Chapter 21Lipid Metabolism

Mary K. CampbellShawn O. Farrellhttp://academic.cengage.com/chemistry/campbell

Paul D. Adams • University of Arkansas

Generation and Storage of Energy

• The oxidation of fatty acids (FA)in triacylglycerols is the _________________________________ 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

• ____________ catalyze hydrolysis of bonds between fatty acid and the rest of triacylglycerols

• __________________ catalyze hydrolysis of bonds between fatty acid and the rest of phosphoacylglycerols

• May have multiple sites of action

Fatty Acid Activation

• Fatty acid oxidation begins with ____________• A thioester bond is formed between the carboxyl

group of the FA and the thiol of CoA-SH

The Role of Carnitine in Acyl-CoA Transfer

• The acyl-CoA crosses the ____________ mitochondrial membrane, but not the ____________ membrane

• The acyl group is then transferred to carnitine, carried across the inner mitochondrial membrane, and transferred to mitochondrial CoA-SH

• Carnitine Palmitoyltransferase (CPT-1) has specificity for acyl groups between 14 and 18 carbons long

The Role of Carnitine in Acyl-CoA Transfer

-Oxidation

• -Oxidation:-Oxidation: a series of reactions that cleaves carbon atoms __________ at a time from the carboxyl end of a fatty acid

• The complete cycle of one -oxidation requires four enzymes• Reaction 1: Oxidation of the , 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 of the carbon chain by a

reverse Claisen reaction

-Oxidation

Summary

• Fatty acids are activated and transported to the mitochondrial matrix for further catabolism

• The breakdown of fatty acids takes place in the mitochondrial matrix and proceeds by successive removal of two-carbon units as acetyl-CoA

• Each cleavage of a two-carbon moiety requires a four-step reaction sequences called -oxidation

Energy Yield from FA Oxidation

• The energy released by the oxidation of acetyl-CoA formed by -oxidation of FA can drive ___ synthesis

• ____________ cycles of -oxidation are required for the oxidation of stearic acid to acetyl-CoA

Energy Yield from FA Oxidation

• The overall equation for oxidation of stearic acid can be obtained by adding the equations for -oxidation, the ______________________, and ___________________________________

Energy Yield from FA Oxidation

Summary

• 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 -oxidation and the citric acid cycle, we obtain a net yield of 120 ATP for a single molecule of stearic acid

Catabolism of Odd-Numbered FA

• Odd-numbered FA are not frequently encountered, but do also undergo -oxidation

• The last -oxidation cycle of a fatty acid with an odd number of carbons gives

_______________

_______________

Oxidation of an Unsaturated FA

• A cis-trans isomerization is needed to convert unsaturated FA to acetyl-CoA

• This enzyme is known as an ______________

• Oxidation of unsaturated FA does not generate as much ATP relative to saturated FA with the same # of carbons

Oxidation of an Unsaturated FA

Summary

• FA with odd number of carbons produce propionyl-CoA in the last step of the oxidation

• Propionyl-CoA can be converted to succinyl-CoA, which plays a role in the citric acid cycle

• The oxidation of unsaturated FA requires enzymes that catalyze isomerization around the double bonds so that oxidation can proceed

Ketone Bodies

• Formation of ketone bodies occurs when the amount of acetyl-CoA produced is excessive compared to the amount of oxaloacetate available to react with it• Intake high in _______ and low in ______________ • Diabetes not suitably controlled• Starvation

• Ketone bodies Ketone bodies areare: acetone, -hydroxybutyrate, and acetoacetate• Formed principally in ___________ mitochondria• Can be used as a fuel in most tissues and organs

Ketone Bodies

Summary:

• If an organism has an excess of acetyl-CoA, it produces ketone bodies.

• This situation can arise from an excessive intake of fats compared to carbohydrates, or from diabetes.

Fatty Acid Biosynthesis

• Biosynthesis is not exact reversal of oxidation

• Biosynthetic reactions occur in the ___________

Fatty Acid Biosynthesis

• Carboxylation of acetyl-CoA occurs in the cytosol• Catalyzed by acetyl-CoA carboxylase• ___________ is the carrier of the carboxyl group• Malonyl-CoA is key intermediate that is produced

Biosynthesis of Palmitate

Sites of Fatty Acid Metabolism in an Animal Cell

Summary

• Acetyl-CoA is transported to the cytosol and converted to malonyl-CoA• The biosynthesis of FA proceeds by the addition of 2-carbon units to the

hydrocarbon chain. • The process is catalyzed by the fatty-acid synthase complex

Comparison of FA Degradation and Biosynthesis

Triacylglycerol Biosynthesis

Lipids such as triacylglycerols, phosphoacylglycerols, and steroids are derived ___________

__________________

Biosynthesis of Phosphoacylglycerols

Biosynthesis of Sphingosine/Ceramide

Requires starting materials _______________and serine

Cholesterol Biosynthesis

• All carbon atoms of cholesterol and steroids synthesized from it are derived from the two-carbon acetyl group of ___________________

• Involves many reaction steps

• Involvement of ___________ units are key to the biosynthesis of steroids and other biomolecules known as ________

Overall View of Cholesterol Biosynthesis

Cholesterol Biosynthesis

• Synthesis begins with the condensation of 2 molecules of __________________

• Next, condensation with a 3RD molecule of __________

• The formation of mevalonate is completed by reduction of the thioester to a 1° alcohol

Mevalonate to Squalene

• The pyrophosphosphorylation of the 1° alcohol of mevalonate (two moles of ATP) is followed by phosphorylation of the 3° alcohol (one mole of ATP), then the concerted decarboxylation and -elimination of phosphate ion gives ______________________ ______________________

• Then there is an enzyme-catalyzed isomerization of the carbon-carbon double bond that gives dimethylallyl pyrophosphate

• Dimethylallyl pyrophosphate is then converted to isopentyl pyrophosphate, which is followed by H+ loss to give farnesyl pyrophosphate

• The joining together of two units of farnesyl pyrophosphate (C15) units by a 2-electron oxidation gives ___________ (C30)

The Conversion of Mevalonate to Squalene

Squalene to Cholesterol

Cholesterol as a Precursor

Cholesterol is the precursor for a number of ______________________

______________________

Role of Cholesterol in Heart Disease

• Lipids are transported in the blood stream by ______________________

• Cholesterol and its fatty acid esters are packaged into several classes of lipoproteins for transport

The LDL Particle

The Fate of Cholesterol

Summary

• The biosynthesis of cholesterol proceeds by the condensation of five-carbon isoprenoid units

• Isoprenoid units in turn are derived from the reaction of three acetyl-CoA units

• Once cholesterol is formed, it serves as a precursor for other steroids

• Cholesterol must be packaged for transport in the bloodstream. Some of these forms of cholesterol play a role in heart disease