694 Chapter 22 Gluconeogenesis, Glycogen Metabolism, and the Pentose Phosphate Pathwaycalculate the rate of energy consumption by muscles in heavy exer-cise in J/sec.. 696 Chapter 22 Glu
Trang 1stimulates protein phosphatase 2A (PP2A), which dephosphorylates the
bifunc-tional enzyme PFK-2/F-2,6-BPase (Figure 22.34, and see Figure 22.10) Increases
in [fructose-2,6-bisphosphate] stimulate glycolysis and inhibit gluconeogenesis At
the same time, PP2A dephosphorylates carbohydrate-responsive element-binding
protein (ChREBP), a transcription factor that activates expression of liver genes for
lipid synthesis These effects are a powerful combination Increased glycolysis
pro-duces substantial amounts of acetyl-CoA, the principal substrate for lipid synthesis.
The pentose phosphate pathway produces NADPH, the source of electrons for lipid
biosynthesis Elevated expression of the appropriate genes sets the stage for lipid
biosynthesis in the liver, an important consequence of ingestion of carbohydrates.
SUMMARY
22.1 What Is Gluconeogenesis, and How Does It Operate?
Gluconeo-genesis is the generation (Gluconeo-genesis) of new (neo) glucose In addition to
pyruvate and lactate, other noncarbohydrate precursors can be used as
substrates for gluconeogenesis in animals, including most of the amino
acids, as well as glycerol and all the TCA cycle intermediates On the
other hand, fatty acids are not substrates for gluconeogenesis in
ani-mals Lysine and leucine are the only amino acids that are not substrates
for gluconeogenesis These amino acids produce only acetyl-CoA upon
degradation Acetyl-CoA can be a substrate for gluconeogenesis in
plants when the glyoxylate cycle is operating The major sites of
gluco-neogenesis are the liver and kidneys, which account for about 90% and
10% of the body’s gluconeogenic activity, respectively
22.2 How Is Gluconeogenesis Regulated? Glycolysis and
gluconeo-genesis are under reciprocal control, so glycolysis is inhibited when
glu-coneogenesis is active, and vice versa When the energy status of the
cell is low, glucose is rapidly degraded to produce needed energy
When the energy status is high, pyruvate and other metabolites are
uti-lized for synthesis (and storage) of glucose The three sites of
regula-tion in the gluconeogenic pathway are glucose-6-phosphatase,
fructose-1,6-bisphosphatase, and the pyruvate carboxylase–PEP carboxykinase
pair, respectively These are the three most appropriate sites of
regula-tion in gluconeogenesis Glucose-6-phosphatase is under
substrate-level control by glucose-6-phosphate Acetyl-CoA allosterically activates
pyruvate carboxylase Fructose-1,6-bisphosphatase is inhibited by AMP
and activated by citrate Fructose-2,6-bisphosphate is a powerful
in-hibitor of fructose-1,6-bisphosphatase
22.3 How Are Glycogen and Starch Catabolized in Animals? Virtually
100% of digestible food is absorbed and metabolized Digestive
break-down of starch is an unregulated process On the other hand, tissue
glycogen represents an important reservoir of potential energy, and the
reactions involved in its degradation and synthesis are carefully
con-trolled and regulated Glycogen reserves in liver and muscle tissue are
stored in the cytosol as granules exhibiting a molecular weight range
from 6 106to 1600 106 These granular aggregates contain the
en-zymes required to synthesize and catabolize the glycogen, as well as all the enzymes of glycolysis The principal enzyme of glycogen catabolism
is glycogen phosphorylase, a highly regulated enzyme The glycogen phosphorylase reaction involves phosphorolysis at a nonreducing end
of a glycogen polymer
22.4 How Is Glycogen Synthesized? Luis Leloir, a biochemist in Ar-gentina, showed in the 1950s that glycogen synthesis depended upon sugar nucleotides The glycogen polymer is built around a tiny protein core The first glucose residue is covalently joined to the protein glyco-genin via an acetal linkage to a tyrosine–OH group on the protein Sugar units are added to the glycogen polymer by the action of glyco-gen synthase The reaction involves transfer of a glucosyl unit from UDP–glucose to the C-4 hydroxyl group at a nonreducing end of a glycogen strand The mechanism proceeds by cleavage of the COO bond between the glucose moiety and the -phosphate of UDP–glucose,
leaving an oxonium ion intermediate, which is rapidly attacked by the C-4 hydroxyl oxygen of a terminal glucose unit on glycogen
22.5 How Is Glycogen Metabolism Controlled? Activation of glycogen phosphorylase is tightly linked to inhibition of glycogen synthase, and vice versa Regulation involves both allosteric control and covalent mod-ification, with the latter being under hormonal control Glycogen syn-thase is also regulated by covalent modification Storage and utilization
