Chapter 17
1. Bile Salts emulsify dietary fats in the small intestine, forming mixed micelles. 2. Intestinal lipases degrade triacylglycerols. 3. Fatty acids and other breakdown products are taken up by the intestinal mucosa and converted into triacylglycerols. 4. triacylglycerols are incorporated with cholesterol and apolipoproteins into chylomicrons
5. chylomicrons move through the lymphatic system and bloodstream to tissues. 6. Lipoprotein lipase activated by apoC-II in the capillary, converts triacylglycerols to fatty acids and glycerols. 7. fatty acids enter cells. 8. fatty acids are oxidized as fuel or reesterfied.
Which of the following is not true regarding the oxidation of 1 mol of palmitate (16:0) by the -oxidation pathway?
8 mol of FADH2 are formed
ketosis
A condition in which the concentration of ketone bodies in the blood, tissues, and urine is abnormally high.
acidosis
A metabolic condition in which the capacity of the body to buffer H+ is diminished; usually accompanied by decreased blood pH.
Transport of fatty acids from the cytoplasm to the mitochondrial matrix requires:
ATP, carnitine, and coenzyme A
w-oxidation
Alternate pathway by which medium chain fatty acids are oxidized in peroxisomes, producing dicarboxylic acids. Patients with MCAD deficiency have more dicarboxylic acid in their urine. Occurs in the endoplasmic reticulum.
Coenzyme B12
An enzymatic cofactor derived from the vitamin cobalamin, involved in certain types of carbon skeletal rearrangements.
The acetoacetyl-coa then condenses another molecules of acetyl-coa to form
B-hydroxy-B-methylglutaryl-Coa (HMG-CoA)
Ketone bodies are formed in the liver and transported to the extrahepatic tissues mainly as:
B-hydroxybutyric acid
When comparing the B-oxidation and W-oxidation pathways, which one of the following statements is correct?
B-oxidation occurs at the carboxyl end of the fatty acid whereas oxidation occurs at the methyl end.
Two vitamins, biotin and vitamin B12, play crucial roles in the metabolism of propionic acid (propionate). Explain this by showing the steps in which each is essential in propionate metabolism.
Biotin and vitamin B12 act as cofactors for propionyl-CoA carboxylase and methylmalonyl-CoA mutase, respectively; see Fig. 17-12 for the complete sequence of reactions.
Describe the steps in the metabolic pathway in which cells oxidize a four-carbon, straight-chain, saturated fatty acid (butyrate; 4:0) to the fragments that enter the citric acid cycle. Show the structures of intermediates and products, and indicate where any cofactor(s) participate(s).
Butyrate is first activated: Butyrate + ATP + CoA—SH butyryl-CoA + AMP + PPi Then, the butyryl group is transferred to carnitine and transported into the mitochondrial matrix, where it is reconverted to the butyryl-CoA derivative. This passes through the four steps of -oxidation.
Oleate is an abundant 18-carbon monosaturated fatty acid with a cis double bond between
C-9 and C-10
The balanced equation for the degradation of CH3(CH2)10COOH via the B-oxidation pathway is:
CH3(CH2)10COOH + 5FAD + 5NAD+ + 6CoA—SH + 5H2O + ATP 6 Acetyl-CoA + 5FADH2 + 5NADH + 5H+ + AMP + PPi
In the disease sprue, vitamin B12 (cobalamin) is poorly absorbed in the intestine, resulting in B12 deficiency. If each of the following fatty acids were in the diet, for which one would the process of fatty acid oxidation be most affected in a patient with sprue?
CH3(CH2)11COOH
Which compound is an intermediate of the B-oxidation of fatty acids?
CH3—CO—CH2—CO—S—CoA
Which enzyme is the major regulatory control point for B-oxidation?
Carnitine acyl transferase I
The oxidation of acetyl-CoA added to isolated, intact mitochondria is stimulated strongly by carnitine. Why?
Carnitine is essential in the transport of fatty acyl groups into the mitochondrial matrix, where fatty acid oxidation occurs
For each two-carbon increase in the length of a saturated fatty acid chain, how many additional moles of ATP can be formed upon complete oxidation of one mole of the fatty acid to CO2 and H2O?
Each —CH2—CH2— unit yields 14 extra ATP molecules. The two oxidations of the -oxidation pathway produce 1 FADH2 and 1 NADH, which yield 1.5 and 2.5 ATP, respectively, by oxidative phosphorylation. The extra acetyl-CoA, when oxidized via the citric acid cycle, yields another 10 ATP equivalents: 3 NADH, 1 FADH2, and 1 ATP or GTP.
w oxidation 1) -OH group onto the w carbon -the oxygen comes from molecular oxygen in a reaction with cytochrome P450 and NADPH -catalyzed by mixed-function oxygenases. 2)two more enzymes then act on the w carbon -alcohol dehydrogenase oxidized the OH to an aldehyde -aldehyde dehydrogenase oxidizes the aldehyde group to a carboxylic acid
Either end can be attached to coenzyme A, and the molecule can enter the mitochondrion and undergo Beta oxidation by the usual route.
