1

Lipids•Organic compounds found in living organisms (humans, animals, plants, microorganisms) that are insoluble in water but soluble in organic solvents.

•Named for the Greek word lipos, which means “fat.”

Lipids – molecular Structure and Behavior

Generally water insoluble due to the large portion of their structure that is hydrocarbon based.

Hydrophilic

Hydrophobic

Lipids do not form large covalent polymers, instead they tend to associate with each other through noncovalent interactions.

In aq. environments they tend to associate for two reasons: 1. entropy-driven hydrophobic effect between nonpolar tails.2. stabilizing force from van der Waals interactions between nonpolar tails.

Therefore, lipids are rarely found free in solution. Rather, they are part of a complex with soluble protein transporters or higher-order assemblies that sequester the hydrophobic surface area from the surrounding aq. environment.

Exactly what kind of structure is formed when a lipid is in contact with water depends on the specific molecular structure of the hydrophilic and hydrophobic parts of that lipid structure.

4

Fatty acids

• First isolated from naturally occurring fats.

• Simplest type of lipid.

• Are long-chain carboxylic acids.

• Typically contain even number of C atoms, ~12-24 carbon atoms.

• Found as a component of more complex lipids.

saturated

FAs monounsaturated ( 1 double bond)

Unsaturated

polyunsaturated (>1 double bond).

• Unsaturated can be cis or trans.

• FAs exist in the anionic form (RCOO-) at physiological pH.

The simplest lipids are the Fatty acids

• Molecules that fit closely together in a regular pattern.• Strong attractions between fatty acid chains:. More energy required to separate

“melt”• High melting points that make them solids at room temperature.• As the C chain increases, so does the mp.

• Do not pack closely. • Have few attractions between chains:. Less energy to melt.• Have low melting points.• Are liquids at room temperature.• In most unsaturated fatty acids, the cis isomer predominates; the trans isomer is

rare• Unsaturated fatty acids have lower melting points than their saturated

counterparts; the greater the degree of unsaturation, the lower the melting point.

7

More than 500 FAs have been isolated from lipids of microorganisms, plants, animals, and humans. FAs are rarely found free in nature but rather occur as part of the structure of more complex lipid molecule such as triacylglycerols.

Linoleic acid

Linolenic acid

Arachidonic acid

Animals generally do not produce via biosynthesis all the polyunsaturated fatty acids (PUFAs) needed for proper cell function; thus, these must be part of their diet.Humans are capable of synthesizing most PUFAs from carbohydrates and other FAs.Humans do not synthesize sufficient amounts of:

-6

-6

-3

Essential FAs

Omega-6 and Omega 3- Fatty Acids

Linoleic, linolenic, and arachidonic acids are essential fatty acids can not be produced by humans and must be obtained from diet.

9

Omega-6 and Omega 3- Fatty Acidslower the tendency of blood platelets from sticking together:. Reducing the possibility of blood clots.Fish that live in deep, cold water are better sources of omega-3 fatty acids than other fish.

TriacylglycerolsThe long hydrocarbon tails of FAs are extraordinarily efficient for energy storage because they contain C in a reduced form and can yield a large amount of energy on oxidation.

Storage of FAs in organisms is largely in the form of triacylglycerols (TAGs), or triglycerides, or simply fats.

Most TAGs are “mixed fats” containing a mixture of different FAs.

TAGs 9.2 Kcal/gGlycogen 4.0 Kcal/g

C atoms in TAGs are more reduced than those in glycogen. They contain more hydrogen and less oxygen

11

Increases the melting point and shelf life.Produces solids such as margarine and shortening.

Here, the reforming of the double bond competes with hydrogen addition. The reforming yields predominantly the trans isomer because it is more stable than cis.

Chemical properties of TAGs

Hydrogenation

• Adds hydrogen (H2) to the carbon atoms of double bonds in the presence of a Ni or Pt catalyst.

• Converts double bonds to single bonds.

During hydrogenation, • double bonds are converted to C — C single

bonds.• a small number of the cis double bonds are

converted to more stable trans double bonds, causing a change in the overall structure of the fatty acids.

In the body, trans fatty acids •behave like saturated fatty acids.•are estimated to be 2–4% of our total calories.•raise LDL-cholesterol and lower HDL-cholesterol.

13Mozaffarian D et al. N Engl J Med 2006;354:1601-1613

Changes in Total : HDL Cholesterol (Panel A) and Levels of LDL and HDL Cholesterol (Panel B) Resulting from the Replacement of Saturated or Cis Unsaturated Fatty Acids with Trans Fatty Acids

Raises LDL“bad cholesterol”

lowers HDL“good cholesterol”

P< 0.05 statistical treatment of data shows < 5% error95% sure the data is true & supports the hypothesis

Trans fatty acids & Coronary Heart Disease

Several studies reported to raise LDL-”bad cholesterol” and lower HDL-”good cholesterol”.

