chapter 17 Flashcards
Oxidation of fatty acids is a major energy source in many organisms
-About one-third of our energy needs comes from
-About 80% of energy needs of mammalian heart and liver are met by
-Many hibernating animals, such as grizzly bears, rely almost exclusively on
Some animals (camels) store
-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, rely almost exclusively on fats as their source of energy
-Some animals (camels) store fat as an eventual source of water
Fats provide efficient fuel storage
The advantage of fats over polysaccharides:
The advantage of fats over polysaccharides:
-Fatty acids carry more energy per carbon because they are more reduced
-Fatty acids carry less water along because they are nonpolar
-Glucose and glycogen are for short-term energy needs, quick delivery
-Fats are for long-term (months) energy needs, good storage, slow delivery
Fat Storage in White Adipose Tissue
Fat stores in cells. (a) Cross section of human white adipose tissue. Each cell contains a fat droplet (white) so large that it squeezes the nucleus (stained red) against the plasma membrane.
Lipid Digestion
Dietary fatty acids are absorbed in the vertebrate small intestine
1. Bile emusilfies dietary fats producing mixed micelles
2. turn into signle fatty acids by lipase which degrade triacylglycerols
3. they are converted agin into tiacylglecerols
4. turned into chylomicrons
5. chylomicrons move through the blood stream
6. lipases converts triacylglycerols to fatty acids and glycerol
7. fatty acids are oxidized as fuel for storage
Lipids are transported in the blood as
chylomicrons
Hormones trigger mobilization of stored triacylglycerols
Low glucose trigger the release of glucagon, 1 the hormone binds its receptor and 2 stimulates adenylyl cyclase to produce cAMP, activates PKA, which phosphorylates 3 HSL and 4 perilipin molecules on the surface. Phosphorylation of perilipin causes 5 dissociation of the protein CGI from perilipin. CGI then associates with the enzyme adipose triacylglycerol lipase (ATGL), activating it. Active ATGL 6 converts TAGs to DAGs. The phosphorylated perilipin associates with phosphorylated
HSL allowing it access to the surface, where 7 it converts DAGs to MAGs. A third lipase, MAG lipase (MGL) 8, hydrolyzes MAGs. 9 Fatty acids leave the adipocyte, bind serum albumin; they are released from the albumin and 10 enter a myocyte via a specific fatty acid transporter. 11 FAs are oxidized to CO2, and produce ATP for muscle contraction and other energy-requiring metabolism.
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”
Glycerol from fats enters glycolysis
Glycerol kinase activates glycerol at the expense of ATP
Subsequent reactions
recover more than enough
ATP to cover this cost
Allows limited anaerobic catabolism of fats
Energetics of Glycerol as An Energy Source
Can glycerol be FERMENTED?
NO
-glycerol can only produce 1 pyruvate and has a 1 net ATP compared to 2 net ATP in glucose.
-glycerol can’t be fermented because glycerol can only produce 1 pyruvate without oxygen; net NADH is produced. NADH increases and inhibits enzyme and inhibits glycerol to pyruvate when NADH increases, can inhibit ATP
Transport or attachment to phospholipids requires conversion to
-before free fatty acid can be oxidized it must be turned into Acetyl-CoA fatty acid and transported into mitochondria
Overall reaction is fatty acid + CoA + ATP ↔ fatty acyl-CoA + AMP + 2Pi
ΔG’º is -34kJ/mol
Acyl-CoA synthetase reaction
Fatty Acid Transport into Mitochondria
-Fats are degraded into fatty acids and glycerol in the
-Fatty acids are transported to
-β-oxidation of fatty acids occurs in
-Small (< ___carbons) fatty acids
-Larger fatty acids (most free fatty acids) are transported via
-Fats are degraded into fatty acids and glycerol in the cytoplasm of adipocytes
-Fatty acids are transported to other tissues for fuel
-β-oxidation of fatty acids occurs in mitochondria
-Small (< 12 carbons) fatty acids diffuse freely across mitochondrial membranes
-Larger fatty acids (most free fatty acids) are transported via acyl-carnitine/carnitine transporter
Acyl-Carnitine/Carnitine Transport
Carnitine shuttles fatty acids into the mitochondrial matrix
Stages of Fatty Acid Oxidation
-Stage 1 consists of oxidative conversion of two-carbon units into acetyl-CoA via β-oxidation with concomitant generation of NADH and FADH2
involves oxidation of β carbon to thioester of fatty acyl-CoA
-Stage 2 involves oxidation of acetyl-CoA into CO2 via citric acid cycle with concomitant generation NADH and FADH2
-Stage 3 generates ATP from NADH and FADH2 via the respiratory chain
The β-Oxidation Pathway
Each pass removes one acetyl moiety in the form of acetyl-CoA.
