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LIPID
Fatty Acid Biosyntheses:
When fatty acids are used in metabolism, they are first activated by attaching
coenzyme A (CoA) to them. Fatty acyl CoA synthetase enzyme catalyzes this
activation step. The product is referred to as acyl CoA.
Excess dietary glucose can be converted to fatty acids in the liver and
subsequently sent to the adipose tissue for storage. Adipose tissue synthesizes
smaller quantities of fatty acids. Insulin promotes many steps in the conversion
of glucose to acetyl CoA in the liver:
The citrate shuttle transports acetyl CoA groups from the mitochondria to the
cytoplasm for fatty acid synthesis. Factors that indirectly promote this process
include insulin and high-energy status.
AcetylCoACarboxylase:
Acetyl CoA is activated in the cytoplasm for incorporation into fatty acids by
acetyl CoA carboxylase. This enzyme is the rate-limiting enzyme of fatty acid
biosynthesis. Acetyl CoA carboxylase requires 1)biotin.., 2)ATP,..and ..3)CO2.
The Fatty Acid Synthase Complex
In mammals, the fatty acid synthase complex is a dimer comprising two identical
monomers, each containing all seven enzyme activities of fatty acid synthase
on one polypeptide chain .
Initially, a priming molecule of acetyl-CoA combines with a cysteine_SH group
catalyzed by acetyl transacylase . Malonyl-CoA combines with the adjacent _SH
on the 4′ phosphopantetheine of ACP of the other monomer, catalyzed by
malonyl transacylase (reaction 1b), to form acetyl (acyl)-malonyl enzyme. The
acetyl group attacks the methylene group of the malonyl residue, catalyzed by 3ketoacyl synthase, and liberates CO2, forming 3-ketoacyl enzyme (acetoacetyl
enzyme) (reaction 2), freeing the cysteine _SH group. Decarboxylation allows the
reaction to go to completion, pulling the whole sequence of reactions in the
forward direction. The 3-ketoacyl group is reduced, dehydrated, and reduced
again (reactions 3, 4, 5) to form the corresponding saturated acyl-S enzyme. A
new malonyl-CoA molecule combines with the _SH of 4′-phosphopantetheine,
displacing the saturated acyl residue onto the free cysteine _SH group.The
sequence of reactions is repeated six more times until a saturated 16-carbon
acyl radical (palmityl) has been assembled. It is liberated from the enzyme
complex by the activity of a seventh enzyme in the complex, thioesterase
(deacylase). The free palmitate must be activated to acyl-CoA before it can
proceed via any other metabolic pathway.
Biosynthesis of long-chain fatty acids
Elongation of Fatty Acid Chains Occurs in the Endoplasmic Reticulum
This pathway elongates saturated and unsaturated fatty acyl-CoAs (from C10
upward) by two carbons, using malonyl-CoA as acetyl donor and NADPH as
reductant, and is catalyzed by the microsomal fatty acid elongase system of
enzymes . Elongation of stearyl-CoA in brain increases rapidly during myelination
(Myelination is the process by which a fatty layer, called myelin, accumulates around nerve cells (neurons).
Myelin particularly forms around the long shaft, or axon, of neurons. Myelination enables nerve cells to
transmit information faster and allows for more complex brain processes. Thus, the process is vitally
important to healthy central nervous system functioning) in order to provide C22 and C24 fatty
acids for sphingolipids.
Biosynthesis of complex lipids
Phospholipids:
Most of the enzymes involved in this pathway are associated with the membranes
of the smooth endoplasmic reticulum. The synthesis of fats and phospholipids
starts with glycerol 3-phosphate. This compounds can arise via:
[1]
reduction from the glycolytic intermediate glycerone 3-phosphate or
dihydroxyacetone 3-phosphate; (enzyme: glycerol- 3phosphate dehydrogenase)
[2] phosphorylation of glycerol deriving from fat degradation (enzyme: glycerol
kinase) .
[3] Esterification of glycerol 3 phosphate with a long-chain fatty acid produces a
strongly
amphipathic
lysophosphatidate
enzyme:
glycerol-3-phosphate
acyltransferase . In this reaction, an acyl residue is transferred from the activated
precursor acyl-CoA to the hydroxy group at C-1.
[4] A second esterification of this type leads to a phosphatidate (enzyme: 1-
acylglycerol-3- phosphate acyltransferase) . Unsaturated acyl residues,
particularly oleic acid, are usually incorporated at C-2 of the glycerol.
Phosphatidates (anions of phosphatidic acids) are the key molecules in the
biosynthesis of fats, phospholipids, and glycolipids.