Butter Margarine, stick Margarine, tub

15

The reaction of a fat with a strong base.Splits triacylglycerols into glycerol and the salts of fatty acids. The process is used to make “soaps” (salts of fatty acids).With KOH gives softer soaps.

Saponification (sae-pon-if-i-ka-tion)

16

HydrolysisTriacylglycerols are esters and as such undergo:Acid hydrolysis glycerol and three fatty acids Base hydrolysis = saponification glycerol + carboxylate

salts

Digestion = controlled hydrolysisControlling agents = enzymes called lipasesNecessary since TAGs are too large to diffuse through the intestinal membraneTakes place in the small intestine where the pH is basicBile salts help the processEnzyme hydrolysis = digestion DAGs + MAGs + FAs

17

RancidityButter, salad & cooking oils, mayonnaise and fatty meats can become rancid developing unpleasant odors and flavors.

Two reactions: 1. bacterial hydrolysis of ester groups

2. air oxidation of alkene double bonds [O]

/\/\/\/\/\/\CH=CH/\/\/\/\/\/COOH /\/\/\/\/\/\/COOH + HOOC/\/\/\/\/\/\/\/COOH

These low weight CAs and di-CAs are volatile generally malodorous and off-flavors.

The oils (triacylglycerols) present in skin perspiration rapidly undergo oxidation. The oxidation products, short-chain aldehydes and short-chain carboxylic acids, often have strong unpleasant odors.

Phospholipids are lipids that contain a phosphorus atom. Two common types of phospholipids are glycerophospholipids and sphingolipids. 

Both classes are found almost exclusively in the cell membranes of plants and animals.

Glycerophospholipids are the most common type of phospholipid. They form the principal lipid component of most cell membranes. 

There are two prominent types of glycerophospholipids. They differ in the identity of the R” group.

•When R″ = CH2CH2NH3+, the compound is called

a cephalin or phosphatidylethanolamine.•When R″ = CH2CH2N(CH3)3

+, the compound is called a lecithin or phosphatidylcholine.

A glycerophospholipids has two distinct regions: two nonpolar tails due to the long-chain fatty acids, and a very polar head from the charged phosphodiester.

Phospholipids, especially glycerophospholipids, are the major component of the cell membrane.

Sphingolipids, the second major class of phospholipids, differ in two important ways from the triacylglycerols and the phosphoacylglycerols:

•Sphingomyelins do not contain a glycerol backbone. Instead, sphingomyelins are derived from sphingosine.•Sphingomyelins do not contain an ester. Instead, their single fatty acid is bonded to the carbon backbone by an amide bond.

They were discovered in brain extracts in the 1870s and were named for the mythological Sphinx because of their mysterious nature. These compounds play important roles in signal transmission and cell recognition.

If the FA is bonded via the –NH2 group, giving rise to an amide, the sphingolipid is referred to as a ceramide (pronounced ser-A-mid).

If the lipid contains saccharides, they go under the general name of glycolipids. Glycosphingolipids include such molecules as: Cerebrosides- monoglycosylceramides.Gangliosides- anionic glycosphingolipids containing one or more sialic acid residues.As the name implies, these are common in the membrane of brain and nerve cells.

The coating that surrounds and insulates nerve cells, the myelin sheath, is particularly rich in sphingomyelins, and is vital for proper nerve function. Deterioration of the myelin sheath, as seen in multiple sclerosis, leads to disabling neurological disorders.

Multiple sclerosis (MS) is a degenerative disease characterized by scarring of the myelin sheath, the insulating layer that surrounds a nerve fiber. Without the protective myelin sheath, normal nerve transmission is disrupted and a variety of effects—numbness, blindness, speech disorders, and tremors—can result.

Further modifications to the hydroxyl group, leads to a variety of other sphingolipids. One important example is sphingomyelin.

Cholesterol an important component of many cell membranes is classified as a lipid even as it bears little resemblance to the compounds just discussed.

It is a biosynthetic precursor for a large group of compounds called steroids.

Steroids = compounds containing the steroid nucleus

The main producer of cholesterol is the liver at around 1,000 mg per day.

cholesterogenesis ~26 separate reactions are believed to be involved in the synthesis of cholesterol:

Acetate -(4 steps) mevalonic acid -(7 steps)squalene -(15 steps) cholesterolOf that amount, about 800 mg becomes bile salts, which are necessary for the digestion of fats. That leaves about 200 available for other functions.

Every 100 mL of human blood plasma contains ~50 mg of free cholesterol and ~170 mg of cholesterol esterified with fatty acids.

Transport of fat to tissue Lipoproteins

Lipids are nonpolar and insoluble in the aqueous environment of the blood.

They are more soluble when combined with glycerophospholipids & polar proteins, in a complex called a lipoprotein.

