Prepared By: Hazel Anne C.

Lamadrid, RPh

LIPIDS OF PHYSIOLOGIC SIGNIFICANCE

The

lipids are a heterogeneous group of compounds, including fats, oils, steroids, waxes, and related compounds, which are related more by their physical than by their chemical properties. have the common property of being

They

(1) relatively insoluble in water and (2) soluble in nonpolar solvents such as ether and chloroform.

 Fat

is stored in adipose tissue, where it also serves as a thermal insulator. Combinations of lipid and protein (lipoproteins) are important cellular constituents. Knowledge of lipid biochemistry is necessary in understanding many important biomedical areas, eg, obesity, diabetes mellitus, atherosclerosis, and the role of various polyunsaturated fatty acids in nutrition and health.

LIPIDS ARE CLASSIFIED AS SIMPLE OR COMPLEX

1.

Simple lipids: Esters of fatty acids with various alcohols. a. Fats: Esters of fatty acids with glycerol. Oils are fats in the liquid state. b. Waxes: Esters of fatty acids with higher molecular weight monohydric alcohols.

2. Complex lipids: Esters of fatty acids containing

groups in addition to an alcohol and a fatty acid.

a. Phospholipids: Lipids containing, in addition to fatty acids and an alcohol, a phosphoric acid residue. They frequently have nitrogen containing bases and other substituents, eg, in glycerophospholipids the alcohol is glycerol and in sphingophospholipids the alcohol is sphingosine. b. Glycolipids (glycosphingolipids): Lipids containing a fatty acid, sphingosine, and carbohydrate.

c. Other complex lipids:

Lipids such as sulfolipids and aminolipids. Lipoproteins may also be placed in this category.
3.

Precursor and derived lipids: These include fatty acids, glycerol, steroids, other alcohols, fatty aldehydes, and ketone bodies.

FATTY ACIDS ARE ALIPHATIC CARBOXYLIC ACIDS

Fatty

acids occur mainly as esters in natural fats and oils but do occur in the unesterified form as free fatty acids, a transport form found in the plasma. Fatty acids that occur in natural fats are usually straight-chain derivatives containing an even number of carbon atoms. The chain may be saturated (containing no double bonds) or unsaturated (containing one or more double bonds).

FATTY ACIDS ARE NAMED AFTER CORRESPONDING HYDROCARBONS

The

most frequently used systematic nomenclature for fatty acid are after the hydrocarbon with the same number and arrangement of carbon atoms, with -oic being substituted for the final -e (Genevan system). Thus, saturated acids end in -anoic, eg, octanoic acid, and unsaturated acids with double bonds end in -enoic, eg, octadecenoic acid (oleic acid).

NOMENCLATURE
Carbon atoms are numbered from the carboxyl carbon (No. 1). The carbon atoms adjacent to the carboxyl carbon (Nos. 2, 3, and 4) are also known as the , , and carbons, respectively, and the terminal methyl carbon is known as the or n-carbon. Various conventions use for indicating the number and position of the double bonds eg, 9 indicates a double bond between carbons 9 and 10 of the fatty acid.

OMEGA-REFERENCE
9

SYSTEM OR

(N-X)

indicates a double bond on the ninth carbon counting from the - carbon.

Oleic acid. n 9 (n minus 9) is equivalent to 9.

According to chemical nature, lipids fall into two main groups 1. Open-chain compounds with polar head groups and long non-polar tails. Fatty acids Triacylglycerols Spingolipids Phosphoacylglycerols Glycolipids 2. Fused-ring compounds Steroids (cholesterol)

CHEMICAL NATURES OF THE LIPID TYPES

FATTY ACID
-

has a carboxyl group at the polar end and a hydrocarbon chain at nonpolar tail. Amphiphilic - carboxyl group is hydrophilic
and the hydrocarbon tail is hydrophobic.

SATURATED FATTY ACIDS CONTAIN NO DOUBLE BONDS

Saturated

fatty acids may be envisaged as based on acetic acid (CH3--COOH) as the first member of the series in which -CH2- is progressively added between the terminal CH3- and -COOH groups.