W (omega) oxidation enzymes are located in the
Endoplasmic reticulum of liver and the kidney, and preferred substrates are fatty acids of 10 to 12 carbon atoms.
mixed function oxygenases
Enzymes that catalyze reactions in which two reductants- one generally NADPH the other the substrate are oxidized by molecular oxygen, with one oxygen atom incorporated into the product and the other reduced to H2O; often use cytochrome P-450 to carry electrons from NADPH to O2. Oxygenases, unlike oxidase, promote reactions in which at least one oxygen atom is incorporated into the final product.
Explain why lipases are required in both the intestine and in the bloodstream?
Fats ingested in the diet are mostly found as triacylglycerols. In order to be taken up through the intestinal mucosa these triacylglycerols must be converted to free fatty acids by the intestinal lipases. Once in the bloodstream, the free fatty acids are again converted to triacylglycerols for transport in chylomicrons. For absorption into remote tissues from the bloodstream, the triacylglycerols must again be converted to free fatty acids, this time by lipases found in the bloodstream.
Which of these is able to cross the inner mitochondrial membrane?
Fatty acyl-carnitine
Why is it more efficient to store energy as lipid rather than as glycogen
First, the energy yield per gram of lipid (about 38 kJ/g) is more than twice that for carbohydrate (about 17 kJ/g). Second, lipid is stored as anhydrous lipid droplets, but carbohydrates such as glycogen and starch are stored hydrated, and the water of hydration roughly triples the effective weight of the carbohydrate, reducing the energy yield to about 6 kJ/g.
Malonyl CoA
Formed from Acetyl-CoA and HCO3 via the Acetyl-CoA carboxylase (ACC). Serves as a regulator of FA catabolism and precursor in FA synthesis.
During B-oxidation of fatty acids, ___________ is produced in peroxisomes but not in mitochondria.
H2O2
Trifunctional Protein (TFP)
Hetero-octamer made up of: Four alpha subunits -Enoyl-CoA hydratase activity -beta-hydroxyacyl-CoA dehydrogenase activity -Responsible for binding to membrane Four beta subunits -Long-chain thiolase activity -Close association of these three enzymes may allow efficient substrate channeling Associated with inner mitochondrial membrane
The long alkyl chains of triacylglycerols make them suitable as storage fuels.
Hydrocarbons with highly reduced structures with an energy of complete oxidation more than twice that for the same weight of carbohydrate or protein.
methylmalonyl CoA mutase
Involved in the oxidation of odd-numbered carbon fatty acids, producing succinyl-CoA for entry into the TCA; requires B12.
MCAD
Medium-chain acyl-CoA dehydrogenase
The flavoprotein acyl-CoA oxidase that introduces the double bond passes electrons directly to
O2 producing H2O2. Which is then cleaved to H2O and O2 by catalase.
An experimenter studying the oxidation of fatty acids in extracts of liver found that when palmitate (16:0) was provided as substrate, it was completely oxidized to CO2. However, when undecanoic acid (11:0) was added as substrate, incomplete oxidation occurred unless he bubbled CO2 through the reaction mixture. The addition of the protein avidin, which binds tightly to biotin, prevented the complete oxidation of undecanoic acid even in the presence of CO2, although it had no effect on palmitate oxidation. Explain these observations in light of what you know of fatty acid oxidation reactions.
Oxidation of odd-chain fatty acid yields acetyl-CoA + propionyl-CoA. The reaction CO2 + propionyl-CoA methylmalonyl-CoA is catalyzed by propionyl-CoA carboxylase, a biotin-containing enzyme, which is therefore inhibited by avidin.
Beta oxidation
Oxidative degradation of fatty acids into acetyl-coa by successive oxidations at the beta carbon atoms; as distinct from w oxidation.
Explain the chemical reason why the addition of water across the double bond in the second step of B-oxidation occurs with the OH adding at the B-carbon, not the B-carbon. Also, how does addition at the B-carbon aid in the subsequent step(s) of B-oxidation?
Recall that the carbon that is to a carbonyl is readily able to become a carbanion; i.e. it is not a good electrophilic center for nucleophilic addition of a hydroxide (see Chapter 13). The B-carbon, by contrast is a good electrophilic center as can be readily shown by "pushing" the electrons from the C=C double bond onto the carbonyl oxygen. Addition of the OH in the B-position is useful for later steps since after oxidation of the OH to a carbonyl, the B-carbon is even more susceptible to becoming a carbanion, as is needed for the reverse Claisen condensation catalyzed by thiolase.
Although the Beta-oxidation reactions in mitochondira are essentially the same as those in peroxisomes and glyoxysomes, the enzymes (isozymes) differ significantly between the two types of organelles.
Reflect an evolutionary divergence that occured with the separation of gram positive and gram negative bacteria.
Briefly explain the basic concept of -oxidation.
Relatively short chain fatty acids (i.e., 10-12 carbons) are oxidized on the -end (in three steps) to form a second carboxyl group. The "double-ended" fatty acid is then taken into the mitochondria and subjected to normal -oxidation, except that the last product is not acetyl-CoA, but rather succinate or adipate.
