SYNTHESIS OF

BIOLOGICAL
MEMBRANES

D r. M E H W I S H H A M I D
• Phosphataidate is a common intermediate in synthesis of phospholipids
and triacylglycerols
• Cholesterol is synthesized from acetyl-CoA
• Synthesis of Cholesterol is regulated at several levels
• Derivatives of cholesterol -------- bile salts, steroid hormones
P H O S P H AT I DAT E I S A C O M M O N
I N T E R M E D I AT E
• Phosphatidate (diacylglycerol 3-phosphate)
• In mammalian cells, phosphatidate is synthesized in the endoplasmic
reticulum and the outer mitochondrial membrane.
• It is formed by the addition of two fatty acids to glycerol 3-phosphate,
which in turn is formed primarily by the reduction of dihydroxyacetone
phosphate, which is a glycolytic intermediate, and to a lesser extent by
the phosphorylation of glycerol.
 S Y N T H E S I S O F P H O S P H AT I DAT E

• glycerol phosphate acyltransferase

• most phosphatidates, the fatty acyl chain attached to the C-1 atom is saturated,
whereas the one attached to the C-2 atom is unsaturated.
 T R I A C Y L G LY C E R O L

• In the synthesis of triacylglycerols, phosphatidate is hydrolyzed by a specific

phosphatase to give a diacylglycerol (DAG).
• This DAG is acylated to a triacylglycerol in a reaction that is catalyzed by
diglyceride acyltransferase.
SYNTHESIS OF PHOSPHOLIPIDS
• Phospholipid synthesis requires the combination of a diacylglyceride
with an alcohol.
• The de novo pathway starts with the reaction of phosphatidate with
cytidine triphosphate (CTP) to form cytidine diphosphodiacylglycerol
(CDP-diacylglycerol)
• The activated phosphatidyl unit then reacts with the hydroxyl group of
an alcohol to form a phosphodiester linkage
• Subsequent phosphorylations catalyzed by specific kinases lead to the
synthesis of phosphatidyl inositol 4,5-bisphosphate
A C T I VAT I O N O F I N T E R M E D I AT E
 SPHINGOLIPIDS
• Sphingolipids are a class of lipids containing a backbone of sphingoid
bases, which are a set of aliphatic amino alcohols that
includes sphingosine
• Sphingolipids are synthesized from Ceramide
• These lipids are found in the plasma membranes of all eukaryotic cells,
although the concentration is highest in the cells of the central nervous
system.
• The backbone of a sphingolipid is sphingosine, rather than glycerol
• In all sphingolipids, the amino group of sphingosine is acylated: a long-
chain acyl CoA reacts with sphingosine to form ceramide (N-acyl
sphingosine)
 GANGLIOSIDE
• Gangliosides are Carbohydrate-rich
Sphingolipids that contain acidic sugars
• an oligosaccharide chain attached to the
ceramide contains at least one acidic sugar. The
acidic sugar is N-acetylneuraminate or N-
glycolylneuraminate
• Gangliosides are synthesized by the ordered,
step-by-step addition of sugar residues to
ceramide
 DISORDERS LINKED WITH
P H O S P H O L I P I D M E TA B O L I S M

• Respiratory distress syndrome is a pathological condition resulting from a

failure in the biosynthetic pathway for dipalmitoyl phosphatidyl choline.
• This phospholipid, in conjunction with specific proteins and other
phospholipids, is found in the extracellular fluid that surrounds the alveoli of
the lung, where it decreases the surface tension of the fluid to prevent lung
collapse at the end of the expiration phase of breathing.
• Premature infants may suffer from respiratory distress syndrome because
their immature lungs do not synthesize enough dipalmitoyl phosphatidyl
choline.
 SYMPTOMS OF RDS
• blue-coloured lips, fingers and toes
• rapid, shallow breathing
• flaring nostrils
• a grunting sound when breathing
 TAY- S A C H S D I S E A S E
• caused by a failure of lipid degradation: an inability to degrade
gangliosides.
• Gangliosides are normally degraded inside lysosomes but, in Tay-Sachs
disease, this degradation does not occur.
• As a consequence, neurons become enormously swollen with lipid-filled
lysosomes
• An affected infant displays weakness and retarded psychomotor skills
before 1 year of age. The child is demented and blind by age 2 and
usually dead before age 3.
 CHOLESTEROL
• Is synthesized from Acetyl-COA in 3 stages
1. Stage one is the synthesis of isopentenyl pyrophosphate, an activated
isoprene unit that is the key building block of cholesterol.
2. Stage two is the condensation of six molecules of isopentenyl
pyrophosphate to form squalene.
3. In stage three, squalene cyclizes and the tetracyclic product is
subsequently converted into cholesterol.
 R E G U L AT I O N O F C H O L E S T E R O L
BIOSYNTHESIS
• The feedback regulation is mediated primarily by changes in the amount and
activity of 3-hydroxy-3-methylglutaryl CoA reductase
1. The rate of synthesis of reductase mRNA is controlled by the sterol regulatory
element binding protein (SREBP).
2. The rate of translation of reductase mRNA is inhibited by nonsterol
metabolites derived from mevalonate as well as by dietary cholesterol.
3. Phosphorylation decreases the activity of the reductase. This enzyme, like
acetyl CoA carboxylase (which catalyzes the committed step in fa synthesis),
is switched off by an AMP-activated protein kinase. Thus, cholesterol
synthesis ceases when the ATP level is low.
 TRANSPORT OF CHOLESTEROL

• Cholesterol and triacylglycerols are transported in body fluids in the form

of lipoprotein particles.
• Each lipoprotein particle consists of a core of hydrophobic lipids
surrounded by a shell of more polar lipids and apoproteins.
• The protein components of these macromolecular have two roles: they
solubilize hydrophobic lipids and contain cell-targeting signals.
• Lipoprotein particles are classified according to increasing density
 C H O L E S T E R O L D E R I VAT I V E S
• Cholesterol is a precursor for other important steroid molecules: the bile
salts, steroid hormones, and vitamin D
• Bile salts: Bile salts are synthesized in the liver, stored and concentrated
in the gall bladder, and then released into the small intestine. Bile salts,
the major constituent of bile, solubilize dietary lipids. Bile salts are also the
major breakdown products of cholesterol.
 STEROID HORMONES

• Cholesterol is the precursor of the five major classes of steroid hormones:

progestagens, glucocorticoids, mineralocorticoids, androgens, and
estrogens
• The major sites of synthesis of these classes of hormones are the corpus
luteum, for progestagens; the ovaries, for estrogens; the testes, for
androgens; and the adrenal cortex, for glucocorticoids and
mineralocorticoids.
• These small, relatively similar molecules are able to have greatly differing
effects because the slight structural differences among them
 V I TA M I N D

• Cholesterol is also the precursor of vitamin D, which plays an essential

role in the control of calcium and phosphorus metabolism.
• Vit-D is derived from cholesterol by the ring-splitting activity of light
• 7-Dehydrocholesterol (provitamin D3) is photolyzed by the ultraviolet light
of sunlight to previtamin D3, which spontaneously isomerizes to vitamin
D3
• Vitamin D3 (cholecalciferol) is converted into calcitriol (1,25-
dihydroxycholecalciferol), the active hormone, by hydroxylation reactions
in the liver and kidneys
 RICKETS
• Vitamin D deficiency in childhood produces rickets,
a disease characterized by inadequate calcification
of cartilage and bone.
• The 7-dehydrocholesterol in the skin of these
children was not photolyzed to previtamin
D3,because there was little sunlight for many
months of the year
• it's usually treated by increasing a child's intake of
vitamin D and calcium