Chapter 17: Fatty Acid Catabolism

Question 1

• The oxidation of long-chain fatty acids to acetyl-CoA is a central _____-_____ pathway in many organisms and tissues.
• The electrons removed from fatty acids during oxidation pass through the ______ _____, driving _____ synthesis
• The _____ produced from the fatty acids may be completely oxidized to _____ in the citric acid cycle, resulting in further energy conservation

Answer 1

• energy-yielding
• respiratory chain, ATP
• acetyl-CoA, CO₂

Question 2

β oxidation overview

Answer 2

• repetitive four-step process
• converts fatty acids into acetyl-CoA
• To overcome the relative stability of the C—C bonds in a fatty acid, the carboxyl group at C-1 is activated by attachment to coenzyme A, allowing stepwise oxidation of the fatty acyl group at the C-3, or β, position

Question 3

properties of triacylglycerols (triglycerides, neutral fats) that make them especially suitable as storage fuels

Answer 3

• The long alkyl chains of their fatty acids are highly reduced hydrocarbons w/an energy of complete oxidation (≈38 kJ/g) more than twice of carbohydrate or protein
• extreme insolubility of lipids in water
• because of their relative chemical inertness they can be stored in large quantity in cells without the risk of undesired chemical reactions

Question 4

Because they are insoluble in water, ingested triacylglycerols must be _____ before they can be digested by water-soluble enzymes in the intestine. Triacylglycerols absorbed in the intestine or mobilized from storage tissues must be carried in the blood bound to _____ that counteract their insolubility.

Answer 4

• emulsified
• proteins

Question 5

The complete oxidation of fatty acids to CO2 and H2O takes place in three stages:

Answer 5

• oxidation of long-chain fatty acids to two-carbon fragments, in the form of acetyl-CoA (β oxidation)
• oxidation of acetyl-CoA to CO2 in the citric acid cycle (
• the transfer of electrons from reduced electron carriers to the mitochondrial respiratory chain

Question 6

Cells can obtain fatty acid fuels from three sources:

Answer 6

• consumed in the diet
• stored in cells as lipid droplets
• synthesized in one organ for export to another

Question 7

emulsify

Answer 7

• make into or become an emulsion
• mixing of two liquids that usually are unmixable together to form an emulsion

Question 8

bile salts

Answer 8

• synthesized from cholesterol in the liver
• stored in the gallbladder, and released into the small intestine after ingestion of a fatty meal
• amphipathic compounds
• biological detergents that convert dietary fats into mixed micelles of bile salts and triacylglycerols

Question 9

apolipoproteins

Answer 9

• lipid-binding proteins in the blood
• responsible for the transport of triacylglycerols, phospholipids, cholesterol, and cholesteryl esters between organs
• combine with lipids to form several classes of lipoprotein particles
  
  • chylomicrons
  • very-low-density lipoproteins (VLDL)
  • very-highdensity lipoproteins (VHDL
• ​lipoprotein particles structures
  
  • spherical aggregates
  • hydrophobic lipids at the core
  • hydrophilic protein side chains
  • lipid head groups at the surface

Question 10

chylomicrons

Answer 10

• lipoprotein aggregates
• surface is a layer of phospholipids, with head groups facing the aqueous phase
• Triacylglycerols sequestered in the interior (yellow) make up more than 80% of the mass
• Several apolipoproteins protrude from the surface (B-48, C-III, C-II) & act as signals in the uptake and metabolism of chylomicron contents
• diameter ranges from about 100 to 500 nm
• fate of chylomicrons
  
  • once depleted of most of their triacylglycerols
  • contains cholesterol and apolipoproteins
  • travel in the blood to the liver
  • taken up by endocytosis, mediated by receptors for their apolipoproteins
  • Triacylglycerols may be oxidized to provide energy or to provide precursors for the synthesis of ketone bodies

Question 11

Digestion and absorption of dietary lipids occur in the _____ _____, and the _____ _____ released from triacylglycerols are packaged and delivered to muscle and adipose tissues.