FATTY ACID

SATURATED FATTY ACIDS SOURCES

FATTY ACID
12:0

18:0

UNSATURATED FATTY ACIDS CONTAIN ONE OR MORE DOUBLE BONDS

Fatty acids may be further subdivided as follows:

(1) Monounsaturated (monoethenoid, monoenoic) acids, containing one double bond. (2) Polyunsaturated (polyethenoid, polyenoic) acids, containing two or more double bonds. (3) Eicosanoids: These compounds, derived from eicosa- (20-carbon) polyenoic fatty acids, comprise the prostanoids, leukotrienes (LTs), and lipoxins (LXs). Prostanoids include prostaglandins (PGs), prostacyclins (PGIs), and thromboxanes (TXs).

STRUCTURES OF EICOSANOIDS

FATTY ACID

MOST NATURALLY OCCURRING UNSATURATED FATTY ACIDS HAVE CIS DOUBLE BONDS
If the acyl chains are on the same side of the bond, it is cis-; if on opposite sides, it is trans-, as in elaidic acid, the trans isomer of oleic acid. Naturally occurring unsaturated long-chain fatty acids are nearly all of the cis configuration, the molecules being bent 120 degrees at the double bond.

18:1 n9

18:2 n6 18:2 9,12

20:4 n6 20:4 58,11,14

Note: the unsaturated fatty acids have lower melting points than the saturated fatty acids.

Length of fatty acids longer generally higher melting temperature.

ESSENTIAL FATTY ACIDS, OR EFAS

fatty

acids that cannot be constructed within an organism from other components by any known chemical pathways. Must be obtained from the diet. Two families of EFAs: - -3 (or omega-3 or n3) - -6 (omega-6, n6).
Fats

from each of these families are essential, as the body can convert one omega-3 to another omega- 3

 The

essential fatty acids start with the short chain polyunsaturated fatty acids (SCPUFA): -3 fatty acids: -Linolenic acid or ALA (18:3) -6 fatty acids: Linoleic acid or LA (18:2)
- starting point for the creation of longer and more desaturated fatty acids, referred to as long-chain polyunsaturated fatty acids (LC-PUFA):

LONG-CHAIN POLYUNSATURATED FATTY ACIDS (LC-PUFA):

-3

fatty acids: *eicosapentaenoic acid or EPA (20:5) *docosahexaenoic acid or DHA (22:6)

-6

fatty acids: *gamma-linolenic acid or GLA (18:3) dihomo-gamma-linolenic acid or DGLA (20:3) *arachidonic acid or AA (20:4)

NON-ESSENTIAL OMEGA-3 FATTY ACIDS

DHA

(docosahexaenoic acid) and EPA (eicosapentaenoic acid). The body can convert ALA to EPA, and then EPA to DHA. conversion does not always seem to happen efficiently and then these oils would need to be obtained from diet. Non-essential omega-6 fatty acids AA (arachidonic acid) and GLA (gammalinolenic acid) which your body makes from LA (the omega-6 essential fatty acid).

TRIACYLGLYCEROLS (TRIGLYCERIDES)
are

the main storage forms of fatty acids

Glycerol simple compound that contains three OH group.

three

alcohol groups form ester linkages with fatty acid.

o o

Triacylglycerol do not occur as components of membranes but accumulate in adipose tissue (fat cells) and provide a means of storing FA. serve as concentrated stores of metabolic energy: complete oxidation of fat =9kcal/g carbohydrates and proteins = 4kcal/g

HYDROLYSIS

OF

TRIACYLGLYCEROL

Physiologically in body: oTriacylglycerols are hydrolyzed by enzymes called lipases present in adipocytes and intestines. oHydrolyzed into 3 fatty acids and 1 glycerol

HYDROLYSIS OUTSIDE MICROORGANISM:

one with the use of acids or bases - Sodium or potassium hydroxide. Saponification- reaction of a glyceryl ester with sodium or potassium hydroxide to produce a soap, w/c is the corresponding salt of the long chain fatty acid.

SAPONIFICATION

When soaps are used in hard water, Ca and Mg ions in water react with the FA and form ppt.

PHOSPHOLIPIDS
Are

the main lipid constituents of membranes Regarded as derivatives of phosphatidic acid in which the phosphate is esterified with the -OH of a suitable alcohol. Phosphatidic acid is important as an intermediate in the synthesis of triacylglycerols as well as phosphoglycerols.

A.

PHOSPHATIDYLCHOLINES (LECITHINS)

Phosphoacylglycerols

containing choline are the most abundant phospholipids of the cell membrane. Choline is important in nervous transmission, as acetylcholine, and as a store of labile methyl groups.