of tissue glycogen are regulated by hormones, including insulin, glucagon, epinephrine, and the glucocorticoids Insulin stimulates glyco-gen synthesis and inhibits glycoglyco-gen breakdown in liver and muscle, whereas glucagon and epinephrine stimulate glycogen breakdown
22.6 Can Glucose Provide Electrons for Biosynthesis? The pentose phosphate pathway is a collection of eight reactions that provide NADPH for biosynthetic processes and ribose -5- phosphate for nucleic acid synthesis Several metabolites of the pentose phosphate pathway can also be shuttled into glycolysis Utilization of glucose-6-P in the pen-tose phosphate pathway depends on the cell’s need for ATP, NADPH, and ribose-5-P
PROBLEMS
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chapter at www.cengage.com/login
1.Consider the balanced equation for gluconeogenesis in Section 22.1
Account for each of the components of this equation and the
indi-cated stoichiometry
2.(Integrates with Chapters 3 and 18.) Calculate G° and G for
gluconeogenesis in the erythrocyte, using data in Table 18.2
(as-sume NAD/NADH 20, [GTP] [ATP], and [GDP] [ADP])
See how closely your values match those in Section 22.1
3. Use the data of Figure 22.9 to calculate the percent inhibition of
fructose-1,6-bisphosphatase by 25 mM fructose-2,6-bisphosphate when fructose-1,6-bisphosphate is (a) 25 mM and (b) 100 mM.
4. (Integrates with Chapter 3.) Suggest an explanation for the exergonic nature of the glycogen synthase reaction (G° 13.3 kJ/mol).
Consult Chapter 3 to review the energetics of high-energy phosphate compounds if necessary
5. Using the values in Table 23.1 for body glycogen content and the data in part b of the illustration for A Deeper Look (page 680),
Trang 2694 Chapter 22 Gluconeogenesis, Glycogen Metabolism, and the Pentose Phosphate Pathway
calculate the rate of energy consumption by muscles in heavy
exer-cise (in J/sec) Use the data for fast-twitch muscle
6. Which reactions of the pentose phosphate pathway would be
inhibited by NaBH4? Why?
7. (Integrates with Chapter 7.) Imagine a glycogen molecule with
8000 glucose residues If branches occur every eight residues, how
many reducing ends does the molecule have? If branches occur
every 12 residues, how many reducing ends does it have? How many
nonreducing ends does it have in each of these cases?
8. Explain the effects of each of the following on the rates of
gluco-neogenesis and glycogen metabolism:
a Increasing the concentration of tissue fructose-1,6-bisphosphate
b Increasing the concentration of blood glucose
c Increasing the concentration of blood insulin
d Increasing the amount of blood glucagon
e Decreasing levels of tissue ATP
f Increasing the concentration of tissue AMP
g Decreasing the concentration of fructose-6-phosphate
9.(Integrates with Chapters 3 and 15.) The free energy change of the glycogen phosphorylase reaction is G° 3.1 kJ/mol If [Pi]
1 mM, what is the concentration of glucose-1-P when this reaction
is at equilibrium?
10.Based on the mechanism for pyruvate carboxylase (Figure 22.3), write reasonable mechanisms for the reactions that follow:
O SCoA CH
H3C
H3C
Pi
Pi
CH
ATP
HCO3
O
SCoA
CH3
SCoA
H3C
CH3
CH3
COO
ATP
O
H
O
OOC
C
H
O
COO
C
H3C
O
OOC
H C H
H C
O
COO
C O
-Methylglutaconyl-CoA

-Methylcrotonyl-CoA

Methylmalonyl-CoA
Transcarboxylase
COO
C
CH3
O
C
CH3
O COO
C
CH3
O
OH
CH3
HOCH
HCOH
HCOH
CH2OPO3
H2C OH
O HCOH HCOH
CH2OPO3
HC
OPO32–
C
H3C O
Acetolactate synthase
H2O
Erythrose-4-P Phosphoketolase
11. The mechanistic chemistry of the acetolactate synthase and
phos-phoketolase reactions (shown here) is similar to that of the
trans-ketolase reaction (Figure 22.30) Write suitable mechanisms for
these reactions
Trang 312.Metaglip is a prescribed preparation (from Bristol-Myers Squibb) for
treatment of type 2 diabetes It consists of metformin (see Human
Biochemistry, page 668) together with glipizide The actions of
met-formin and glipizide are said to be complementary Suggest a
mech-anism for the action of glipizide
13.Study the structures of tolrestat and epalrestat in the Human
Bio-chemistry box on page 687 and suggest a mechanism of action for
these inhibitors of aldose reductase
14.Based on the discussion on page 691, draw a diagram to show how
several steps in the pentose phosphate pathway can be bypassed to
produce large amounts of ribose-5-phosphate Begin your diagram
with fructose-6-phosphate
15.Consider the diagram you constructed in problem 14 Which
car-bon atoms in ribose-5-phosphate are derived from carcar-bon atoms in
positions 1, 3, and 6 of fructose-6-phosphate?