Answer 11

• small intestine
• fatty acids

Question 12

Processing steps of dietary lipids in vertebrates

Answer 12

1. Bile salts emulsify dietary fats in the small intestine, forming mixed micelles.
2. Intestinal water-soluble lipases degrade triacylglycerols to monoacylglycerols (monoglycerides), diacylglycerols (diglycerides), free fatty acids, and glycerol
3. Products of step 2 are taken up by the intestinal mucosa and reconverted into triacylglycerols
4. Triacylglycerols are incorporated, with cholesterol and apolipoproteins, into chylomicrons
5. Chylomicrons move through the lymphatic system and bloodstream to tissues.
   
   • Chylomicrons contain apolipoprotein C-II (apoC-II) which are recognized by receptors on cell surfaces allowing uptake
6. Lipoprotein lipase, activated by apoC-II in the capillary, converts triacylglycerols to fatty acids and glycerol.
7. Fatty acids enter cells
8. In muscle, the fatty acids are oxidized for energy; in adipose tissue, they are reesterified for storage as triacylglycerols

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Question 13

When the diet contains more fatty acids than are needed immediately for fuel or as precursors, the liver converts them to ______, which are packaged with specific apolipoproteins into _____ which are transported in the blood to ______ tissues, where triacylglycerols are removed and stored in ______ _____ within adipocytes.

Answer 13

• triacylglycerols
• VLDLs (very-low-density lipoproteins)
• adipose
• lipid droplets

Question 14

perilipins

Answer 14

• coats the surface of lipid droplets
• a family of proteins that restrict access to lipid droplets
• prevents untimely lipid mobilization

Question 15

When hormones signal the need for metabolic energy, triacylglycerols stored in adipose tissue are mobilized and transported to tissues. List the steps.

Answer 15

1. hormones epinephrine and glucagon, secreted in response to low blood glucose levels or impending activity bind to a receptor in the adipocye plasma membrane
2. Adenylyl cyclase in the adipocyte plasma membrane is stimulated via a G protein, and produces cyclic AMP (cAMP)
3. cAMP activated Cyclic AMP–dependent protein kinase (PKA) triggers changes that open the lipid droplet up to the action of three lipases, which act on tri-, di-, and monoacylglycerols, releasing fatty acids and glycerol
   
   • PKA phosphorylzes perilipin and hormone-sensitive lipase (HSL)
   • perilipin phosphorylation causes dissociation of the protein CGI from perilipin
   • CGI associates with adipose triacylglycerol lipase (ATGL)
   • ATGL converts triacylglycerols to diacylglycerols
   • phosphorylated perilipin associates with phosphorylated HSL coverting diacylglycerols to monoacylglycerols
   • monoacylglycerol lipase (MGL) hydrolizes monoacylglycerols
4. free fatty acids (FFA) pass from the adipocyte into the blood
5. bind to the blood protein serum albumin
   
   • makes up about half of the total serum protein
   • noncovalently binds as many as 10 fatty acids per protein monomer
6. FFA are carried to target tissues and dissociate from albumin and moved by plasma membrane transporters into cells
7. Glycerol is phosphorylated by glycerol kinase and oxidized to dihydroxyacetone phosphate
8. triose phosphate isomerase converts this compound to glyceraldehyde 3-phosphate, which is oxidized via glycolysis

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Question 16

• enzymes of fatty acid oxidation in animal cells are located in the _____ _____
• fatty acids with chain lengths of _____ or fewer carbons enter mitochondria without the help of membrane transporters
• Those with _____ or more carbons (majority of FFA) cannot pass directly and must first undergo the three enzymatic reactions of the _____ _____

Answer 16

• mitochondrial matrix
• 12
• 14, carnitine shuttle

Question 17

carnitine shuttle

Answer 17

has 3 reactions

1. esterification to CoA:
   
   • catalyzed by a family of isozymes, acylCoA synthetases, in the outer mitochondrial membrane
   • Fatty acid + CoA + ATP → fatty acyl–CoA + AMP + 2P_i
     