Acetylcholine

B. DIPALMITOYL LECITHIN
A

very effective surface active agent and a major constituent of the surfactant preventing adherence, due to surface tension, of the inner surfaces of the lungs. Its absence from the lungs of premature infants causes respiratory distress syndrome.

C. PHOSPHATIDYLETHANOLAMINE (CEPHALIN)
AND PHOSPHATIDYLSERINE
found

in most tissues, differ from phosphatidylcholine only in that ethanolamine or serine, respectively, replaces choline.

D.

PHOSPHATIDYL INOSITOL

inositol is present as the stereoisomer, myoinositol Phosphatidylinositol4,5bisphosphate is an important constituent of cell membrane phospholipids; upon stimulation by a suitable hormone agonist, it is cleaved into diacylglycerol and inositol trisphosphate, both of which act as internal signals or second messengers.

E. CARDIOLIPIN
major

lipid of mitochondrial membranes Phosphatidic acid is a precursor of phosphatidylglycerol which, in turn, gives rise to cardiolipin

F. LYSOPHOSPHOLIPIDS
intermediates

in the metabolism of phosphoglycerols these are phosphoacylglycerols containing only one acyl radical, eg, lysophosphatidylcholine (lysolecithin), important in the metabolism and interconversion of phospholipids. implicated in some of their effects in promoting atherosclerosis.

G. PLASMALOGENS
These

compounds constitute as much as 10% of the phospholipids of brain and muscle. Structurally resemble phosphatidylethanolamine but possess an ether link on the sn-1 carbon instead of the ester link found in acylglycerols.

Phospholipids can be degraded to their component parts by a family of enzymes called PHOSPHOLIPASES o EXAMPLE: SNAKE VENOM

SPHINGOLIPIDS
Membrane

lipids based on the core structure of SPHINGOSINE, a long chain amino alcohol. o Glycerol is replaced by sphingosine

SPINGOLIPIDS
The

simpliest compound of this class are the ceramides (combination of sphingosine plus fatty

acid)

If X

= = = =

H Ceramide Sugar Cerebroside phosphocholine Sphingomyelin complex oligosaccharide Ganglioside

SPHINGOMYELINS
found

in large quantities in brain and nerve tissue. hydrolysis of sphingomyelins yield a fatty acid, phosphoric acid, choline, and a complex amino alcohol, No glycerol is present. Significance: Insulates nerve axons Major lipid of myelin sheaths

STRUCTURE OF SPHINGOMYELIN

GLYCOLIPIDS (GLYCOSPHINGOLIPIDS)
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 glycosphingolipid of brain and other nervous tissue. Gangliosides are complex glycosphingolipids derived from glucosylceramide that contain in addition one or more molecules of a sialic acid.

Structure of galactosylceramide (galactocerebroside, R= H), and sulfogalactosylceramide (a sulfatide, R= SO4 2).

GLYCOLIPIDS

Improper degradation: Tay-Sachs Disease

caused by a defective gene on chromosome 15 Gangliosides accumulate in nerve cells, brain, and spleen. Spasticity, paralysis, dementia, & blindness. Children usually die by age 3 or 4. Cannot be treated or cured.

Gaucher

Disease

Deficiency in the enzyme glucocerebrosidase. Accumulation of glucocerebrosides Enlarged liver and spleen Bone pain & Anemia Tx enzyme replacement therapy.

STEROIDS
Cholesterol

is probably the best known steroid because of its association with atherosclerosis. Biochemically it is also of significance because it is the precursor of a large number of equally important steroids that include the bile acids, adrenocortical hormones, sex hormones, D vitamins, cardiac glycosides, sitosterols of the plant kingdom, and some alkaloids.

 All

of the steroids have a similar cyclic nucleus resembling phenanthrene (rings A, B, and C) to which a cyclopentane ring (D) is attached.

STEROIDS INCLUDE:
CHOLESTEROL

precursor) for synthesis of steroid hormones. plant stigmasterol fungi ergosterol

HORMONES

Alkyl side chain

testosterone progesterone Estrogen

ROLES OF CHOLESTEROL IN MAMMALS:

Major

constituent of plasma membrane and of plasma lipoprotein modulates membrane fluidity. Precursor of steroid hormones and bile acids.