[5] To biosynthesize fats (triacylglycerols), the phosphate residue is again
removed by hydrolysis (enzyme: phosphatidate phosphatase
This produces diacylglycerols (DAG).
[6] Transfer of an additional acyl residue to DAG forms triacylglycerols (enzyme:
diacylglycerol acyltransferase . This completes the biosynthesis of neutral fats.
They are packaged into VLDLs by the liver and released into the blood. Finally,
they are stored by adipocytes in the form of insoluble fat droplets.
[7] Transfer of a CMP(Cytidine monophosphate ) residue to phosphatidate gives
rise first to CDP-diacylglycerol (enzyme: phosphatidatecytidyl transferase ).
[8] Substitution of the CMP residue by inositol then provides phosphatidylinositol
(PtdIns; enzyme: CDPdiacylglycerolinositol-3- phosphatidyl transferase) .
[9]and [10] An additional phosphorylation (enzyme: phosphatidylinositol-4-
phosphate kinase ) finally provides phosphatidylinositol- 4,5-bisphosphate .
PIP2 is the precursor for the second messengers 2,3-diacylglycerol (DAG) and
inositol-1,4,5-trisphosphate
[11] Transfer of a phosphocholine residue to the free OH group gives rise to
phosphatidylcholine
(lecithin;
enzyme:
1-alkyl-2-acetylglycerolcholine
phosphotransferase ).The phosphocholine residue is derived from the precursor
CDP-choline
.
Phosphatidylethanolamine
is
similarly
formed
from
CDPethanolamine and DAG. By contrast, phosphatidyl serine is derived from
phosphatidylethanolamine by an exchange of the amino alcohol. Further
reactions serve to interconvert the phospholipids—e. g., phosphatidylserine can
be converted into phosphatidylethanolamine by decarboxylation, and the latter
can then be converted into phosphatidylcholine by methylation
Sphingolipid :
The biosynthesis of sphingolipids takes place in four stages: (1) synthesis of the
18-carbon amine sphinganine from palmitoyl-CoA and serine; (2) attachment of
a fatty acid in amide linkage to yield N-acylsphinganine; (3) desaturation of the
sphinganine moiety to form N-acylsphingosine (ceramide); and (4) attachment
of a head group to produce a sphingolipid such as a cerebroside or
sphingomyelin . The pathway shares several features with the pathways leading
to glycerophospholipids: NADPH provides reducing power, and fatty acids enter
as their activated CoA derivatives. Phosphatidylcholine, rather than CDP-choline,
serves as the donor of phosphocholine in the synthesis of sphingomyelin.
Sphingolipids are commonly believed to protect the cell surface against harmful
environmental factors by forming a mechanically stable and chemically resistant
outer leaflet of the plasma membrane lipid bilayer. Simple sphingolipid
metabolites, such as ceramide and sphingosine-1-phosphate, have been shown
to be important mediators in the signaling cascades involved in apoptosis,
proliferation, stress responses, necrosis, inflammation, and differentiation.
Sphingolipids are synthesized in a pathway that begins in the ER and is
completed in the Golgi apparatus, but these lipids are enriched in the plasma
membrane and in endosomes, where they perform many of their functions.
Glycolipids:
Glycolipids are widely distributed in every tissue of the body, particularly in
nervous tissue such as brain. They occur particularly in the outer leaflet of the
plasma membrane, where they contribute to cell surface carbohydrates. The
major glycolipids found in animal tissues are glycosphingolipids. They contain
ceramide and one or more sugars. Galactosylceramide is a major glyco
sphingolipid of brain and other nervous tissue, found in relatively low amounts
elsewhere.
Structure of galactosylceramide(galactocerebroside,if R = H), and
sulfogalactosylceramide(a sulfatide, if R = SO4).
Galactosylceramide can be converted to Sulfo -galactosylceramide (sulfatide),
present in high amounts in myelin. Glucosylceramide is the predominant simple
glycosphingolipid of extra neural tissues, also occurring in the brain in small
amounts. Sulfogalactosylceramide and other sulfolipids are formed after further
reactions
Where PAPS = 3'-Phosphoadenosine 5'-phosphosulfate
Glycolipids in blood grouping
glycolipids are membrane components composed of lipids that are covalently
bonded to monosaccharides or polysaccharides. One type of glycolipid found in
human red blood cells is involved in the ABO blood type antigens. The table
below shows the relationship between the ABO blood type, the RBC glycolipid
and antibodies to the glycolipids in the blood plasma.
blood
type
glycolipid
antibodies
in blood
anti A
and
anti B
O
Individuals
with type O
blood have
antibodies
RBC of O type blood have this glycolipids in their against the
type A and
RBCs plasma membranes.
type B
antigens
anti B
A
individuals
of type A
blood have
antibodies
Individuals with type A blood have this type of
glycolipid in their RBCs plasma membranes. The against the
type B
A type glycolipid has the same carbohydrate
composition as does the type O antigen with the determinant
addition of a additional NAcetylgalactosamine which is the A type
antigenic determinant.
anti A
B
Individuals with type B blood have the above
kind of glycolipid in their RBC plasma
membrane. The B type glycolipid has the same
carbohydrate composition as does the type O
antigen with the addition of an additional
galactose which is the B type antigenic
determinant.
