1. Complex Lipid Metabolism

2. Phospholipids (PL) or Sphingosine Sphingolipids
PL are composed of an alcohol (ethanolamine, serine, choline, inositol) attached by a phosphodiester bridge to:
Diacylglycerol Glycerophospholipids
or Sphingosine Sphingolipids
Phospholipids are amphopathic in nature:
Hydrophilic head: phosphate + alcohol (e.g. serine, choline)
Hydrophobic tail: fatty acids

4. Where are Phospholipids ?
Cell membrane PL
PL are the predominant lipids of cell membrane
Hydrophobic portion of PL:
is associated with the the nonpolar portion of the membrane constituents
(glycolipids, proteins & cholesterol)
Hydrophilic head of PL (polar):
Extends outward facing intracellular or extracellular aqueous environment
Non-membrane-bound PL
with certain functions in the body:
e.g Components of lung surfactant
Essential components of bile (solubilization of cholesterol)

5. Structure of Phospholipids
1- Glycerolphospholipids: with glycerol backbone
2- Sphingolipids (sphingomyelin):with sphingosine
backbone

6. Glycerophospholipids (phosphoglycerides)
Types:
1-Phosphatidic acid (PA)
diacylglycerol + phosphate group on the 3rd carbon (ONLY)
Phospatidic acid (PA) is the precursor of others
2-Phosphatidic acid (PA) derivatives:
are formed of phosphatidic acid & an alcohol (bound to P group)
Serine + PA phosphatidylserine (PS)
Ethanolamine + PA phosphatidylethanolamine (PE)
Choline + PA phosphatidylcholine (PC)
inositol + PA phosphatidylinositol (PI)
glycerol + PA phosphatidylglycerol (PG)

7. Cardiolpin (diphosphaidylglycerol)
synthesized from phosphatidyl glycerol
Structure:
2 PA bound through their P by 1 glycerol
(2 PA + 1 glycerol)
important component of
inner mitochondrial membrane
antigenic
it is recognized by antibodies
against Trponema pallidum
bactri (bacteria causing syphilis)

9. Plasmalogens (ether glycerolphospholipids)
Fatty acid in carbon 1 is replaced by an unsaturated alkyl
group attached by an ether linkage to glycerol molecule
Examples:
Phosphatidalethanolamine (abundant in nerve tissue)
Phosphatidalcholine (abundant in heart muscles)

10. Platelet-activating factor (PAF)
- Fatty acid at C1 is replaced by Saturated alkyl group
linked by an ether link to C1
- Acetyl residue (instead of fatty acid) at C2
PAF binds to surface receptors to induce
thrombotic & acute inflammation:
Activation of inflammatory cells
Mediates hypersenesitivity
Induce acute inflammatory reactions
Induces platelet aggragation
Induce neutrophils & alveoli to generate superoxide radicals

12. Synthesis of Phosphatidic Acid

13. Phosphatidic acid is the precursor of triacylglycerol
All cells except mature RBCs can synthesize phospholipids
Triacylglycerol (triglycetides) synthesis occurs
essentially only in:
liver
adipose tissue
lactating mammary glands
intestinal mucosal cells

14. Synthesis of Phosphatidic acid Derivatives

15. Phosphatidylethanolamine (PE) & Phosphatidylcholine (PC)
PE & PC are the most abundant PLs in most eukaryotes
Synthesis:
choline & ethanolamine
(from diet of from turnover of body PLs)
Choline or etyhanolamine are phosphorylated by kinases
conversion to CDP-choline or CDP-ethanolamine
diacylglycerol + CDP-choline (or CDP-ethanolamine)
PE or PC
Synthesis of choline is insufficient. So, reutilization of choline is important
Choline is essential dietary nutrient with adequate intake of 550 mg for
male & 420 mg for females

16. Synthesis of PC from phosphatidylserine (PS) in
the liver
When free choline levels are low
PS is decarboxylated to PE by PS decarboxylase
(requiring PLP, active form of vitamin B6)
PE is methylated (3 methyl droups) to PC by methyl donor
S-adenosylmethionine
Why PC is important in the liver:
The liver exports significant amounts of PC in
the bile
PC is a component of lipoproteins in blood

18. Role of Phosphatidylcholine (PC) in lung surfactant
Dipalmitoylphosphatidylcholine (DPPC) or Dipalmitoyllecithin
In DPPC, C 1 & 2 of glycerol are occupied by palmitate
DPPC is synthesized by granular pneumocytes
DPPC is the major lipid component of lung surfactant
Extracellular fluid layer lining the alveoli
Surfactant reduces the pressure needed to reinflate alveoli
So, it prevents alveolar collapse (atelectasis)