SCAD
Short Chain Acyl-CoA Dehydrogenase
Formation of carboxybiotin intermediate requires energy, which is provided by ATP.
The D-methylmalonyl-CoA thus formed is enzymatically epimerized to its stereoisomer by methylmalonyl Coa epimerase.
1. The fatty acyl-carnitine ester then diffuses across the intermembrane space and enters the matrix by passive transport through the acylcarnitine/carnitine cotransporter of the inner mitochondrial membrane 2.The acylcarnitine/carnitine cotransporter moves one molecule of carnitine from the matrix to the intermediate space as one molecule of fatty acyl-carnitine moves into the matrix 3.
The fatty acyl group is transferred from carnitine to intramitochondrial coenzyme A by carnitine acyl-transferase 2.
What are the two major differences between the B-oxidation pathway in mitochondria and the B-oxidation pathway in peroxisomes?
The first major difference lies in the detailed chemistry of the first of the four steps of -oxidation. In the mitochondria, the reduced flavin that is a product of the first step is re-oxidized via the electron transport chain. In the peroxisomes, the reduced flavin is re-oxidized by O2, thus producing H2O2. The second major difference is that the peroxisomal enzymes are much more active on longer (i.e., 26-carbons) fatty acids than the mitochondrial enzymes.
Which of the following statements concerning the B-oxidation of fatty acids is true?
The free fatty acid must be converted to a thioester before the process of -oxidation commences
In the first step of fatty acid oxidation, the fatty acid (R—COOH) is converted to its coenzyme A derivative in the following reaction: R-COOH + ATP + CoA-SH R-CO-S-CoA + AMP + PPi The standard free-energy change (G') for this reaction is -15 kJ/mol What will tend to make the reaction even more favorable when it takes place within a cell?
The hydrolysis of PPi by inorganic pyrophosphatase, for which G' is -19 kJ/mol, makes the overall G' more negative.
Write a balanced equation for the complete oxidation (to acetyl-CoA and any other products that might be formed) of pelargonic acid, CH3(CH2)7COOH.
The odd-chain fatty acid is first activated to the CoA derivative, then oxidized to 3 acetyl-CoA and 1 propionyl-CoA by -oxidation. The propionyl-CoA is converted to succinyl-CoA through the sequence of reactions shown in Fig. 17-12. The overall reaction is therefore: Pelargonic acid + HCO3- + ATP + 4CoASH + 3FAD + 3NAD+ 3 acetyl-CoA + succinyl-CoA + 3FADH2 + 3NADH + AMP + PPi
Write a balanced equation for the B-oxidation of palmitoyl-CoA, a 16-carbon, fully saturated fatty acid, and indicate how much of each product is formed
The overall reaction is: Palmitoyl-CoA + 7CoA-SH + 7FAD + 7NAD+ + 7H2O 8 acetyl-CoA + 7FADH2 + 7NADH + 7H+
If you received a laboratory report showing the presence of a high concentration of ketone bodies in the urine of a patient, what disease would you suspect? Why do ketone bodies accumulate in such patients?
The patient is probably an untreated diabetic, but the condition might also result from fasting. In either case, the unavailability of glucose from the blood stimulates gluconeogenesis in the liver. As the substrate for glucose formation, oxaloacetate is withdrawn from the citric acid cycle, bringing that cycle to a near halt. The fatty acids being oxidized in the liver yield acetyl-CoA, which now cannot be oxidized via the citric acid cycle. Reversal of the thiolase reaction produces acetoacetyl-CoA, which is then converted into ketone bodies and exported from the liver
The formation of fatty acyl-coa is made more favorable by the hydrolysis of two high energy bonds in ATP
The pyrophosphate formed in the action reaction is immediately hydrolyzed by inorganic pyrophosphatase which pulls the preceding activation reaction in the direction of the fatty acyl-coa formation.
One of the steps in fatty acid oxidation in mitochondria involves the addition of water across a double bond. What is the next step in the process? Show structures and indicate where any cofactor(s) participate(s).
The reaction is that catalyzed by B-hydroxyacyl-CoA dehydrogenase, for which NAD+ is cofactor.
Draw the first two steps of B-oxidation of saturated fatty acids. Show structures and indicate where any cofactors participate.
The reactions are those catalyzed by fatty acyl-CoA dehydrogenase and enoyl hydratase. Note the formation of FADH2 for the first step and the addition of water across the double bond in the second step.
In the citric acid cycle, a double bond is introduced into a four-carbon compound containing the —CH2—CH2— group, producing fumarate. Show a similar reaction that occurs in the -oxidation pathway.
This is the reaction catalyzed by acyol-CoA dehydrogenase.
Describe the steps in the metabolic pathway in which cells oxidize a five-carbon, straight-chain, saturated fatty acid (valerate; 5:0) to the fragments that enter the citric acid cycle. Show the structures of intermediates and products, and indicate where any cofactor(s) participate(s).
