17 | fatty acid catabolism © 2009 w. h. freeman and company
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17 | Fatty Acid Catabolism
© 2009 W. H. Freeman and Company
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Oxidation of Fatty Acids is a Major Energy-Yielding Pathway in
Many Organisms
• About one third of our energy needs comes from dietary triacylglycerols
• About 80% of energy needs of mammalian heart and liver are met by oxidation of fatty acids
• Many hibernating animals, such as grizzly bears relay almost exclusively on fats as their source of energy
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Hydrolysis of Fats Yields Fatty Acids and Glycerol
• hydrolysis of triacylglycerols is catalyzed by lipases
• some lipases are regulated by hormones glucagon
and epinephrine
• epinephrine means:
“we need energy now”
• glucagon means:
“we are out of glucose”
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Mobilization of triacylglycerols stored in adipose tissue. Low glucose triggers glucagon release, initiating the cascade.
PKA phosphorylates 3 the hormone-sensitive lipase and 4 perilipin molecules on the surface of the lipid droplet. Phosphorylation of perilipin permits hormone-sensitive lipase access to the surface of the lipid droplet, where 5 it hydrolyzes triacylglycerols. 6 Fatty acids leave the adipocyte, bind serum albumin and are carried in the blood, to myocytes where they are released from the albumin and 7 enter a myocyte via a specific fatty acid transporter. 8
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Fatty Acid Transport into Mitochondria
• Fats are degraded into fatty acids and glycerol in the cytoplasm
-oxidation of fatty acids occurs in mitochondria
• Small (< 12 carbons) fatty acids diffuse freely across mitochondrial membranes
• Larger fatty acids are transported via acyl-carnitine / carnitine transporter
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Glycerol from Fats Enters Glycolysis
• Glycerol kinase prepares glycerol for glycolysis at
the expense of ATP
• Subsequent reactions recover more than enough
ATP to cover this cost
• Allows limited anaerobic catabolism of fats
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Fatty Acids are Converted into
Fatty Acyl-CoA
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Step: 1Dehydrogenation of Alkane to Alkene
• Catalyzed by isoforms of acyl-CoA dehydrogenase (AD) on the inner mitochondrial membrane– Very-long-chain AD (12-18 carbons)– Medium-chain AD (4-14 carbons)– Short-chain AD (4-8 carbons)
• Analogous to – succinate dehydrogenase reaction in the citric acid cycle
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Note that this is the L-isomer.
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Step: 2Hydration of Alkene
• Catalyzed by two isoforms of enoyl-CoA hydratase:– Soluble short-chain hydratase (crotonase)– Membrane-bound long-chain hydratase, part of
the trifunctional complex• Water adds across the double bond yielding
alcohol• Analogous to
– fumarase reaction in the citric acid cycle
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Note that this is the TRANS isomer
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Step: 3 Dehydrogenation of Alcohol
• Catalyzed by -hydroxyacyl-CoA dehydrogenase• The enzyme uses NAD cofactor as the hydride
acceptor• Only L-isomers of hydroxyacyl CoA act as
substrates• Analogous to
malate dehydrogenase reaction in the citric acid cycle
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Step: 4 Transfer of Fatty Acid Chain
• Catalyzed by acyl-CoA acetyltransferase (thiolase) via a covalent mechanism– The carbonyl carbon in -ketoacyl-CoA is
electrophilic– Active site thiolate acts as nucleophile and
releases acetyl-CoA– Terminal sulfur in CoA-SH acts as nucleophile
and picks up the fatty acid chain from the enzyme
• The net reaction is thiolysis of carbon-carbon bond facilitated by making a very stable bond more susceptible to cleavage!
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Trifunctional Protein• Hetero-octamer
– Four subunits• enoyl-CoA hydratase activity -hydroxyacyl-CoA dehydrogenase activity• Responsible for binding to membrane
– Four subunits• long-chain thiolase activity
• May allow substrate channeling• Associated with inner mitochondrial membrane• Processes fatty acid chains with 12 or more
carbons; shorter ones by enzymes in the matrix
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Fatty Acid Catabolism for Energy
• Repeating the above four-step process six more
times results in the complete oxidation of palmitic
acid into eight molecules of acetyl-CoA
– FADH2 is formed in each cycle
– NADH is formed in each cycle
• Acetyl-CoA enters citric acid cycle and is further
oxidizes into CO2
– This makes more GTP, NADH and FADH2
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Oxidation of Monounsaturated Fatty Acids
http://www.csulb.edu/~cohlberg/Songs/betaox.mp3
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What’s wrong here??