     • _​ΔG’° = -34 kJ/mol
     • thioester linkage formed between the fatty acid carboxyl group and the thiol group of coenzyme A forming fatty acyl–CoA
     • ATP is cleaved to AMP and PP_i
       
       • makes formation of a fatty acyl–CoA more favorable
   • Occurs in 2 steps and involves a fatty acyl–adenylate intermediate
   • Fatty acyl–CoAs are high-energy compounds
     
     • hydrolysis to FFA and CoA has a large, negative standard free-energy change (ΔG’° = -31 kJ/mol
2. transesterification to carnitine followed by transport
   
   • Fatty acyl–CoA esters formed at the cytosolic side of the outer mitochondrial membrane can be transported into the mitochondrion and oxidized to produce ATP or used in the cytosol to synthesize membrane lipids
   • Fatty acids are transiently attached to the hydroxyl group of carnitine to form fatty acyl–carnitine in the outer membrane
     
     • catalyzed by carnitine acyltransferase I
   • passage into the intermembrane space occurs via porin
   • fatty acyl–carnitine ester enters the matrix by facilitated diffusion through the acyl-carnitine/carnitine transporter of the inner mitochondrial membrane
   • carnitine-mediated entry process is the rate limiting step
3. transesterification back to CoA
   
   • fatty acyl group is enzymatically transferred from carnitine to intramitochondrial coenzyme A by carnitine acyltransferase II
     
     • located on the inner face of the inner mitochondrial membrane
     • regenerates fatty acyl–CoA and releases it and the free carnitine into the matrix
   • Carnitine reenters intermembrane space via the acylcarnitine/carnitine transporter

Question 18

• carnitine shuttle links two separate pools of _____ _____,
• one in the _____ and the other in the _____, both with different functions
• Coenzyme A in the mitochondrial matrix is largely used in
• cytosolic coenzyme A is used in

Answer 18

• coenzyme A
• cytosol, mitochondria
• oxidative degradation of pyruvate, fatty acids, and some amino acids
• the biosynthesis of fatty acids

Question 19

Stages of fatty acid oxidation

Answer 19

1. β oxidation
   
   • fatty acids undergo oxidative removal of successive two-carbon units in the form of acetyl-CoA
   • removal starts from the carboxyl end of the fatty acyl chain
   • for example, 16-carbon palmitic acid
     
     • undergoes seven passes through the oxidative sequence
     • loses 2 C in each pass, as acetyl-CoA
     • Takes seven cycles
     • 16-carbon chain is converted to to eight two-carbon acetyl groups
   • Formation of each acetyl-CoA requires removal of four hydrogen atoms (two pairs of e^- and four H⁺) from the fatty acyl by dehydrogenases
2. acetyl groups of acetyl-CoA are oxidized to CO₂ in the citric acid
   
   • takes place in the mitochondrial matrix
3. the transfer of electrons from reduced electron carriers (NADH and FADH₂) from stage 1 & 2, to the mitochondrial respiratory chain
   
   • electrons pass to oxygen
   • phosphorylation of ADP to ATP occurs
   • energy released by fatty acid oxidation is thus conserved as ATP

Question 20

Acetyl-CoA derived from _____ ______ thus enters a final common pathway of oxidation with the acetyl-CoA derived from ______ via glycolysis and pyruvate oxidation

Answer 20

• fatty acids
• glucose

Question 21

β oxidation

Four Reactions

Answer 21

1. Dehydrogenation of fatty acyl–CoA
   
   • produces a double bond between the α and β carbon atoms yielding trans-Δ²-enoyl-CoA
   • new double bond has the trans configuration, whereas the double bonds in naturally occurring unsaturated fatty acids are normally in the cis configuration
   • catalyzed by three isozymes of acylCoA dehydrogenase, each specific for a range of fattyacyl chain lengths:
     