Valerate is first activated: valerate + ATP + CoA—SH valeryl-CoA + AMP + PPi Then, the valeryl group is transferred to carnitine and transported into the mitochondrial matrix, where it is reconverted to the valeryl;-CoA derivative. This passes through the four steps of -oxidation producing acetyl-CoA and propionyl-CoA. (See Fig. 17-8a.) Propionyl-CoA would be converted to succinyl-CoA by the reaction sequence in Fig. 17-12.
Which of the following is not true about Vitamin B12?
Vitamin B12 catalyzes hydrogen atom exchange with solvent H2O
Carnitine acyltransferase I
What enzyme catalyzes the rate-limiting step in fatty acid oxidation?
Carnitine acyl CoA transferase II
Which shuttle is used to bring fatty acyl CoA from the cytoplasm for ketogenesis?
The total degradation of a fatty acid with an odd number of carbons yields acetyl-CoA and another compound, X. Show the structure of X and describe the pathway by which it is converted into a citric acid cycle intermediate, including where any cofactors participate.
X is propionyl-CoA, and its conversion into succinyl-CoA is accomplished by the reactions
intrinsic factor
a gastric secretion that combines with vitamin B12 so that the vitamin can be absorbed
lipoprotein
a lipid protein aggregate that carries water-insolube lipids in the blood. The protein component alone is an apolipoprotein.
carnitine shuttle
a mechanism for moving fatty acids from the cytosol to the mitochondrial matrix as fatty esters of carnitine.
chylomicron
a plasma lipoprotein consisting of a large droplet of triacylglycerols stabilized by a coat of protein and phospholipid; carries lipids from the intestine to tissues.
Each molecule of FADH2 formed during oxidation of the fatty acid donates a pair of electrons to ETF of the respiratory chain
about 1.5 molecules of ATP are generates during the transfer of each electron pair to O2.
Linoleoyl-Coa undergoes three passes through the beta-oxidation sequence to yield three molecules of
acetyl-coa and the coenzyme A ester of a 12-carbon undersaturated fatty acid with a cis-D^3,cis-D^6 configuration
The increased blood levels of acetoacetate and D-hydroxybutyrate lower the blood pH causing
acidosis
To over the relative stability of the C-C bonds in a fatty acid, the carboxyl groups at C-1 is
activated by attachment to coenzyme A, which allows stepwise oxidation of the fatty acyl group at C-3, or beta position. Hence the name beta oxidation.
MCAD Medium-chain acyl-CoA dehydrogenase
acts on fatty acids 4 to 14 carbons
SCAD short chain Acyl-Coa Dehydrogenase
acts on fatty acids 4 to 8 carbons
Fatty acids are activates to acyl-CoAs and the acyl group is further transferred to carnitine because
acyl-carnitines readily cross the mitochondrial inner membrane, but acyl-CoAs do not.
alpha oxidation
an alternative path for the oxidation of beta methyl fatty acids in peroxisomes.
perilipin
are a family of proteins that associate with the surface of lipid droplets. Phosphorylation of perilipin is essential for the mobilization of fats in adipose tissue
PPAR (peroxisome proliferator activated receptor)
are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of the following three subtypes: PPARα, PPARγ, and PPARβ/δ.
The major sites of fatty acid oxidation, at rest and during exercise,
are skeletal and heart muscle.
During starvation, the liver can recycle lipids by
autophagy
In the third step, L-beta-hydroxyacyl-CoA is dehydrogenated to form beta-ketoacyl-CoA by the action of
beta-hydroxyacyl-CoA dehydrogenase. NAD+ is the electron acceptor.
The combined action of enoyl-coa isomerase and 2,4-dienoyl-CoA reductase transforms this intermediate into one that can enter the
beta-oxidation pathway and be degraded to six-acetyl-CoAa
The liver contains only a limited amount of coenzyme A, and when most of it is tied up in acetyl-Coa
beta-oxidation slows for want of the free coenzyme. The production and export of ketone bodies frees coenzyme A, allow continued fatty acid oxidation.
Bile salts are amphipathic compounds that act as
biological detergents, converting dietary fats into mixed micelles of bile salts and triacylglycerols.
In peroxisomes the energy released in the first oxidative step of fatty acid breakdown is not conversed as ATP
but is dissipated as heat.
Mitochondrial oxidation of fatty acids takes place in three stages. Beta oxidation-fatty acids undergo oxidative removal of successive two-carbon units in the form of acetyl-coa, starting from the
carboxyl end of the fatty acyl chain.
The formation of fatty acyl-carnitine is catalyzed by
carnitine acyl-transferase I (also called carnitine palmitoyltransferase 1, CPT1) in the outer membrane.
acetyl coa synthetase catalyzes
carnitine shuttle
Fatty acids destined for mitochondrial oxidation are transiently attached to the hydroxyl group of
carnitine to form fatty acyl-carnitine.
Free fatty acids in the bloodstream are:
carried by the protein serum albumin
Acteyl-CoA formed in the liver during oxidation of fatty acids can either enter the
citric acid cycle or undergo conversion to the ketone bodies: acetone, acetoacetate, and D-B-hydroxybutyrate.