5 steroid hormones 1. Glucocorticoids (cortisol) synthesized by adrenal cortex 2. Mineralocorticoids (aldosterone) adrenals 3. Estrogens- ovaries 4. Progestins sex hormones 5. Testosterone - testes

STRUCTURES OF SOME HORMONE

POLYPRENOIDS SHARE THE SAME PARENT COMPOUND AS CHOLESTEROL

not

steroids but are related to cholesterol because they are synthesized, like cholesterol from five-carbon isoprene units. This include ubiquinone - a member of the respiratory chain in mitochondria, and the longchain longchain alcohol dolichol - which takes part in glycoprotein synthesis.

ERGOSTEROL IS A PRECURSOR OF VITAMIN D

occurs

in plants and yeast and is important as a precursor of vitamin D. When irradiated with ultraviolet light, it acquires antirachitic properties consequent to the opening of ring B.

LIPID PEROXIDATION IS A SOURCE OF FREE RADICALS

Peroxidation

(auto-oxidation) of lipids exposed to oxygen is responsible not only for deterioration of foods (rancidity) but also for damage to tissues in vivo cancer, inflammatory diseases, atherosclerosis, and aging. Free radicals (ROO, RO, OH) produced during peroxide formation from fatty acids.

ANTIOXIDANTS
- control and reduce lipid peroxidation
Antioxidants

used as food additives. Propyl gallate Butylated hydroxyanisole (BHA) butylated hydroxytoluene (BHT)
occurring antioxidants vitamin E (tocopherol), which is lipid-soluble, urate and vitamin C, which are water-soluble Beta-carotene

Naturally

FOUR MAJOR GROUPS OF PLASMA LIPOPROTEINS

(1) chylomicrons, derived from intestinal

absorption of triacylglycerol and other lipids (2) very low density lipoproteins (VLDL, or pre-lipoproteins), derived from the liver for the export of triacylglycerol (main lipid component) (3) low-density lipoproteins (LDL, or lipoproteins), representing a final stage in the catabolism of VLDL (4) high-density lipoproteins (HDL, or -lipoproteins), involved in VLDL and chylomicron metabolism and also in cholesterol transport.

 IDL, intermediate-density lipoproteins LDL - highest in cholesteryl esters as % of

weight
Cholesterol is the main lipid component
(21%:79% protein/lipid ratio) Bad cholesterol

HDL - highest in density due to high

protein/lipid ratio (HDL3 57%:43%).

Good cholesterol

LDL and HDL Cholesterol: What's Bad and What's Good? LDL (Bad) Cholesterol Low Density Lipoprotein carries & contain high concentration of cholesterol & cholesterol esters LDL delivers these cholesterols to the peripheral tissues where it is stored or utilized High LDL results in fat deposition in arterial walls which leads to plaque formation over time

HDL (GOOD) CHOLESTEROL

About 1/4 to 1/3 of blood cholesterol is carried by

HDL. high levels of HDL seem to protect against heart attack. Low levels of HDL (less than 40 mg/dL) also increase the risk of heart disease. Medical experts think that HDL tends to carry cholesterol away from the arteries and back to the liver. Some experts believe that that HDL removes excess cholesterol from arterial plaque, thus slowing its buildup.

LIPOPROTEINS CONSIST OF A NONPOLAR CORE & A SINGLE SURFACE LAYER OF AMPHIPATHIC LIPIDS
Nonpolar

lipid core consists of mainly triacylglycerol and cholesteryl ester and is surrounded by a single surface layer of amphipathic phospholipid and cholesterol molecules. The protein moiety of a lipoprotein is known as an apolipoprotein or apoprotein, constituting nearly 70% of some HDL and as little as 1% of chylomicrons.

GENERALIZED STRUCTURE OF A PLASMA

LIPOPROTEIN

BIOLOGICAL MEMBRANES
membranes

surround all cells and organelles membranes are based on LIPID BILAYERS made up of phospholipids, glycosphingolipids, sphingolipids and cholesterol (in animal) Non-polar components minimize exposure to water by forming a bilayer. Polar head groups face outward and H-bond with water Lipid fatty acid chains face inward and interact via hydrophobic interactions

Polar surface contains charged group Hydrophilic surfaces

Hydrophobic tails

Liposome

Inner aqueous compartment

Liposomes are artificially prepared vesicles made of lipid bilayer. - can be filled with drugs and used for drug delivery.