19. Respiratory Distress Syndrome (RDS)
occurs in preterm infants
associated with insufficient surfactant production
is a significant cause of neonatal death
Ratio of DPPC/sphingomyelin (L/S) in amniotic fluid
used to estimate lung maturity of newborn
a ratio of 2 or more is evident of maturity of lung
as it reflects major shift from sphingomyelin to DPPC synthesis
occurs in pnemcytes at about 32 weeks of gestation
Lung maturation can be accelerated
by giving glucocorticoids to mothers shortly before delivery
RDS in treated or prevented in newborns
by intratracheal instillation of surfactant (natural or synthetic)

20. RDS may occur in adults
when surfactant-producing pnemocytes are damaged (e.g. by
immunosuppressive medication or chemotheraputic drugs)

21. Phosphatidylinositol (PI)
Synthesized from inositol & CDP-diacylglycerol
PI contains stearic acid on carbon 1
arachidonic acid on carbon 2
So, it is the reservoir of arachidonic acid in membrane
(provides the substrate for prostaglandin synthesis)

22. Role of PI in signal transduction
PI bound to membranes is phosphorylated
to Phosphatidylinositol 4,5 bisphosphate (PIP2)
PIP2 is degraded by phospholipase C to:
Inositol 1,4,5- triphosphate (IP1,4,5) & diacylglycerol
Phospholipase C is activated by protein G (a subunit)
as a result of binding of hormone to its receptor on the cell
membrane

24. Sphingomyelin
sphingosine-based phospholipid
A long chain fatty acid is attached to sphingosine to form ceramide
Ceramide is bound to phosphorylcholine producing sphingomyelin.
(Ceramide is the precursor of sphingomyelin)
Sphingomyelin synthesis
begins by condensation of palmitoyl CoA & serine by decarboxylation (reaction requires active vitamin B6, PLP)

25. Sphingosine + Fatty Acid Ceramide
(Long Chain)
Phosphorylcholine
P-Choline
(from Phosphatidyl Choline)
Sphingomyelin

28. Sphingomyelin is a major lipid in nerve tissue membranes
1-Sphingomyelin of the myelin sheath contains
predominantly longer-chain fatty acids such as lgnoceric &
nervonic acid
Myelin sheath is a layered membranous structure that
insulates & protects neuronal fibres of CNS
2-Sphingomyelin of the grey matter of the brain
contains primarily stearic acid

29. Degradation of phosphoglycerides

30. Phospholipase activity is also available in:
1- toxins & venoms
2- several pathogenic bacteria
produce phosphlipases that dissolve cell membranes & allow the
spread of infection

31. Degradation of Sphingomyelin
P-Choline sphingomyelinase
(a lysosomal enzyme)
Ceramide
ceramidase
sphingosine FA

32. Niemann-Pick disease (type A & B)
Autosomal recessive less than 1:100,000
Deficiency in sphingomyelinase
Inability to degrade sphingomyelin
Type A: severe infantile (rare)
lipid is deposited in liver and spleen ---enlarged
Progressive neurodegeneration: as a result of
deposition of sphingomyelin in CNS
Death in early childhood
Type B: less severe
no damage (or little) damage to neural tissue
but, spleen, liver & lung & bone marrow are
affected
death in early adulthood

35. GLYCOLIPIDS Molecules that contain carbohydrates & lipids
are derivatives of CERAMIDE
(Sphingosine backbone + long chain Fatty Acid)
Ceramide + carbohydrate (mono- or oligosaccharide)
Glycolipids
N.B. ceramide + P-Choline sphingomyelin

36. Importance of Glycolipids
Essential components of all membranes of the body
but are found in greatest amounts in nerve tissue
They are located on the outer leaflet of plasma membrane
where they interact with the extracellular environment
Glycolipids are antigenic:
e.g identified as source of blood group antigens
Carbohydrate portion is the antigenic determinant
Glycolipids are cell surface receptors
e.g. for:
cholera, tetanus toxins
certain bacteria & viruses

39. Structure of glycolipids
Carbohydrate (monosaccharide or oligosaccharide) attached to lipid (ceramide) by an O-glycosidic bond (glycosphingolipids)
Type of glycolipid depends on number & type of carbohydrate:
1- Neutral glycosphingolipids (with no charge.i.e. no NANA,no sulfate)
A. ceramide monosaccharides (cerebrosides)
i. Galactocerebrosides : ceramide+ galactose
most common cerebroside in membranes
ii. Glucocerebrosides : ceramide + glucose
In brain & peripheral nervous tissue (high concentration in myelin sheath)
B. ceramide oligosaccharides (globosides)
attaching additional monosaccharides to glucocerebrosides