     • very-long-chain acyl-CoA dehydrogenase (VLCAD): 12 - 18 C
     • medium-chain (MCAD): 4 to 14 C
     • short-chain (SCAD): 4 to 8 C
     • bound to the inner membrane
     • all three flavoproteins with FAD as a prosthetic group
     • electrons removed from the fatty acyl–CoA are transferred to FAD
     • the reduced form of the dehydrogenase immediately donates its electrons to an electron carrier of the mitochondrial respiratory chain, the electron-transferring flavoprotein (ETF)
   • analogous to succinate dehydrogenation in the citric acid cycle
2. H₂O is added to the double bond of the trans-Δ²-enoyl-CoA
   
   • forms L stereoisomer of β-hydroxyacyl-CoA (3-hydroxyacyl-CoA)
   • catalyzed by enoyl-CoA hydratase
   • analogous to the fumarase reaction in the citric acid cycle
3. L-β-hydroxyacyl-CoA is dehydrogenated to form β-ketoacyl-CoA
   
   • catalyzed by β-hydroxyacyl-CoA dehydrogenase
   • NAD⁺ is the electron acceptor
   • specific for L stereoisomer of hydroxyacyl-CoA
   • NADH donates its electrons to NADH dehydrogenase, an electron carrier of the respiratory chain
   • ATP is formed from ADP as the electrons pass to O₂
   • analogous to the malate dehydrogenase reaction of the citric acid cycle
4. thyolisis
   
   • catalyzed by acyl-CoA acetyltransferase (thiolase)
   • reaction of β-ketoacyl-CoA with a molecule of free coenzyme A
   • β-ketoacyl-CoA is cleaved by reaction with the thiol group of coenzyme A at the carboxyl-terminal two-carbon fragment of the original fatty acid as acetyl-CoA
   • other product is the coenzyme A thioester of the fatty acid, now shortened by two carbon atoms
   • a reverse Claisen condensation

PDF pg. 74 - 706

• typical when the incoming fatty acid is saturated

Question 22

β oxidation

• fatty acyl chains of 12 or more carbons are catalyzed by a multienzyme complex associated with the inner mitochondrial membrane, the ______ ______
• its’s structure is
• When TFP has shortened the fatty acyl chain to 12 or fewer carbons, further oxidations are catalyzed by

Answer 22

• trifunctional protein (TFP)
• structure
  
  • heterooctamer of α₄β₄ subunits
  • α subunit contains two activities
    
    • enoyl-CoA hydratase
    • β-hydroxyacyl-CoA dehydrogenase
  • β subunits contain the thiolase activity
• a set of four soluble enzymes in the matrix

Question 23

β oxidation

products in one pass

Answer 23

• removed from the long-chain fatty acyl–CoA, shortening it by 2 C
  
  • one molecule of acetyl-CoA
  • 2 pairs of electrons
  • 4 protons (H⁺)
• Each FADH₂ donates
  
  • ​2 e^- to ETF
  • 1.5 molecules of ATP during the transfer of e^- to O₂
• Each NADH
  
  • 2 e^- → NADH dehydrogenase → O₂
  • 2.5 molecules of ATP during the transfer of e^- to O₂
• ​4 ATP formed for each two-carbon unit removed in one pass
• H₂O is produced
  
  • Transfer of electrons from NADH or FADH2 to O2 yields one H₂O per electron pair
  • Reduction of O₂ by NADH also consumes one H⁺ per NADH molecule
    
    • NADH + H⁺ + ½O₂ → NAD⁺ + H₂O
• overall equation

Question 24

the acetyl-CoA produced from the oxidation of fatty acids, via ____, can be oxidized to _____ and _____ by the citric acid cycle

Answer 24

• β-Oxidation
• CO₂
• H₂O

Question 25

β oxidation

• most of the fatty acids are _____, having one or more double bonds.
• These bonds are in the _____ configuration and cannot be acted upon by enoyl-CoA hydratase because it acts only on _____ double bonds
• Two auxiliary enzymes are needed for β oxidation:

Answer 25

• unsaturated
• cis, trans
• an isomerase and reductase
  
  • isomerase
    
    • Δ³,Δ²-enoyl-CoA isomerase isomerizes the cis-Δ³-enoyl-CoA to the trans-Δ²-enoylCoA
    • trans-Δ²-enoylCoA can then be converted by enoyl-CoA hydratase into L-β-hydroxyacyl-CoA (trans-Δ²dodecenoyl-CoA)
  • reductase
    
    • combined action of isomerate and reductase converts a trans-Δ²,cis-Δ⁴-dienoyl-CoA intermediate to the trans-Δ²enoyl-CoA substrate necessary for β oxidation

Question 26

β Oxidation

of Odd-Number Fatty Acids

Answer 26

• the substrate for the last pass through the β-oxidation sequence is a fatty acyl–CoA with a five-carbon fatty acid
• the five-carbon fatty acid is oxidized and cleaved producing
  
  • acetyl-CoA
    
    • can be oxidized in the citric acid cycle
  • propionyl-CoA
    
    • enters a different pathway
    1. carboxylated to form the D stereoisomer of methylmalonyl-CoA
       
       • catalized by propionyl-CoA carboxylase, which contains the cofactor biotin
       • activated by attachment to biotin before it’s transferred to the substrate
       • forms intermediate carboxybiotin
       • requires ATP
    2. D-methylmalonyl-CoA is epimerized to its L stereoisomer
       
       • catalyzed by methylmalonylCoA epimerase
    3. L-methylmalonylCoA undergoes intramolecular rearrangement to form succinyl-CoA
       
       • can enter the citric acid cycle
       • catalyzed by methylmalonyl-CoA mutase
         
         • requires coenzyme 59-deoxyadenosylcobalamin, or coenzyme B12

Question 27

Fatty Acid Oxidation Is Tightly Regulated

• Oxidation of fatty acids consumes precious _____
• It’s regulated so it occurs only when the need for energy requires it. In the liver, fatty acyl–CoA formed in the cytosol has two major pathways open to it:
• The pathway taken depends on
• _____ _____ is the rate limiting for fatty acid oxidation and is an important point of regulation
• Once fatty acyl groups have entered the mitochondrion, they are committed to oxidation to ______

Answer 27

• fuel
• β oxidation by enzymes in mitochondria or conversion into triacylglycerols and phospholipids by enzymes in the cytosol
• the rate of transfer of long-chain fatty acyl–CoA into mitochondria
• carnitine shuttle
• acetyl-CoA

Question 28

Coordinated regulation of fatty acid synthesis and breakdow

Answer 28

• When the diet is high in carbohydrate, β oxidation of fatty acids is unnecessary and is downregulated
• Two enzymes are key to the coordination of fatty acid metabolism:
  
  • acetyl-CoA carboxylase (ACC)
    
    • first enzyme in the synthesis of fatty acids
  • carnitine acyltransferase I
    
    • limits the transport of fatty acids into the mitochondrial matrix for β oxidation
• blood glucose level rises and triggers the release of insulin
• Insulin dependent protein phosphatase dephosphorylates ACC, activating it.
• ACC catalyzes the formation of malonyl-CoA, the first intermediate of fatty acid synthesis
• malonyl-CoA inhibits carnitine acyltransferase I, thereby preventing fatty acid entry into the mitochondrial matrix
• When blood glucose levels drop between meals, glucagon release activates cAMP-dependent protein kinase (PKA)
• PKA phosphorylates and inactivates ACC
• concentration of malonyl-CoA falls
• inhibition of fatty acid entry into mitochondria is relieved
• fatty acids enter the mitochondrial matrix and become the major fuel
• Because glucagon also triggers the mobilization of fatty acids in adipose tissue, a supply of fatty acids begins arriving in the blood.