A liposome encapsulates a region on aqueous solution inside a hydrophobic membrane; dissolved hydrophilic solutes cannot readily pass through the lipids. Hydrophobic chemicals can be dissolved into the membrane, and in this way liposome can carry both hydrophobic molecules and hydrophilic molecules.

CHOLESTEROL:
HARMFUL EFFECTS ON HEALTH
over

accumulation of lipids w/ gradual deposition of fats in arteries leads to atherosclerosis heart attack & stroke Atherosclerosis is a disease in which plaque builds up on the insides of arteries. Hardening of arteries. Plaque is made up of fat, cholesterol, calcium, and other substances found in the blood.

 Over

time, plaque hardens and narrows arteries. This limits the flow of oxygen-rich blood to your organs and other parts of your body. can lead to serious problems, including heart attack, stroke, or even death.

Blood flow is impede at site of narrow artery

CROSS SECTIONAL SLIDE OF AN ARTERY W/ PLAQUE

Narrowed Artery Lumen

PLAQUE

DIFFERENT DISEASES MAY DEVELOP BASED ON WHICH ARTERIES ARE AFFECTED.

Coronary artery disease (CAD). Plaque builds up in

the coronary arteries. When blood flow to your heart is reduced or blocked, it can lead to chest pain and heart attack. CAD also is called heart disease, and it's the leading cause of death in the United States. Carotid artery disease. Plaque builds up in the carotid arteries. Arteries supply oxygen-rich blood to your brain. When blood flow to your brain is reduced or blocked, it can lead to stroke. Peripheral arterial disease (PAD). Plaque builds up in the major arteries that supply oxygen-rich blood to the legs, arms, and pelvis. When blood flow to these parts of your body is reduced or blocked, it can lead to numbness, pain, and sometimes dangerous infections.

LIPID METABOLISM
DIGESTION, ABSORPTION, SECRETION, & UTILIZATION OF DIETARY LIPIDS

THE LIVER PLAYS A CENTRAL ROLE IN LIPID TRANSPORT & METABOLISM

The

liver carries out the following major functions: (1) It facilitates the digestion and absorption of lipids by the production of bile, which contains cholesterol and bile salts synthesized within the liver de novo or from uptake of lipoprotein cholesterol. (2) The liver has active enzyme systems for synthesizing and oxidizing fatty acids and for synthesizing triacylglycerols and phospholipids (3) It converts fatty acids to ketone bodies (ketogenesis). (4) It plays an integral part in the synthesis and metabolism of plasma lipoproteins.

LIPID METABOLISM IS CONCERNED MAINLY WITH FATTY ACIDS & CHOLESTEROL

Fatty acids may be oxidized to acetyl- CoA (-oxidation) or esterified with glycerol, forming triacylglycerol (fat) as the bodys main fuel reserve

Fates of Acetyl-CoA formed by -oxidation (1) As with acetyl-CoA arising from glycolysis, it is oxidized to CO2 + H2O via the citric acid cycle. (2) It is the precursor for synthesis of cholesterol and other steroids. (3) In the liver, it forms ketone bodies (acetone, acetoacetate, and 3-hydroxybutyrate) that are important fuels in prolonged starvation.

OVERVIEW OF FATTY ACID METABOLISM

OXIDATION OF FATTY ACIDS: KETOGENESIS

BIOMEDICAL IMPORTANCE
Increased

fatty acid oxidation is a characteristic of starvation and of diabetes mellitus, leading to ketone body production by the liver (ketosis). Ketone bodies are acidic and when produced in excess over long periods, as in diabetes, cause ketoacidosis, which is ultimately fatal. Gluconeogenesis is dependent upon fatty acid oxidation, any impairment in fatty acid oxidation leads to hypoglycemia.
Occurs

in various states of carnitine deficiency.

LONG-CHAIN FATTY ACIDS PENETRATE THE INNER MITOCHONDRIAL MEMBRANE AS CARNITINE DERIVATIVES
Carnitine

palmitoyltransferase-I in the outer mitochondrial membrane converts long-chain acyl-CoA to acylcarnitine, which is able to penetrate the inner membrane. Carnitine-acylcarnitine translocase acts as an inner membrane exchange transporter.

 Acylcarnitine

is transported in, coupled with the transport out of one molecule of carnitine. Acylcarnitine then reacts with CoA, caltayzed by carnitine palmitoyltransferase-II, located on the inside of the inner membrane. Acyl-CoA is reformed in the mitochondrial matrix, and carnitine is liberated.