Cholesterol is carried through the bloodstream in a

package known as a lipoprotein.

25

Classification of Lipoproteins based on density

LDL is the principal form in which cholesterol is transported to tissue.

HDL plays the primary role in returning excess cholesterol from tissues to the liver for metabolism or excretion.

26

The most common type of lipid carrier is LDL. The LDL-cholesterol complex (LDL-C) is taken into cells by receptor-mediated endocytosis when LDL-C binds to LDL receptors.

People who inherit a genetic defect that decreases the number of LDL receptors can not transport cholesterol normally into the cells. As a result LDL-C remains in the plasma and cholesterol starts to get deposited elsewhere including the coronary arteries.

A physical examination by a physician includes blood work that measures three quantities: total serum cholesterol, HDL cholesterol, and LDL cholesterol

Several drugs called statins are now available to reduce the level of cholesterol in the bloodstream. These compounds act by blocking the synthesis of cholesterol at its very early stages. Two examples include atorvastatin (Lipitor) and simvastatin (Zocor).

28

LDL Receptor

Acetate

LDLLDL

HMG-CoAReductase

Cholesterol

The molecular mechanisms by which statins act include inhibiting the rate of conversion of acetate molecules into cholesterol by the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, in cholesterol biosynthesis. Because a precise amount of cholesterol is required in cells, inhibition of synthesis leads to a homeostatic response in which cells increase the density of LDL receptors on their surface. This increases the clearance rate of LDL particles from the plasma and reduces plasma LDL cholesterol secondarily.

Treatment for high cholesterolInhibitors of Cholesterol Synthesis and

Absorption Inhibitors of Cholesterol Synthesis: Statins

Mechanism: Promote LDL Clearance

• Are synthesized in the liver from cholesterol.

• Are stored in the gallbladder.

• Are secreted into the small intestine.

• Have a polar and a nonpolar region

• Mix with fats to break them part.

• Emulsify fat particles to provide large surface area.

• Lipases digest these smaller segments of fat

• Needed for the efficient intestinal absorption of fat soluble vitamins (A, D, E & K)

Nonpolar region

Polar region

Bile salts also called bile acids or just Bile

30

The conversion of cholesterol into bile salts, as well as solubilization of cholesterol by bile salts in the bile, is the way in which cholesterol is eliminated through the intestinal tract

When bile contains high concentration of cholesterol, it precipitates in the form of gallstones.A large percentage of gallstones are almost pure crystallized cholesterol.

http://youtu.be/hJ_rzvboqKo

31

Steroid Hormones

• Are produced from cholesterol. • Are chemical messengers in cells.• One group of hormones.• Produced in the endocrine glands.

Pituitary GlandHypothalamusThymusPineal GlandTestesOvariesThyroidAdrenal GlandsParathyroidPancreas

• Include sex hormones such as androgens (testosterone) in males and estrogens (estradiol) in females.

Two important classes of steroid hormones are the sex hormones and the adrenal cortical steroids.

There are two types of female sex hormones, estrogens and progestins.

•Estradiol and estrone are estrogens synthesized in the ovaries. They control the development of secondary sex characteristics in females and regulate the menstrual cycle.•Progesterone is a progestin often called the “pregnancy hormone.” It is responsible for the preparation of the uterus for implantation of a fertilized egg.

The male sex hormones are called androgens.

•Testosterone and androsterone are androgens synthesized in the testes. They control the development of secondary sex characteristics in males—growth of facial hair, increase in muscle mass, and deepening of the voice.

Synthetic androgen analogues, called anabolic steroids, promote muscle growth. They were first developed to help individuals whose muscles had atrophied from lack of use following surgery. They have since come to be used by athletes and body builders, although their use is not permitted in competitive sports. Many physical and psychological problems result from their prolonged use.Anabolic steroids, such as stanozolol, nandrolone, and tetrahydrogestrinone have the same effect on the body as testosterone, but they are more stable, so they are not metabolized as quickly. Tetrahydrogestrinone (also called THG or The Clear), the performance-enhancing drug used by track star Marion Jones during the 2000 Sydney Olympics, was considered a “designer steroid” because it was initially undetected in urine tests for doping. After its chemical structure and properties were determined, it was added to the list of banned anabolic steroids in 2004.

34

Cell Membranes

Consist of a lipid bilayer made of two rows of phospholipids.Have an inner portion made of the nonpolar tails of phospholipids with the polar heads at the outer and inner surfaces.

Both inner and outer layers of bilayer contain mixtures of lipids

Compositions on inside and outside of lipid bilayer can be different

This is what distinguishes the layers

35

Fluid Mosaic Model of Membrane Structure

The lipid bilayer • Contains proteins, carbohydrates, and cholesterol.• Has unsaturated fatty acids that make cell membranes fluid-like rather than rigid.• Has proteins and carbohydrates on the surface that communicate with hormones

and neurotransmitters.