Individuals
of type B
blood have
antibodies
against the
type A
antigenic
determinant
neither A
or B
Individuals
with they
AB blood
have
antibodies
against
neither the
the A nor B
antigens
AB
Individuals with type AB blood have both of the
above glycolipids in their RBC plasma
membranes
Gangliosides
Gangliosides are complex glycosphingolipids derived from glucosylceramide that
contain in addition one or more molecules of a sialic acid.
Structure of N-acetylneuraminic acid,a sialic acid (NeuAc) .
Neuraminic acid (NeuAc); is the principal sialic acid found in human tissues.
Gangliosides are present in nervous tissues in high concentration. They appear to
have receptor and other functions. The simplest ganglioside found in tissues is
GM3, which contains ceramide, one molecule of glucose, one molecule of
galactose, and one molecule of NeuAc.
Gangliosides are synthesized from ceramide by the stepwise addition of
activated sugars (eg, UDPGlc and UDPGal) and a sialic acid, usually
N-acetylneuraminic acid .
A large number of gangliosides of increasing molecular weight may be formed.
Most of the enzymes transferring sugars from nucleotide sugars (glycosyl
transferases) are found in the Golgi apparatus. Glycosphingolipids are
constituents of the outer leaflet of plasma membranes and are important in cell
adhesion and cell recognition. Certain gangliosides function as receptors for
bacterial toxins (eg, for cholera toxin ). Cholera toxin a First
binds
to GM1 gangliosides on the surface of target cells . Once bound, the entire toxin
complex is endocytosed by the cell. The endosome is moved to the Golgi
apparatus and after many steps it leads to increased adenylate cyclase activity,
which increases the intracellular concentration of 3',5'-cyclic AMP (cAMP) to
more than 100-fold over normal and over-activates cytosolic protein kinase
A (PKA). These active PKA then phosphorylate the regulator of the
chloride
channel proteins, which leads to ATP-mediated efflux of chloride ions and leads
to secretion of H2O, Na+, K+, and HCO3− into the intestinal lumen. In addition,
the entry of Na+ and consequently the entry of water into enterocytes are
diminished. The combined effects result in rapid fluid loss from the intestine, up
to 2 liters per hour, leading to severe dehydration and other factors associated
with cholera, including a rice-water stool.
Expression of cholera toxin was shown to be prevented by the drug virstatin,
which acts to prevent its transcription. It has been identified as a possible
treatment for cholera.
Metabolism of Unsaturated Fatty Acids &Eicosanoids
Unsaturated fatty acids in phospholipids of the cell membrane are important in
maintaining membrane fluidity. A high ratio of polyunsaturated fatty acids to
saturated fatty acids (P:S ratio) in the diet is a major factor in lowering plasma
cholesterol concentrations and is considered to be beneficial in preventing
coronary heart disease. Certain long-chain unsaturated fatty acids of metabolic
significance in mammals.
Linoleic and α-linolenic acids are the only fatty acids known to be essential for
the complete nutrition of many species of animals, including humans, and are
known as the nutritionally essential fatty acids.
EICOSANOIDS THE
C20
POLYUNSATURATED FATTY ACIDS
Arachidonate and some other C20 polyunsaturated fatty acids give rise to
eicosanoids, physiologically and pharmacologically active compounds known as
prostaglandins (PG), thromboxanes (TX), leukotrienes (LT), and lipoxins (LX).
Physiologically, they are considered to act as local hormones functioning through
G-protein-linked receptors to elicit their biochemical effects.
There are three groups of eicosanoids that are synthesized from C20 eicosanoic
acids derived from the essential fatty acids linoleate and α-linolenate, or directly
from dietary arachidonate and eicosapentaenoate as shown below.
Prostaglandin E2 (PGE2).
Thromboxane A2 (TXA2).
Leukotriene A4 (LTA4).
Arachidonic acid synthesis:
Arachidonate is usually derived from the 2 position of phospholipids in the
plasma membrane by the action of phospholipase A2, but also from the diet.