ROLE OF CARNITINE IN THE TRANSPORT OF LC-FA

BETA -OXIDATION OF FATTY ACIDS INVOLVES SUCCESSIVE CLEAVAGE WITH RELEASE OF ACETYL-COA
Two

carbons at a time are cleaved from acyl-CoA molecules, starting at the carboxyl end. The chain is broken between the (2)- and (3)-carbon atomshence the name -oxidation. The two-carbon units formed are acetyl-CoA; thus, palmitoyl-CoA (forms eight acetyl-CoA molecules)

OVERVIEW OF -OXIDATION OF FATTY ACIDS

THE CYCLIC REACTION SEQUENCE GENERATES FADH2 & NADH

Enzymes,

known collectively as fatty acid oxidase, catalyze the oxidation of acyl-CoA to acetyl-CoA, the system being coupled with the phosphorylation of ADP to ATP.

1st step is the removal of 2 H atoms from the 2()- & 3()-C atoms, by acyl-CoA dehydrogenase and requiring FAD. This results in the formation of 2-trans-enoyl-CoA and FADH2.

The 3-hydroxy derivative undergoes dehydrogenation on the 3-carbon by L(+)-3- hydroxyacyl-CoA dehydrogenase to form 3-ketoacyl-CoA compound. NAD+ is the coenzyme involved resulting to NADH.

OXIDATION OF A FATTY ACID WITH AN ODD NUMBER OF CARBON ATOMS

Fatty

acids with an odd number of carbon atoms are oxidized by the pathway of -oxidation, producing acetyl- CoA, until a three-carbon (propionyl-CoA) residue remains. This compound is converted to succinyl-CoA, a constituent of the citric acid cycle. The propionyl residue from an oddchain fatty acid is the only part of a fatty ac id that is glucogenic.

METABOLISM OF PROPIONATE

OXIDATION OF FATTY ACIDS PRODUCES A LARGE QUANTITY OF ATP

Transport

in the respiratory chain of electrons from FADH2 and NADH will lead to the synthesis of 5 high-energy phosphates for each of the first seven acetyl-CoA molecules formed by -oxidation of palmitate (7 5 = 35). A total of 8 mol of acetyl-CoA is formed, and each will give rise to 12 mol of ATP on oxidation in the citric acid cycle, making 8 12 = 96 mol ATP. Two must be subtracted for the initial activation of the fatty acid, yielding a net gain of 129 mol of ATP per mole of palmitate.

high energy bonds due to thiokinase rxn is considered in the production of palmitoyl CoA so the Net energy yield is 129 ATP

KETOGENESIS
During high rates of fatty acid oxidation,

primarily in the liver, large amounts of acetylCoA are generated. These exceed the capacity of the TCA cycle result synthesis of ketone bodies, or ketogenesis. Ketone bodies: acetoacetate, b-hydroxybutyrate acetone

CLINICAL SIGNIFICANCE OF KETOGENESIS

Normal physiological responses to carbohydrate

shortages cause the liver to increase the production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation. This allows the heart and skeletal muscles primarily to use ketone bodies for energy, thereby preserving the limited glucose for use by the brain. The most significant disruption in the level of ketosis, leading to profound clinical manifestations, occurs in untreated insulindependent diabetes mellitus)

DIABETIC KETOACIDOSIS (DKA)

results from a reduced supply of glucose (due to

a significant decline in circulating insulin) and a concomitant increase in fatty acid oxidation (due to a concomitant increase in circulating glucagon). The increased production of acetyl-CoA leads to ketone body production that exceeds the ability of peripheral tissues to oxidize them. Ketone bodies are relatively strong acids (pKa around 3.5), and their increase lowers the pH of the blood. This acidification of the blood is dangerous chiefly because it impairs the ability of hemoglobin to bind oxygen.

KETONE SYNTHESIS
In early stages of starvation, when the last

remnants of fat are oxidized, heart and skeletal muscle will consume primarily ketone bodies to preserve glucose for use by the brain. HMG-CoA (or 3-hydroxy-3-methylglutarylcoenzyme A) is an intermediate in the mevalonate and ketogenesis pathways formed from acetyl CoA and acetoacetyl CoA by HMG-CoA synthase. HMG-CoA synthetase Rate limiting step

Ketones utilized by extrahepatic tissues the conversion of b-hydroxybutyrate to acetoacetate & of acetoacetate to acetoacetyl-CoA The first step involves reversal of the b-hydroxybutyrate dehydrogenase reaction, the second involves the action of acetoacetate:succinyl-CoA transferase, also called ketoacyl-CoA-transferase.