In extrahepatic tissues, D-B-hydroxybutyrate is oxidized to acetoacetate by D-B-hydroxybutyrate dehydrogenase. the acetoacetate is activated to its
coenzyme A ester by transfer of CoA from succinyl-CoA and intermediate of the citric acid cycle.
Once fatty acyl groups have entered the mitochondrion, they are
committed to oxidation to acetyl-coa.
When each enzyme activity is on a seperate polypeptide, some mechanism is required to
coordinate the synthesis of all the gene products.
In healthy people, acetone is forced in very small amounts from acetoacetate, which is easily
decarboxylated, either spontaneously or by the action of acetocetate decarboxylase.
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency
deficiency is a condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting)
Formation of each acetyl-coa requires removal of four hydrogen atoms from the fatty acyl moiety by
dehydrogenases.
The glycerol produced from the hydrolysis of triacylglycerides enters glycolysis as:
dihydroxyacetone phosphate
The first two stages of fatty acid oxidation produce the reduced electron carriers NADH and FADH2, which in the third stage
donate electrons to the mitochondrial respiratory chain, through which the electrons pass to oxygen with the concomitant phosphorylation of ADP to ATP. The energy released by fatty acid oxidation is thus conserved as ATP.
The electrons are removed from the fatty acyl-coa are transferred to FAD, on one of the isoenzymes, and then the reduced form of the dehydrogenase immediately
donates its electrons to an electron carrier of the mitochondrial respiratory chain, the electron-transferring flavoprotein.
The double bonds are in the cis configuration and cannot be acted upon by
enoyl-CoA hydratase, the enzyme catalyzing the addition of water to the trans double bond of the delta^2-enoyl-CoA generated during beta oxidations.
The first step in the formation of acetoacetate, occuring in the liver is the
enzymatic condensation of two acetyl-coa, catalyzed by thiolase.
PPARa acts in the muscle, adipose tissue, and liver to turn on a set of genes
essential for fatty acid oxidation.
Carnitine is
essential for intracellular transport of fatty acids
ketoacidosis
excessive production of ketones, making the blood acid
The liver converts excess dietary carbohydrates to fats for
export to other tissues.
perilipins
family of proteins that restrict access to lipid droplets, preventing untimely lipid mobilization.
The mitochondrial matrix is the major site of
fatty acid oxidation in animal cells.
The PPAR family of nuclear receptors are transcription factors that affect many metabolic processes in response to a variety of
fatty acid-like ligands.
Lipoprotein lipase, activated by apoC-I hydrolyzes triacylglycerols to
fatty acids and glycerol
In untreated diabetes, when the insulin level is insufficient, levels of malonyl-coa fall inhibition of carnitine acyltransferase 1 is relieved and
fatty acids enter mitochondria to be degraded to acetyl-CoA
very long chain acyl-coa dehydrogenase works on
fatty acids of 12 to 18 carbons
Cattle and other ruminant animals form large amounts of propionate during
fermentation of carbohydrates in the rumen.
Before ingested triacylglycerols can be absorbed through the intestinal wall they must be converted from insoluble macroscopic fat particles to
finely dispersed microscopic micelles by bile salts.
The presence of a methyl group on the beta carbon of Phytanic acid prevents the
formation of a beta-keto intermediate, making its beta-oxidation impossible.
When TFP has shortened the fatty acyl chain to 12 or fewer carbons, further oxidations are catalyzed by a set of
four soluble enzyme in the matrix.
When TFP has shortened the fatty acyl chain to 12 or fewer carbons
further oxidations are catalyzed by a set of four soluble enzymes in the matrix.
The glycerol released by lipase action is phosphorylated by
glycerol kinase and the resulting glycerol 3-phosphate is oxidized to dihydroxyacetone phosphate. Which is later oxidized via glycolysis.
The disadvantage of having several activities on the same polypeptide is that the longer the polypeptide chain, the
greater the probability of a mistake in its synthesis. A single incorrect amino acid in the chain may make all the enzyme activities in the chain useless.
Most of the fatty acids in the triacylglycerols and phospholipids of animals and plants are unsaturated
having one or more double bonds.
Lipoprotein lipase acts in
hydrolysis of triacylglycerols of plasma lipoproteins to supply fatty acids to various tissues.
The role of hormone sensitive triacylglycerol lipase is to
hydrolyze triacylglycerols stored in adipose tissue.
High concentrations of fats in the diet result in increased synthesis of the enzymes of peroxisomal oxidation
in the liver.
Malonyl-CoA, the first intermediate in the cytosolic biosynthesis of long-chain fatty acids from acetyl coa
increases in concentration when the animal is well supplied with carbohydrate.
When the [NADH]/[NAD+] ratio is high, beta-hydroxyacyl-CoA dehydrogenase is
inhibited.