Arachidonate is the substrate for the synthesis of the PG2, TX2 series
(prostanoids) by the cyclooxygenase pathway, or the LT4 and LX4 series by the
lipoxygenase pathway, with the two pathways competing for the arachidonate
substrate.
Prostaglandins (PG)
contain a five-carbon ring originating from the chain of arachidonic acid. Prostaglandins act
in many tissues by regulating the synthesis of the intracellular messenger 3_,5_-cyclic AMP
(cAMP). Because cAMP mediates the action of diverse
hormones, the prostaglandins affect a wide range of cellular and tissue functions. Some
prostaglandins stimulate contraction of the smooth muscle of the uterus during menstruation
and labor. Others affect blood flow to specific organs, the wake-sleep cycle, and the
responsiveness of certain tissues to hormones such as epinephrine and glucagon.
Prostaglandins elevate body temperature (producing fever) and cause inflammation and
enhance pain perception .
The thromboxanes
have a six-membered ring containing an ether. They are produced by platelets and act in the
formation of blood clots and the reduction of blood flow to the site of a clot.
The nonsteroidal antiinflammatory drugs (NSAIDs)aspirin, ibuprofen, and meclofenamate,
for example— were shown to inhibit the enzyme prostaglandin H2 synthase (also called
cyclooxygenase or COX1), which catalyzes an early step in the pathway from arachidonate
to prostaglandins .
Leukotrienes : first found in leukocytes, contain three conjugated double bonds. They are
powerful biological signals. For example, leukotriene D4 induces contraction of the muscle
lining the airways to the lung. Overproduction of leukotrienes causes asthmatic attacks, and
leukotriene synthesis is one target of antiasthmatic drugs such as prednisone. The strong
contraction of the smooth muscles of the lung that occurs during anaphylactic shock
is part of the potentially fatal allergic reaction in individuals hypersensitive to bee stings,
penicillin, or others.
CHOLESTEROL MLETABOLISM:
Cholesterol is required for membrane synthesis, steroid synthesis, and in the
liver, bile acid synthesis.Most cells derive their cholesterol from LDL or HDL, but
some cholesterol may be synthesized de novo. Most de novo synthesis occurs in
the liver, where cholesterol is synthesized from acetyl CoA in the cytoplasm. The
citrate shuttle carries mitochondrial acetyl CoA into the cytoplasm, and NADPH is
provided by the PPP and malic enzyme. Important points are noted below
3-Hydroxy-3-methylglutaryl -CoA (HMG-CoA) reductase on the smooth
endoplasmic reticulum (SER) is the rate-limiting enzyme. Insulin activates the
enzyme (dephosphorylation), and glucagon inhibits it. Mevalonate is the product,
and the statin drugs competitively inhibit the enzyme. Cholesterol represses the
expression of the HMG-CoA reductase gene and also increases degradation of
the enzyme.
Regulation of the Cholesterol Level in Hepatocytes
HMG CoA reductase, the rate-limiting enzyme, is the major control point for
cholesterol biosynthesis, and is subject to different kinds of metabolic control.
1. Sterol-dependent regulation of gene expression:
Expression of the HMG CoA reductase gene is controlled by a transcription
factor (sterol regulatory element-binding protein, or SREBP) that binds to
DNA at the sterol regulatory element (SRE) located upstream of the
reductase gene. The SREBP is initially associated with the ER membrane, but
proteolytic cleavage liberates the active form, which travels to the nucleus.
When the SREBP binds, expression of the reductase gene increases. When
cholesterol levels are low, activation of SREBP occurs, resulting in increased
HMG CoA reductase
and, therefore, more cholesterol synthesis.Conversely,
high levels of cholesterol prevent activation of the transcription factor.
2. Sterol-independent phosphorylation/dephosphorylation:
HMG CoA reductase activity is controlled covalently through the actions of a
protein kinase and a phosphoprotein phosphatase The phosphorylated form of
the enzyme is inactive, whereas the dephosphorylated form is active. [Note:
Protein kinase is activated by AMP, so cholesterol synthesis is decreased
when ATP availability is decreased.]
3. Hormonal regulation: The amount (and, therefore, the activity) of HMG CoA
reductase is controlled hormonally. An increase in insulin favors up regulation of
the expression of the HMG CoA reductase gene. Glucagon has the opposite
effect.
4. Inhibition by drugs: The statin drugs, including simvastatin, lovastatin, and
mevastatin are structural analogs of HMG CoA, and are reversible, competitive
inhibitors of HMG CoA reductase .They are used to decrease plasma
cholesterol levels in patients with hypercholesterolemia.