One round (a) and Further round (b) of β-oxidation
Step 1:
Dehydrogenation 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)
Results in trans double bond, different from naturally occurring unsaturated fatty acids
Analogous to succinate dehydrogenase reaction in the citric acid cycle
-Electrons from bound FAD transferred directly to the electron- transport chain via electron-transferring flavoprotein (ETF)
Step 2:
Hydration of Alkene
Catalyzed by two isoforms of enoyl-CoA hydratase:
-Soluble short-chain hydratase (crotonase)
-Membrane-bound long-chain hydratase, part of trifunctional complex
Water adds across the double bond yielding alcohol
Analogous to fumarase reaction in the citric acid cycle
-Same stereospecificity
Step 3:
Dehydrogenation of Alcohol
-Catalyzed by β-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
Step 4:
Transfer of Fatty Acid Chain
Catalyzed by acyl-CoA acetyltransferase (thiolase) via covalent mechanism
-The carbonyl carbon in β-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
Trifunctional Protein
Hetero-octamer
Four α subunits
-enoyl-CoA hydratase activity
-β-hydroxyacyl-CoA dehydrogenase activity
-Responsible for binding to membrane
Four β subunits
-long-chain thiolase activity
-May allow substrate channeling
-Associated with inner-mitochondrial membrane
-Processes fatty acid chains with 12 or more carbons
-Shorter chains processed by soluble enzymes in the matrix
Fatty Acid Catabolism for Energy
-For palmitic acid (C16)
Repeating the above four-step process six more times (7 total) results in eight molecules of acetyl-CoA
-FADH2 is formed in each cycle (7 total)
-NADH is formed in each cycle (7 total)
-Acetyl-CoA enters citric acid cycle and further oxidizes into CO2
–This makes more GTP, NADH, and FADH2
-Electrons from all FADH2 and NADH enter ETF
Each round produces an acetyl-CoA and shortens the chain by two carbons
-Trifunctional protein, a membrane bound multi subunit protein degrades carbon chains till they are down to C12
-When they are 12 or fewer C, 4 soluble enzymes of the mitochondrial matrix do the job
Oxidation of Palmitoyl-CoA
-The overall reaction is
-Palmitoyl-CoA + CoA + FAD + NAD+ + H2O → myristoyl –CoA + acetyl-CoA + FADH2 + NADH + H+
-When electrons are donated from FADH2 and NADH, 4 ATP are generated (1.5 from FADH2 and 2.5 from NADH). Water is also generated from transfer of two electrons to oxygen via the reaction NADH + H+ + ½ O2→ NAD+ + H2O
-Palmitoyl is a 16-C, while myristoyl is a 14-C
-Overall reaction to break down the entire 16-C is
Palmitoyl-CoA + 7CoA + 7FAD + 7NAD+ + 7H2O → 8 acetyl-CoA +7 FADH2 + 7 NADH + 7H+
Or Palmitoyl-CoA + 7CoA + 7O2 + 28Pi + 28ADP → 8 acetyl-CoA + 7H2O + 28ATP
Complete Oxidation of Palmitoyl-CoA
-Acetyl-CoA can be fed into the TCA cycle and electrons can be transferred down the respiratory chain to form more ATP
-Overall oxidation from TCA and into the respiratory chain is
8 Acetyl-CoA + 16O2 + 80Pi + 80ADP → 8CoA + 16H2O + 80ATP +16 CO2
-Combining the β-oxidation and acetyl-CoA oxidation
Palmitoyl-CoA + 23O2 + 108Pi + 108ADP → CoA + 23H2O + 108ATP +16 CO2
NADH and FADH2 serve as sources of
ATP
Assumes 1 NADH = 2.5 ATP, and 1 FADH2 = 1.5 ATP from Respiratory Electron Transport
How many total ATP from 16C FA-CoA?