The acylcarnitine/carnitine cotransporter moves one molecule of carnitine from the matrix to the
intermediate space as one molecule of fatty acyl-carnitine moves into the matrix.
acyl-carnitine/carnitine transporter
is responsible for transporting both carnitine-fatty acid complexes and carnitine across the inner mitochondrial membrane. This enzyme is required since fatty acids cannot cross the mitochondrial membranes without assistance
The major site of formation of acetoacetate from fatty acids is the:
kidney
pernicious anemia
lack of mature erythrocytes caused by inability to absorb vitamin B12 into the bloodstream
Refsum disease results from a genetic defect in phytanoyl-CoA hydroxylase
leads to the accumulation of very high blood levels of phytanic acid, causing severe neurological defects.
Cycle AMP-dependent protein kinase A (PKA) triggers changes that open the
lipid droplet to the action of three cytosolic lipases, which act on tri, di, and monoacylglycerols, releasing fatty acids and glycerol.
Neutral lipids are stored in adipocytes in the form of
lipid droplets, with a core of triacylglycerols and sterol esters surrounded by a monolayer of phospholipids.
Phytanic acid
long-chain fatty acid with methyl branches, derived from the phytol side of chlorophyll.
The inhibition of carnitine acyltransferase by malonyl-CoA ensures that the oxidation of fatty acids is inhibited whenever the liver is amply supplied with glucose as fuel and is actively
making triacylglycerols from excess glucose.
The metabolite that regulates the activity of carnitine acyl transferase I is:
malonyl-CoA
The production and export of ketone bodies by the liver allows continues oxidation of fatty acids with only
minimal oxidation of acetyl-CoA.
In the second stage of fatty acid oxidation, the acetyl groups of acetyl-coa re oxidized to CO2 in the citric acid cycle, which also takes place in the
mitochondrial matrix.
The enzymes of fatty acid oxidation are located in the
mitochondrial matrix.
Fatty acyl-coa esters formed on the cytosolic side of the outer mitochondrial membrane can be transported in the
mitochondrion and oxidized to produce ATP
Phytanoyl-Coa is first hydroxylated on its alpha carbon in a reaction that involved
molecular oxygen
The protein moieties of lipoproteins are recognized by receptors on the cell surface. In lipid uptake from the intestine, chylomicrons, which contain apolipoprotein C-II
move from the intestinal mucosa into the lymphatic system, and then enter the blood, which carries them to muscle and adipose tissue.
For fatty acyl chains of 12 or more carbons, the reactions are catalyzed by a
multienzyme complex associated with the inner mitochondrial membrane- the trifunctional protein (TFP)
In hibernating animals, fatty acid oxidation provides metabolic energy heat and water, all essential for survival of an animal that
neither eats not drinks for long periods.
The liver is therefore a producer of ketone bodies
not a consumer
The three step process for transferring fatty acids into the mitochondrion links two separate pools of coenzyme A and of fatty acyl-CoA
one in the cytosol and the other in the mitochondria.
Four molecules of ATP are formed for each two-carbon unit removed in
one pass through the sequence.
Fatty acyl-CoA in the cytosolic pool can be used there for membrane lipid synthesis or can be moved into the mitochondrial matrix for
oxidation and ATP production.
acetyl-coa derived from fatty acids thus enters a final common pathway of
oxidation with the acetyl-coa derived from glucose via glycolysis and pyruvate oxidation.
Coenzyme A in the mitochondrial matrix is largely used in
oxidative degradation of pyruvate, fatty acids, and some amino acids whereas cytosolic coenzyme A is used in the biosynthesis of fatty acids.
The products of lipase action diffuse into the epithelial cells lining the intestinal surface where the are reconverted to triacylglycerols and
packed with dietary cholesterol and specific proteins into lipoprotein aggregates called chylomicrons.
If an aerobic organism (e.g., the bacterium E. coli) were fed each of the following four compounds as a source of energy, the energy yield per mole from these molecules would be in the order:
palmitate > glucose > alanine
triacylglycerols provide more than half the energy requirements of some organs
particularly the liver, heart, and resting skeletal muscle.
The fatty acyl-carnitine ester then diffuses across the intermembrane space and enters the matrix by
passive transport through the acylcarnitine/carnitine cotransporter of the inner mitochondrial membrane
The surface of these droplets is coated with
perilipins.
X-linked adrenoleukodystrophy
peroxisomes fail to oxidize very-long chain fatty acids, apparently due to lack of a functional transporter for these fatty acids in the peroxisomal membrane.
In plant cells, the major site of beta oxidation is
peroxisomes.
In the target tissues, fatty acids dissociate from albumin and are moved by
plasma membrane transporters into cells to serve as fuel.
Once triacylglycerols are hydrolyzed into fatty acids and glycerol, they are taken up by specific transporters in the
plasma membranes of cells in target tissues.
The fourth and the last step of Beta-Oxdation cycle is catalyzed by acyl-CoA acetyltransferase (thiolase) which
promotes reaction of beta-ketoacyl-CoA with a molecule of free coenzyme A to split off the carboxyl-terminal two-carbon fragment of the original fatty acid as acetyl-coa.
Propionyl-CoA is firs carboxylated to form the D-stereoisomers of methylmalonyl-CoA by
propionyl-CoA carboxylase, which contains the cofactor for biotin.
