CHAPTER 7

CHAPTER 7: LIPID METABOLISM

LIPID STRUCTURE & FUNCTION

What is a Lipid

Lipids: a heterogeneous class of naturally occurring organic compounds
•insoluble in water, but soluble in organic solvents including diethyl ether, chloroform, methylene chloride, and acetone

Lipids include:
Open Chain forms:
•fatty acids, triacylglycerols, sphingolipids, phosphoacylglycerols, glycolipids,
•lipid-soluble vitamins
Cyclic forms:
•cholesterol, steroid hormones, and bile acids

Fatty Acids (an unbranched-chain carboxylic acid)
•FA are amphipathic compounds (carboxyl group is hydrophilic & hydrocarbon tail is hydrophobic)
•Fatty acids derived from hydrolysis of animal fats, vegetable oils, or phosphodiacylglycerols of biological membranes
•Length of fatty acid plays a role in its chemical character
•Usually contain even numbers of carbons
•FA that contain double bond (C=C), are unsaturated
•If  FA contain only single bond (C-C), they are saturated

Unsaturated Fatty Acids
•In most unsaturated FA, the cis isomer predominates; the trans isomer is rare
•Unsaturated FA have lower melting points than the saturated FA.
•Plant oils are liquid at room temperature (RT) because they have higher proportions of unsaturated FA than the saturated animal fats which tend to be solid at RT.

Triacylglycerols (TAG)
• Triacylglycerol (triglyceride): an ester of glycerol with three fatty acids
• TAG is a non-polar lipid
• TAG are the major storage form of fats in animal and plant, ie as animal fats or vegetable oils.
• TAG yields higher energy than glycogen

Hydrolysis of triglycerides (TAG)
•In organisms, the ester linkages of TAG are hydrolyzed by enzyme lipase.
•Outside organisms, the ester linkages can be hydrolyzed with acids or bases.
•Soaps are prepared by boiling TAG with NaOH, in a reaction called saponification (Latin, sapo, soap)
•Soap is the ‘salt’ of the long-chain FA.

Phospholipids
•When one alcohol group of glycerol is esterified by a phosphoric acid rather than by a carboxylic acid, phosphatidic acid (phospholipids) is produced
•Phosphoacylglycerols (phosphoglycerides) are the second most abundant group of naturally occurring lipids, and they are found in plant and animal membranes

Waxes
•A complex mixture of esters of long-chain carboxylic acids and alcohols
•Found as protective coatings for plants and animals

Sphingolipids
•Contain sphingosine, a longchain amino alcohol sphingosine
•Found in plants and animals
•Abundant in nervous system
Glycolipids
•Glycolipid: a compound in which a carbohydrate (sugar) is bound to an -OH of the lipid
•In most cases, sugar is either glucose or galactose
Steroids
•Steroids: a group of lipids that have fused-ring structure of 3 six-membered rings, and 1 fivemembered ring.
•The steroid of most interest in biological membranes is cholesterol

Biological Membranes
•Every cell has a cell membrane (plasma membrane)
•Eukaryotic cells also have membrane-enclosed organelles (nuclei, mitochondria…etc)
•Molecular basis of membrane structure is in lipid component(s) –known as ‘lipid bilayer’.
•Polar head groups are in contact with the aqueous environment
•Nonpolar tails are buried within the bilayer
•The arrangement of hydrocarbon tails in the interior can be rigid (if rich in saturated fatty acids) or fluid (if rich in unsaturated fatty acids)

Lipid Bilayers
•The polar surface of the bilayer contains charged groups
•The hydrophobic
tails lie in the interior of the bilayer

LIPID METABOLISM

 
A) LIPID CATABOLISM

Lipids are Involved in Generation and storage of Energy
•The oxidation of fatty acids (FA) in triacylglycerols (TAG) are the principal storage form of energy for most organisms
•Their carbon chains are in a highly reduced form
•The energy yield per gram of fatty acid oxidized is greater than that per gram of carbohydrate oxidized

Catabolism of Lipids
•Lipases catalyze hydrolysis of bonds between FA and the rest of triacylglycerols
•Phospholipases catalyze hydrolysis of bonds between fatty acid and the rest of phosphoacylglycerols

Fatty Acid Activation
•Fatty acid must be activated to begin the β-Oxidation.
•The FA is linked to Acyl- carrier protein (ACP) as the carrier of FA.
•The FA is activated with CoA-SH to form Fatty Acyl-CoA. This reaction requires ATP.
•The reaction occurs in the cytosol.

