Glycolipid structure — cerebrosides
• The carbohydrate component is linked by an Oglycosidic bond to ceramide
GLYCOLIPIDS
• Cerebrosides contain a single sugar (Glu or Gal) or
few sugars; they are abundant in brain and myelin
Glycolipid structure — gangliosides
• Gangliosides are acidic glycosphingolipids
• They contain oligosaccharides with terminal, charged
N-acetyl neuraminic acids (NANA)
GLYCOLIPIDS
• Depending on the number of NANA sugars,
gangliosides are designated M, D, T, Q (e.g., GM)
Ganglioside GM2
Glycolipid synthesis
• Synthesis of glycosphingolipids takes place in the
ER and Golgi by the sequential addition of sugars by
specific glycosyltransferases
• The sugars are activated: UDP-Glu, UDP-Gal, CMPNANA
GLYCOLIPIDS
• Sulfate groups are added last by a sulfotransferase
using PAPS (3'-phosphoadenosine-5'-phosphosulfate)
Glycolipid degradation
GLYCOLIPIDS
• Degradation of glycosphingolipids occurs
in lysosomes after endocytosis of
membrane portions
• A series of acid hydrolases participate in
the degradation
• Degradation is sequential in the order:
last on, first off
Glycolipid degradation
GLYCOLIPIDS
• Sphingolipidoses result from
deficiencies of specific degradative
enzymes
• They are diagnosed by accumulation of
specific sphingolipid, enzyme activity
measurements, and histologic
examination of affected tissue
GLYCOLIPIDS
Some
sphingolipidoses
GLYCOLIPIDS
Fabrazyme® = α-galactosidase A
Eicosanoids
• Eicosanoids are specialized FA
EICOSANOIDS
• They include prostaglandins (PG),
thromboxanes (TX), and leukotrienes (LT)
• Eicosanoids have strong hormone-like actions
in the tissues where they are produced
• Eicosanoids are not stored and are very
unstable
Eicosanoid synthesis
• Dietary linoleic acid is the precursor. It is elongated and further
desaturated to 20-carbon, 3, 4, or 5 double bond FAs
• Arachidonate, 20:4 (5, 8, 11, 14), is the precursor of many
eicosanoids
• Arachidonate is normally part of membrane phospholipids
(especially phosphatidylinositol).
EICOSANOIDS
• Arachidonate is released by a specialized phospholipase A2
Synthesis of prostaglandins from
arachidonate
EICOSANOIDS
• The free arachidonic acid is
oxidized and cyclized in the ER
by endoperoxide synthase
( = PGH2 synthase)
• This enzyme has two activities
– cyclooxygenase (COX) and
peroxidase
• Initially yields PGH2
• Subsequent steps lead to
thromboxane A2 and various
prostaglandins
EICOSANOIDS
Synthesis of leukotrienes from arachidonate
• Leukotrienes are
produced from
arachidonic acid via
a different enzyme:
lipoxygenase
EICOSANOIDS
Biological actions of eicosanoids
EICOSANOIDS
• Biologic actions of eicosanoids are
diverse in various organs:
– vasodilation, constriction, platelet
aggregation, inhibition of platelet
aggregation, contraction of smooth muscle,
chemotaxis of leukocytes, release of
lysosomal enzymes
• Excess production symptoms: pain,
inflammation, fever, nausea, vomiting
EICOSANOIDS
Some major polyunsaturated fatty acids
Name
Linoleate
Structure
18:2(9,12)
Type
ω-6
Significance
Essential FA
Linolenate
18:3(9,12,15)
ω-3
Essential FA
Arachidonate
20:4(5,8,11,14) ω-6
Prostaglandin
precursor
Metabolism of linoleate versus linolenate into
polyunsaturated fatty acids (PUFAs):
EICOSANOIDS
Linoleate (18:2) (ω-6)
arachidonate (AA) (20:4) (ω-6)
Linolenate (18:3)(ω-3)
eicosapentanoic acid (EPA) (20:5) (ω-3)
and
docosahexanoic acid (DHA) (22:6) (ω-3)
Omega-3 fatty acids
EICOSANOIDS
• EPA & DHA are precursors for different
eicosanoids than arachidonate
• When we were evolving, dietary ratio of
ω-6 FA (linoleate) to ω-3 FA (linolenate)
was about 1:1 to 2:1
• Currently it is about 10:1 to 20:1 in
Western diets
• Fish oils have high content of ω-3 FA
Inhibitors of prostaglandin synthesis
• Corticosteroids (e.g., cortisol) inhibit at the level
of phospholipase A2
• Antiinflammatory drugs (NSAIDS) like
indomethacin & ibuprofen reversibly inhibit COX
EICOSANOIDS
• Aspirin irreversibly inactivates COX
Cyclooxygenase
EICOSANOIDS
• There are at least two isozymes of PGH2 Synthase
(COX-1 and COX-2)
• COX-1 is constitutively expressed at low levels in
many cell types
• Specifically, COX-1 is known to be essential for
maintaining the integrity of the gastrointestinal
epithelium.
Cyclooxygenase
• COX-2 expression is stimulated by growth factors,
cytokines, and endotoxin
EICOSANOIDS
• COX-2 levels increase in inflammatory disease states
such as arthritis and cancer
• Up-regulation of COX-2 is responsible for the
increased formation of prostaglandins associated with
inflammation
Next generation NSAIDs
• Older NSAIDs inhibit both inhibit both COX-1 &
COX-2:
– acetylsalicylate (Aspirin®, Anacin®, etc.)
EICOSANOIDS
– ibuprofen (Motrin IB®, Advil®, etc.)
• Newer generation drugs are specific COX-2
inhibitors:
– Celebrex®
– Vioxx®