The following fatty acid, in which the indicated carbon is labeled with 14C, is fed to an animal: 14CH3(CH2)9COOH After allowing 30 minutes for fatty acid -oxidation, the label would most likely be recovered in:
propionyl-CoA.
The three step process by which fatty acyl groups are carried from cytosolic fatty acyl-CoA into the mitochondrial matrix is
rate limiting for fatty acid oxidation and is important point of regulation.
The pathway taken depends on the
rate of transfer or long-chain fatty acyl-CoA into mitochondria.
Beta oxidation
reaction that converts fatty acids to acetyl CoA to enter the Krebs cycle
One advantage to the cell in having several enzyme activities of the same pathway encoded in a single polypeptide chain is that this solves the problem of regulating the synthesis of enzymes that must interact functionally
regulation of the expression of one gene ensures production of the same number of active sites for all enzyme activities in the path.
The fatty acids thus released (free fatty acids FFAs) pass from the adipocyte into the blood, where they bind t the protein
serum albumin, where they are carried to tissues.
Apolipoproteins combine with lipids to form several classes of lipoprotein particles
spherical aggregates with hydrophobic lipids at the core and hydrophilic protein side chains and lipid head groups at the surface.
The brain, which prefers glucose, can adapt to the use o acetoacetate and D-B-hydroxybutyrate under
starvation conditions.
Bile salts, like taurocholic acid, are synthesized from cholesterol n the liver,
stored in the gallbladder, and released into the small intestine after ingestion of a fatty meal.
B-hydroxy-B-methylglutaryl-Coa (HMG-CoA) is stereospecific for the D-stereoisomer. This difference in stereospecificity of the two enzymes that use B-hydroxyacyl-CoA as
substrated in fatty acid breakdown and fatty acid synthesis means that the cell can maintain separate pools of B-hydroxyacyl-CoA, earmarked for either breakdown or synthesus.
The carbon atoms from a fatty acid with an odd number of carbons will enter the citric acid cycle as acetyl-CoA and:
succinyl-CoA.
Mutation in medium-chain acyl-CoA dehydrogenase. 1 in 40, and the mutant MCAD allele is unable to oxidize fatty acids of 6 to 12 carbons.
the disease is characterized by recurring episodes of a syndrome that includes fat accumulation in the liver, high blood glucose levels of octanoic acid, low blood glucose (hypoglycemia), sleepiness, vomiting, and coma.
When the diet contains more fatty acids than are needed immediately for fuel or as precursors
the liver converts them to triacylglycerols.
serum albumin
the most abundant protein in human blood plasma; it constitutes about half of serum protein. It is produced in the liver. It is soluble in water and monomeric.
A second important difference between mitochondrial and peroxisomal beta oxidation in mammals is in the specificity for fatty acyl-CoAs
the peroxisomal system is must more active on very long chain fatty acids and branched chains.
Long-chain odd-number fatty acids are oxidized in the same pathway as the even number acids
the products are acetyl-coa and propionyl-CoA
apolipoprotein
the protein component of a lipoprotein
Acyl-coa synthetases catalyze the formation of a thioester linkage between the fatty acid carboxyl group and the thiol group of coenzyme A to yield a fatty acyl-CoA
the reaction occurs in two steps and involves a fatty acyl-adenylate intermediate.
Acetoacetate and β-hydroxybutyrate are transported by the blood to tissues other than the liver (extrahepatic tissue) where
they are converted to acetyl-coa and oxidized in the citric acid cycle.
In muscle, the fatty acids are oxidized for energy. In adipose tissues
they are reesterfied for storage as triacylglycerols.
The brain cannot use fatty acids as fuel because
they do not cross the blood-brain barrier.
Fatty acids with chain lengths of 14 or more cannot pass through the mitochondrial membranes
they must first undergo 3 enzymatic reactins of carnitine shuttle.
Oleoyl-CoA then undergoes three passes through the fatty acid oxidation cycle to yield
three molecules of acetyl-CoA and the coenzyme A ester of a Delta^3, 12-carbon unsaturated fatty acid, cis-Delta^3-dodecenoyl-Coa
VLCAD, MCAD, AND SCAD are all isozymes are flavoproteins with
tightly bound FAD as a prosthetic group.
gluconeogenesis depletes citric acid cycle intermediates, diverting acetyl-coa
to ketone body production.
Four enzyme-catalyzed reactions make up the first stage of fatty acid oxidation. 1) dehydrogenation of fatty acyl-coa produces a double bond between alpha and beta carbon atoms. yielding a
trans-delta^2-enoyl-coa
In the second step of the beta-oxidation cycle, water is added to the double bond of the
trans-delta^2-enoyl-coa to form the L stereoisomer of Beta-hydroxyacyl-CoA (3-hydroxyacyl-CoA). catalyzed by enoyl-coA hydratase
When hormones signal the need for metabolic energy, triacylglycerols stored in adipose tissues are mobilized and
transported to tissues (skeletal muscle, heart, and renal cortex) in which fatty acids can be oxidized for energy production.