The Role of Carnitine in Acyl-CoA Transfer
•β-Oxidation occurs in the matrix of mitochondria. However, the fatty acyl-CoA can only cross the outer mitochondrial membrane, but not the inner membrane
•In the intermembrane space, the acyl group is  transferred to carnitine to form acyl-carnitine
•Acyl-carnitine can cross the inner mitochondrial membrane via a specific carnitine/acyl-carnitine transporter.
•Once in the matrix, the acyl group is transferred from carnitine to mitochondrial-CoA-SH to form back fatty acylCoA.
•Fatty acyl-CoA will be then degraded via β-Oxidation in the matrix of mitochondria

The Role of Carnitine in Acyl-CoA Transfer
•β-Oxidation occurs in the matrix of mitochondria.
•β-Oxidation: a series of reactions that cleaves carbon atoms two at a time from the carboxyl end of a fatty acid
•The carbon of the original FA becomes the carboxyl carbon in the next stage of oxidation.
•The complete cycle of one β-oxidation requires 4 reactions:
•Reaction 1: Oxidation of the ,β carbon-carbon single bond to a carbon-carbon double bond
•Reaction 2: Hydration of the carbon-carbon double bond
•Reaction 3: Oxidation of the -hydroxyl group to a carbonyl group
•Reaction 4: Cleavage (cleavage of the carbon chain to produce acetyl-CoA and an acyl-CoA that is two carbon shorter).
•The smaller acyl-CoA then undergoes another round of β-oxidation.
The complete cycle of one β-Oxidation produces:
•1 FADH2
•1 NADH
•1 acetyl-CoA
•1 acyl-CoA



Total β-Oxidation product:
8 FADH2
8 NADH
9 acetyl-CoA

Energy yield from stearic acid  oxidation
•The energy released by the oxidation of acetyl-CoA formed by β-oxidation of FA can be used to produce
ATP
•Eight cycles of β-oxidation are required for the oxidation of Stearic acid (18C) to acetyl-CoA

Energy yield from stearic acid oxidation
•The overall equation for oxidation of stearic acid can be obtained by adding the equations for β-oxidation, the citric acid cycle, and oxidative phosphorylation

Energy yield from stearic acid  oxidation (18C)
+
 
Energy yield from stearic acid  oxidation
•The complete oxidation of FA by the citric acid cycle and the electron transport chain releases large amounts of energy
•When we include the reoxidation of NADH and FADH2 from β-oxidation and the citric acid cycle, we obtain a net yield of 120 ATP  from one molecule of stearic acid

Metabolic fates of acetyl-CoA
• Major metabolic fates of acetyl-CoA:
1.ATP productions
2.Ketone bodies production
3.Fatty acid biosynthesis
4.Cholesterol biosynthesis
•If an organism has an excess of acetyl-CoA, it produces ketone bodies.
•Formation of ketone bodies occurs when the amount of acetyl-CoA produced is excessive compared to the amount of oxaloacetate available in the kreb cycle.

•This situation can arise from:

1. Intake high in lipids and low in carbohydrates
2. Diabetes not suitably controlled
3. Starvation

Ketone Bodies

LIPID ANABOLISM

Fatty Acid Biosynthesis

•Carboxylation of acetyl-CoA to produce malonylCoA.
•Malonyl-CoA is a key intermediate in FA biosynthesis
•Malonyl-CoA is produced from Acetyl-CoA.
•Catalyzed by acetyl-CoA carboxylase
•9 Biotin is the carrier of the carboxyl group
•Acetyl-CoA is the precursor for FA biosynthesis.
•The biosynthesis of FA proceeds by the addition of 2carbon units from malonyl-CoA to the hydrocarbon chain.
•The process is catalyzed by the fatty-acid synthase complex
•The process uses NADPH as the reducing agents.
•FA forms thiodiester with acyl-carrier protein (ACP)
Biosynthesis of Palmitate (16 carbon)
•Acetyl and malonyl building blocks are introduced as acylcarrier protein conjugates.
•Decarboxylation drives addition of 2-carbon units from malonyl-CoA to the growing chain to produce butyryl-ACP.
•Cycle repeats 6 more time to produce 16C palmitate


Biosynthesis of Palmitate (16 carbon) 


Cholesterol Biosynthesis
•Cholesterol is only synthesized in animal cells.
•Cholesterol and steroids are synthesized from two acetyl-CoA
•Involves many reaction steps. Some reactions require ATP and NADPH.
•Involvement of isoprene units are key to the biosynthesis of steroids and other biomolecules known as terpenes
•Cholesterol is the precursor for bile salts and a number of steroid hormones

Overall View of Cholesterol Biosynthesis

Lipoproteins
•Lipids are transported in the blood stream by lipoproteins.
•Lipoproteins are water soluble lipids
•Cholesterol and its fatty acid esters are packaged into several classes of lipoproteins for transport
•4 major lipoproteins:
1) Chylomicrons: transport dietary lipids (TAG) from intestine to tissues
2) VLDL: transport endogenous lipids (TAG) from liver to tissues
3) LDL:  transport cholesterol to cells/tissues
4) HDL: reverse cholesterol transport

Role of Cholesterol in Heart Disease
•LDL (known as bad cholesterol) plays a role in heart disease
•LDL transport cholesterol to peripheral tissues
•HDL (known as good cholesterol)- transport cholesterol from peripheral tissues to liver for elimination