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Oxidation of Polyunsaturated Fatty Acids
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Oxidation of Propionyl-CoA
• Most dietary fatty acids are even-numbered
• Many plants and some marine organisms also synthesize odd-numbered fatty acids
• Propionyl-CoA forms from -oxidation of odd-numbered fatty acids
• Bacterial metabolism in the rumen of ruminants also produces propionyl-CoA
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Oxidation of propionyl-CoA produced by β oxidation of odd-number fatty acids.
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Conversion to succinate requires epimerization of D- to L-methylmalonyl-CoA followed by some really strange chemistry!,
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Intramolecular Rearrangement in Propionate Oxidation Requires Coenzyme B12
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Complex Cobalt-Containing Compound: Coenzyme B12
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Pag
e 92
6Figure 25-23Proposed mechanism of methylmalonyl-CoA mutase.
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Regulation of Fatty Acid Synthesis and Breakdown
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-Oxidation in Plants Occurs in Mainly in Peroxisomes
• Mitochondrial acyl-CoA dehydrogenase passes
electrons into respiratory chain via electron-
transferring flavoprotein
– Energy captured as ATP
• Peroxisomal acyl-CoA dehydrogenase passes
electrons directly to molecular oxygen
– Energy released as heat
– Hydrogen peroxide eliminated by catalase
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Formation of Ketone Bodies
• Entry of acetyl-CoA into citric acid cycle requires oxaloacetate
• When oxaloacetate is depleted, acetyl-CoA is converted into ketone bodies
• The first step is reverse of the last step in the -oxidation: thiolase reaction joins two acetate units
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Liver as the Source of Ketone Bodies
• Production of ketone bodies increases during starvation
• Ketone bodies are released by liver to bloodstream
• Organs other than liver can use ketone bodies as fuels
• Too high levels of acetoacetate and -hydroxybutyrate lower blood pH dangerously
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19 | Oxidative Phosphorylation and Photophosphorylation
© 2009 W. H. Freeman and Company
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Energy from Reduced Fuels is Used to Synthesize ATP in
Animals• Carbohydrates, lipids, and amino acids are the
main reduced fuels for the cell
• Electrons from reduced fuels used to reduce NAD+ to NADH or FAD to FADH2.
• In oxidative phosphorylation, energy from NADH and FADH2 are used to make ATP
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Oxidative Phosphorylation
• Electrons from the reduced cofactors NADH and FADH2 are passed to proteins in the respiratory
chain
• In eukaryotes, oxygen is the ultimate electron acceptor for these electrons
• Energy of oxidation is used to phosphorylate ADP
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Energy of Light is Used to Synthesize ATP in
Photosynthetic Organisms
• Light causes charge separation between a pair chlorophyll molecules
• Energy of the oxidized and reduced chlorophyll molecules is used drive synthesis of ATP
• Water is the source of electrons that are passed via a chain of transporters to the ultimate electron acceptor, NADP+
• Oxygen is the byproduct of water oxidation
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Chemiosmotic Theory
• How to make an unfavorable
ADP + Pi = ATP
possible?• Phosphorylation of ADP is not a result of a direct
reaction between ADP and some high energy phosphate carrier
• Energy needed to phosphorylate ADP is provided by the flow of protons down the electrochemical gradient
• The electrochemical gradient is established by transporting protons against the electrochemical gradient during the electron transport
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Chemiosmotic Energy Coupling Requires
Membranes• The proton gradient needed for ATP synthesis can be
stably established across a topologically closed membrane– Plasma membrane in bacteria– Cristae membrane in mitochondria– Thylakoid membrane in chloroplasts
• Membrane must contain proteins that couple the “downhill” flow of electrons in the electron transfer chain with the “uphill” flow of protons across the membrane
• Membrane must contain a protein that couples the “downhill” flow of proton to the phosphorylation of ADP
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Structure of a Mitochondrion
• The proton gradient is established across the inner membrane
• The cristae are convolutions of the inner membrane and serve to increase the surface area
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Metabolic Sources of Reducing Power
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“Alfonse, Biochemistry makes my head hurt!!”\