40. 2- Acidic glycolipid (with NANA or Sulfate)
Have negative charge at physiological pH provided by N-acetylneuraminic
acid (NANA) or sulfate groups
Gangliosides (with NANA)
ceramide oligosaccharides + one or more NANA
in ganglion cells of CNS
Sulfatides (with sulfate groups)
galactocerebroside (with galactose is sulfated)
in nerve cells & kidney

41. Glycolipids Neutral Acidic Ceramide monosaccharides (cerbrosides)
Ceramide oligosaccharides
(globosides)
Gangliosides
Ceramide
oligosaccharide
+ NANA
Sulfatides
galctocerebroside with sulfated galactose
Glucocerebroside Galactocerebroside

43. Synthesis of Glycospingolipids
Synthesis occurs in ER & Golgi
By specifig Glycosyl transferases
Sequential addition of glycosyl monomers to acceptor molecule (ceramide)
Added sugar is activated (e.g. UDP-gucose)

44. Degradation of Glycolipids
Glycolipids are internalized to lysosomes by endocytosis
Lysosomal enzymes cleave specific bonds in glycolipids
Degradation is a sequential process

46. Prostaglandins & Related compounds
EICOSANOIDS
(origin from polyunstaurated fatty acids with 20carbons)
Prostaglandins (PG)
Thromboxanes (TX)
Leukotrienes (LT)

47. Eicosanoids (derived from 20 C polyunsat. FA)
Potent compounds
Their action mediated by plasma & nuclear receptors
not stored in tisues
Have extremely short half-life (rapidly metabolized)
Differ from true hormones
in that
Elicit both physiologic & pathologic responses
Produced in very small amounts
In almost all tissues (not by a specialized glands)
Act locally (not transported in blood to distant sites)

48. Synthesis of PG & TX Sources of arachidonic acid
Diet or cell membrane PL
linoleic acid
(18 carbons, 2 double bonds)
elongation & desaturation
Arachidonic acid
(20 carbons, 4 double bonds)
Arachidonic acid is the immediate precursor of the of PG
Sources of arachidonic acid
1- Dietary linoleic acid
2- Phospholipids of cell membrane : by phospholipase A2

49. Synthesis of PGH2 PGH2 is converted to a variety of PGs & TXs
Arachidonic acid is subject to oxidative cyclization by prostaglandin endoperoxidase synthase
to yield PGH2
Prostaglandin endoperoxidase synthase has 2 catalytic activities:
1- COX (cycoloxygenase)
2- peroxidase
PGH2 is converted to a variety of PGs & TXs

50. COX-1 Peroxidase Linoleic acid In diet Arachidonic acid COX Peroxidase
PGH2
PG & TX

51. Isozymes of PG endoperoxidase synthase
COX-1
constitutively synthesis.
in most tissues
required to
maintain healthy gastric
tissue, renal homeostasis
& platelet aggregation (Physiological Role)
COX-2
inducible
in a limited number of cells
in response to inflammation
(substances from inflam.cells)
resulting in increased PG
synthesis causing pain,
heat, redness & swelling of
inflammation & fever in
infection
(Pathological Role)

52. Inhibition of PG synthesis
1- Steroidal anti-inflammatory agent
(as CORTISOL)
1- Cortisol Inhibits phospholipase A2 activity
So, the precursor arachidonic acid is not available
2- Cortisol inhibits COX-2 but not COX-1

53. So, prevent synthesis of PGH2 (anti inflammatory)
2- All non-steroidal anti-inflammatory agents
(as aspirin, indomethacin & phenylbutazone)
inhibits COX-2
So, prevent synthesis of PGH2 (anti inflammatory)
BUT they inhibit COX-1 also with subsequent:
damage to stomach & kidneys
impaired clotting of blood
(aspirin's toxicity)
3- Inhibitors of COX-2 (as celecoxib)
maintain the physiologic functions of COX-1
while having anti-inflammatory power (inh. of COX-2)

54. Role of PG in plateletet homeostasis
Thromboxane A2 (TXA2)
produced by activated platelets
promotes adherence & aggregation of platelets
So, promotes formation of blood clots (thrombotic)
Prostacyclin (PGI2)
produced by vascular endothelial cells
inhibits platelet aggregation
So, prevents formation blood clots (anti thrombotic)

55. Aspirin has antithrombogenic effect Basis of Low-dose aspirin therapy
In platelets
As aspirin inhibits TXA2 productionin platelets by irreversible inhibition of COX-1
as platelets can not synthesize more COX-1 (no nucleus)
So, TXA2 synthesis is permanently inhibited in platelets
In endothelium
Although COX-1 is inhibited also in endothelium.
However, this is not permanent as more COX-1 can be synthesized
(endothelium is nucleated)
So, prostacyclin synthesis is not inhibited in endothelium
Basis of Low-dose aspirin therapy
To avoid risk of stroke & heart attacks by decreasing formation of thrombi