Since triacylglycerols are insoluble in water, ingested triacylglycerols must be emulsified before they can be digested by water-soluble enzymes in the intestine, and
triacylglycerols absorbed in the intestine or mobilized from storage tissues must be carried in the blood bound to a protein that counteracts their insolubility.
Apolipoproteins are lipid-binding proteins in the blood that are responsible for the transport of
triacylglycerols, phospholipids, cholesterol, and cholesteryl esters between organs.
Zellweger syndrome
unable to make peroxisomes and therefore lack all the metabolism unique to that organelle.
triacylglycerols can be stored in large quantities in the cell without risk of
undesirable chemical reactions with other cellular constituents
VLCAD
very long chain acyl-CoA dehydrogenase
In the liver, acetyl-CoA may be converted to ketone bodies
water soluble fuels exported to the brain when glucose is not available.
Micelle formation enormously increases the fraction of lipid molecules accessible to the action of
water-soluble lipases in the intestine. Lipase action converts triacylglycerols to monoacylglycerols, diacylglycerols, free fatty acids, and glycerol.
Phytanic acid is metabolized in peroxisomes by alpha oxidation
where a single carbon is removed from the carboxyl end of the acid.
Note that the new double bond has the trans configuration,
whereas the double bonds in naturally occurring unsaturated fatty acids are normally in the cis configuration.
The fatty acid with chain lengths of 12 of fewer carbons enter the mitochondria
without the help of membrane transporters.
free fatty acids
-unesterified FA w/ free carboxylate group - circulate in the blood bonded non-covalently to serum albumin
The conversion of palmitoyl-CoA (16:0) to myristoyl-CoA (14:0) and 1 mol of acetyl-CoA by the -oxidation pathway results in the net formation of:
1 FADH2 and 1 NADH.
In the liver, fatty acyl-CoA formed in the cytosol has two major pathways open to it:
1) Beta oxidation by enzymes in mitochondria or 2) conversion into triacylglycerols and phospholipids by enzymes in the cytosol.
Beta-oxidation enzymes of peroxisomes and glyoxysomes form a complex of proteins
1) acyl-CoA oxidase 2 & 3) multifunctional protein MFP 4)thiolase
Peroxisomes are organelles found in both animal and plant cells, the intermediates for beta-oxidation of fatty acids are coenzyme A derivatives and process consists of four steps:
1) dehydrogenation 2) addition of water to the resulting double bond 3) oxidation of the beta-hydroxyacyl-CoA to a ketone 4)thiolytic cleavage by coenzyme A
The complete oxidation of fatty acids to CO2 and H2O takes place in three stages.
1) the oxidation of long-chain fatty acids to two carbon fragments, in the form of acetyl-coa (beta-oxidation). 2) the oxidation of acetyl-coa to CO2 in the citric acid cycle. 3) the transfer of electrons from reduced electron carriers to the mitochondrial respiratory chain.
Which of the following is (are) true of the oxidation of 1 mol of palmitate (a 16-carbon saturated fatty acid; 16:0) by the -oxidation pathway, beginning with the free fatty acid in the cytoplasm? 1. Activation of the free fatty acid requires the equivalent of two ATPs. 2. Inorganic pyrophosphate (PPi) is produced. 3. Carnitine functions as an electron acceptor. 4. 8 mol of FADH2 are formed. 5. 8 mol of acetyl-CoA are formed. 6. There is no direct involvement of NAD+.
1,2 and 5
Half of the total serum protein, noncovalently binds as many as
10 fatty acids per protein monomer.
If the 16-carbon saturated fatty acid palmitate is oxidized completely to carbon dioxide and water (via the -oxidation pathway and the citric acid cycle), and all of the energy-conserving products are used to drive ATP synthesis in the mitochondrion, the net yield of ATP per molecule of palmitate is:
108
Complete oxidation of 1 mole of which fatty acid would yield the most ATP?
18-carbon mono-unsaturated fatty acid
Which of the following is (are) true of the -oxidation of long-chain fatty acids? 1. The enzyme complex that catalyzes the reaction contains biotin. 2. FADH2 serves as an electron carrier. 3. NADH serves as an electron carrier. 4. Oxidation of an 18-carbon fatty acid produces six molecules of propionyl-CoA. 5. Oxidation of a 15-carbon fatty acid produces at least one propionyl-CoA.
2, 3, and 5
Which of the following statements apply (applies) to the -oxidation of fatty acids? 1. The process takes place in the cytosol of mammalian cells. 2. Carbon atoms are removed from the acyl chain one at a time. 3. Before oxidation, fatty acids must be converted to their CoA derivatives. 4. NADP+ is the electron acceptor. 5. The products of -oxidation can directly enter the citric acid cycle for further oxidation.
3 and 5 only
What is the correct order of function of the following enzymes of -oxidation? 1. B-Hydroxyacyl-CoA dehydrogenase 2. Thiolase 3. Enoyl-CoA hydratase 4. Acyl-CoA dehydrogenase
3,1,4,2
Saturated fatty acids are degraded by the stepwise reactions of B-oxidation, producing acetyl-CoA. Under aerobic conditions, how many ATP molecules would be produced as a consequence of removal of each acetyl-CoA?
4