Question 29

PPAR

Answer 29

• family of nuclear receptors
• transcription factors that affect many metabolic processes in response to a variety of fatty acid–like ligands
• PPARα acts in muscle, adipose tissue, and liver to turn on a set of genes essential for fatty acid oxidation, including
  
  • fatty acid transporter
  • carnitine acyltransferases I and II
  • fatty acyl–CoA dehydrogenases for short, medium, long, and very long acyl chains
  • related enzymes

Question 30

Stored _____ are typically the chief source of energy for muscle contraction, and an inability to oxidize fatty acids from _____ has serious consequences for health

Answer 30

• triacylglycerols
• triacylglycerols

Question 31

peroxisomes

Answer 31

• membrane-enclosed organelles of animal and plant cells
• in certain cells these organelles contain enzymes capable of oxidizing fatty acids to acetyl-CoA
• four steps like mitochondrial β oxidation
  
  • dehydrogenation
  • addition of water to the resulting double bond
  • oxidation of the β-hydroxyacyl-CoA to a ketone
  • thiolytic cleavage by coenzyme A
• Differences
  
  • the chemistry of the first step
    
    • flavoprotein acyl-CoA oxidase that introduces the double bond passes electrons directly to O₂, producing H₂O₂
    • H₂O₂ is immediately cleaved to H₂O and O₂ by catalase
    • energy released is not conserved as ATP, but is dissipated as heat
  • specificity for fatty acyl–CoAs
    
    • more active on very-long-chain fatty acids which are less-common fatty acids obtained from dairy products, the fat of ruminant animals, meat, and fish
    • involves several auxiliary enzymes

Question 32

• Liver peroxisomes do not contain the enzymes of the _____ _____ _____ and cannot catalyze the oxidation of acetyl-CoA to CO₂.
• Instead, long-chain or branched fatty acids are catabolized to shorter-chain products, which are exported to _____ and completely oxidized

Answer 32

• citric acid cycle
• mitochondria

Question 33

• Plant peroxisomes and _____ are similar in structure and function
• _____ occur only in germinating seeds, may be considered ______ _____
• The biological role of β oxidation in these organelles is to store lipids primarily to provide ______ ______, not ______

Answer 33

• glyoxysomes
• glyoxysomes, specialized peroxisomes
• biosynthetic precursors, energy

Question 34

• Although the β-oxidation reactions in mitochondria are essentially the same as those in ______ and ______, the enzymes (isozymes) differ significantly between the two types of organelles
• The differences reflect an ______ _______ that occurred very early, with the separation of gram-positive and gram-negative bacteria

Answer 34

• peroxisomes, glyoxysomes
• evolutionary divergence

Question 35

ω oxidation

Answer 35

• another pathway in some species, including vertebrates, that involves oxidation of the ω (omega) carbon—the carbon most distant from the carboxyl group
• unique enzymes located (in vertebrates) in the endoplasmic reticulum of liver and kidney
• preferred substrates are fatty acids of 10 or 12 C
• a minor pathway, becomes important when β oxidation is defective
• PDF pg. 715

Question 36

α oxidation

Answer 36

• presence of a methyl group on the β carbon of a fatty acid makes β oxidation impossible
• these branched fatty acids are catabolized in peroxisomes of animal cells by α oxidation
• hydroxylation occurs on its α carbon, in a reaction that involves molecular oxygen
• decarboxylated to form an aldehyde one carbon shorter
• oxidized to the corresponding carboxylic acid
• can be oxidized further by β oxidation

Question 37

• In humans and most other mammals, acetyl-CoA formed in the liver during oxidation of fatty acids can either enter the citric acid cycle or undergo conversion to the “ketone bodies,”: ______, ______ and ______, for export to other tissues
• _____, produced in smaller quantities than the other ketone bodies, is exhaled.
• ______ and _____ are transported by the blood to tissues and converted to acetyl-CoA and oxidized in the _____ _____ _____
• The brain, which preferentially uses _____ as fuel, can adapt to the use of _____ or _____ under starvation conditions

Answer 37

• acetone, acetoacetate, and D-β-hydroxybutyrate
• Acetone
• Acetoacetate, D-β-hydroxybutyrate, citric acid cycle
• glucose
• Acetoacetate, D-β-hydroxybutyrate

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