Acetoacetate + Succinyl-CoA AcetoacetylCoA + succinate

The enzyme succinylCoA:acetoacetate CoA

transferase is present in all tissues except the liver. its absence allows the liver to produce ketone bodies but not to utilize them. ensures that extrahepatic tissues have access to ketone bodies as a fuel source during prolonged starvation. Acetoacetyl-CoA is converted into two molecules of acetyl-CoA by a thiolase :

Metabolism of the Eicosanoids

The eicosanoids consist of the prostaglandins

(PGs), thromboxanes (TXs) and leukotrienes (LTs). The PGs and TXs are collectively identified as prostanoids. Prostaglandins were originally shown to be synthesized in the prostate gland, thromboxanes from platelets (thrombocytes) leukotrienes from leukocytes, hence the derivation of their names.

Prostaglandin Synthesis
Dietary precursor of PGs is the essential FA

linoleic acid 20 C PUFA arachidonic acid First step is cyclization of Arachidonic acid PGG2 & PGH2 by the prostaglandin endoperoxide synthethase complex: - 2 complex: FA cyclooxygenase Peroxidase

Biological Actions of PGs

Cyclooxygenases Prostaglandins are produced following the sequential

oxidation of AA, DGLA or EPA by cyclooxygenases (COX-1 and COX-2) and terminal prostaglandin synthases. The classic dogma is as follows: COX-1 is responsible for the baseline levels of prostaglandins. COX-2 produces prostaglandins through stimulation. However, while COX-1 and COX-2 are both located in the blood vessels, stomach and the kidneys, prostaglandin levels are increased by COX-2 in scenarios of inflammation. A third form of COX, termed COX-3, has been identified, but its exact function is still being determined

 COX1 derived

PGs Inhibition of NSAID to Cox is non specific which account for its toxicity in the stomach Leading to stomach ulceration Cox2 selective used in arthritic patients

 Prostaglandins thus act on a variety of cells, and

have a wide variety of actions: cause constriction or dilatation in vascular smooth muscle cells cause aggregation or disaggregation of platelets sensitize spinal neurons to pain constrict smooth muscle regulate inflammatory mediation cox2 drugs regulate calcium movement control hormone regulation control cell growth

Role in Pharmacology
Inhibition Examples of prostaglandin antagonists are: NSAIDs (inhibit cyclooxygenase) Corticosteroids (inhibit phospholipase A2

production) COX-2 selective inhibitors or coxibs However, both NSAIDs and Coxibs can raise the risk of myocardial infarction
Increased platelet aggregations noted in arthritic

patients (RofecoxiB)

CLINICAL

USES

Synthetic prostaglandins are used: To induce childbirth (parturition) or abortion (PGE2 or

PGF2, with or without mifepristone, a progesterone antagonist); To prevent closure of patent ductus arteriosus in newborns with particular cyanotic heart defects (PGE1) To prevent and treat peptic ulcers (PGE) As a vasodilator in severe Raynaud's phenomenon or ischemia of a limb In pulmonary hypertension In treatment of glaucoma (as in bimatoprost ophthalmic solution, a synthetic prostamide analog with ocular hypotensive activity) To treat erectile dysfunction or in penile rehabilitation following surgery (PGE1 as alprostadil).

Phospholipid degradation
results from the action of phospholipases. There are various phospholipases that exhibit

substrate specificities for different positions in phospholipids. In many cases the acyl group which was initially transferred to glycerol, by the action of the acyl transferases, is not the same acyl group present in the phospholipid when it resides within a membrane. The remodeling of acyl groups in phospholipids is the result of the action of phospholipase A1 and phospholipase A2.

Sites of action of the phospholipases A1, A2, C and D.

 The products of these phospholipases are called

lysophospholipids & can be substrates for acyl transferases utilizing different acyl-CoA groups

Lysophospholipids can also accept acyl groups from other phospholipids in an exchange reaction catalyzed by lysolecithin:lecithin acyltransferase (LLAT). Phospholipase A2 is also an important enzyme, whose activity is responsible for the release of arachidonic acid from the C-2 position of membrane phospholipids.
The released arachidonate is then a substrate for the synthesis of the prostaglandins and leukotrienes