Assumes 1 NADH = 2.5 ATP, and 1 FADH2 = 1.5 ATP from Respiratory Electron Transport
One β-oxidation: 1 FADH2 + 1 NADH = 1.5 ATP + 2.5 ATP = 4 ATP
One acetyl-CoA via TCA: 3 NADH + 1 FADH2 + 1 ATP = 10 ATP
16C-CoA by full oxidization: 7 β-oxidation cycles + 8 acetyl-CoA
Total ATP: 7 x 4 ATP + 8 x 10 ATP = 28 ATP + 80 ATP = 108 ATP
Similar mechanisms introduce carbonyls in other
metabolic pathways
Oxidation of Unsaturated Fatty Acids
-Naturally occurring Unsaturated Fatty acids contain cis double bonds
–Are NOT a substrate for enoyl-CoA hydratase
Two additional enzymes are required
-Isomerase: converts cis double bonds starting at -carbon 3 to trans double bonds
-Reductase: reduces cis double bonds not at carbon 3
-Monounsaturated fatty acids require the isomerase
-Polyunsaturated fatty acids require both enzymes
Oxidation of Monounsaturated Fatty Acids
Acetyl- CoA is generated till just before the double bond. Because the enoyl-CoA hydratase recognises only trans double bond, need a Δ3, Δ2, -enoyl-CoA isomerase to change the bond from cis to trans
Oxidation of Polyunsaturated Fatty Acids
Need two enzymes, an enoyl-CoA isomerase and 2,4-dienoyl-CoA reductase to change the double bonds to trans. Odd numbered double bonds are handled by the isomerase only, even numbered are handled by the reductase and isomerase
First double bond requires
Second requires
isomerization
Second requires reduction/isomerization
Oxidation of odd-numbered fatty acids
-Most dietary fatty acids are
-Many plants and some marine organisms also synthesize
-Propionyl-CoA forms from β-oxidation of
-Bacterial metabolism in the rumen of ruminants also produces
-Propionyl-CoA is converted to
-Most dietary fatty acids are even-numbered
-Many plants and some marine organisms also synthesize odd-numbered fatty acids
-Propionyl-CoA forms from β-oxidation of odd-numbered fatty acids
-Bacterial metabolism in the rumen of ruminants also produces propionyl-CoA
-Propionyl-CoA is converted to succinyl-CoA that can enter the TCA cycle. One molecule of ATP is converted to ADP to power the reaction
Regulation of Fatty Acid
Synthesis and Breakdown
what inhibits fatty acid oxidation
-malonyl-CoA
β-Oxidation in Plants Occurs Mainly in
-Mitochondrial acyl-CoA dehydrogenase passes electrons into respiratory chain via electron-transferring
-Peroxisomal/glyoxysomal acyl-CoA dehydrogenase passes electrons directly to molecular
Peroxisomes
-Mitochondrial acyl-CoA dehydrogenase passes electrons into respiratory chain via electron-transferring flavoprotein
–Energy captured as ATP
-Peroxisomal/glyoxysomal acyl-CoA dehydrogenase passes electrons directly to molecular oxygen
–Energy released as heat
–Hydrogen peroxide eliminated by catalase
β-Oxidation in Mitochondria vs.
Peroxisomes or
Glyoxysomes
In plants, fatty acid oxidation occurs primarily in peroxisomes in leaf tissue and in glyoxysomes in germinating seeds
Acetyl-CoA in the glyoxysome is then converted to
metabolic intermediates
ω-Oxidation of Fatty Acids
-In β oxidation, cleavage occurs at the carboxyl end of the fatty acid.
-ω-oxidation starts furthermost away from the carboxylic acid.
-Normally minor
-Occurs in the endoplasmic reticulum of liver and kidney
-Preferred substrate of 10 or 12 carbon atoms
α-Oxidation of Fatty Acids
Presence of a methyl group makes β-oxidation impossible
Use α-oxidation to remove the methyl group
Ketone Bodies
-Two fates of acetyl-CoA formed from oxidation of FAs in liver:
–Entry of acetyl-CoA into citric acid cycle
–Conversion of acetyl-CoA into ketone bodies (soluble in blood and urine)
-Acetone is exhaled
-Acetoacetate and D-β-hydroxybutyrate are transported to extrahepatic tissues (skeletal and heart muscle, renal cortex, and brain (under starvation condition of glucose)) and converted to acetyl-CoA and oxidized by the TCA cycle
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
–Frees Coenzyme A for continued β-oxidation
-The first step is reverse of the last step in the β-oxidation: thiolase reaction joins two acetate units
source of ketone bodies
Liver is the source of ketone bodies
-Production of ketone bodies increases during starvation (and diabetes)
-Ketone bodies are released by liver to bloodstream
-Organs other than liver can use ketone bodies as fuels
-High levels of acetoacetate and β-hydroxybutyrate lower blood pH dangerously (acidosis)