16.As described on pages 691 and 692, the pentose phosphate pathway
may be used to produce large amounts of NADPH without
signifi-cant net production of ribose-5-phosphate Draw a diagram,
beginning with glucose-6-phosphate, to show how this may be
ac-complished
17. The discussion on page 692 explains that the pentose phosphate pathway and the glycolytic pathway can be combined to provide both NADPH and ATP (as well as some NADH) without net ribose-5-phosphate synthesis Draw a diagram to show how this may be ac-complished
18. Consider the pathway diagram you constructed in problem 17 What is the fate of carbon from positions 2 and 4 of glucose-6-phosphate after one pass through the pathway?
19. Glycogenin catalyzes the first reaction in the synthesis of a glycogen particle, with Tyr194of glycogenin (page 676) combining with a glu-cose unit (provided by UDP-gluglu-cose) to produce a tyrosyl gluglu-cose Write a mechanism to show how this reaction could occur
Preparing for the MCAT Exam
20. Study the graphs in the Deeper Look box (page 680) and explain the timing of the provision of energy from different metabolic sources during periods of heavy exercise
21. (Integrates with Chapters 3 and 14.) What is the structure of crea-tine phosphate? Write reactions to indicate how it stores and pro-vides energy for exercise
FURTHER READING
Gluconeogenesis
Boden, G., 2003 Effect of free fatty acids on gluconeogenesis and
glycogenolysis Life Science 72:977–988.
Choe, J.-Y., Iancu, C V., et al., 2003 Metaphosphate in the active site
of fructose-1,6-bisphosphatase Journal of Biological Chemistry 278:
16015–16020
Dzugaj, A., 2006 Localization and regulation of muscle
fructose-1,6-bisphosphatase, the key enzyme of glyconeogenesis Advances in
En-zyme Regulation 46:51–71.
Gerich, J E., Meyer, C., et al., 2001 Renal gluconeogenesis: Its
impor-tance in human glucose homeostasis Diabetes Care 24:382–391.
Hers, H.-G., and Hue, L., 1983 Gluconeogenesis and related aspects of
glycolysis Annual Review of Biochemistry 52:617–653.
Jitrapakdee, S., and Wallace, J C., 1999 Structure, function, and
regu-lation of pyruvate carboxylase Biochemical Journal 348:1–16.
Kondo, S., Nakajima, Y., et al., 2007 Structure of the biotin carboxylase
domain of pyruvate carboxylase from Bacillus thermodenitrificans.
Acta Crystallographica D 63:885–890.
Regulation of Gluconeogenesis
Alves, G., and Sola-Penna, M., 2003 Epinephrine modulates cellular
dis-tribution of muscle phophofructokinase Molecular Genetics and
Me-tabolism 78:302–306.
Arden, C., Hampson, L., et al., 2008 A role for PFK-2/FBPase-2, as
dis-tinct from fructose-2,6-bisphosphate, in regulation of insulin
secre-tion in pancreatic -cells Biochemical Journal 411:41–51.
Moller, D E., 2001 New drug targets for type 2 diabetes and the
meta-bolic syndrome Nature 414:821–827.
Newsholme, E A., and Leech, A R., 1983 Biochemistry for the Medical
Sci-ences New York: John Wiley and Sons.
Newsholme, E A., and Leech, A R., 1983b Substrate cycles: Their role
in improving sensitivity in metabolic control Trends in Biochemical
Sciences 9:277–280.
Rider, M., Bertrand, L., et al., 2004
6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: Head-to-head with a bifunctional enzyme that
controls glycolysis Biochemical Journal 381:561–579.
Rolfe, D J., and Brown, G C., 1997 Cellular energy utilization and
molecular origin of standard metabolic rate in mammals
Physiolog-ical Reviews 77:731–758.
Van Schaftingen, E., and Hers, H G., 1981 Inhibition of
fructose-1,6-bisphosphatase by fructose-2,6-bisphosphate Proceedings of the
Na-tional Academy of Sciences U.S.A 78:2861–2863.
Exercise Physiology
Akermark, C., Jacobs, I., et al., 1996 Diet and muscle glycogen concen-tration in relation to physical performance in Swedish elite ice
hockey players International Journal of Sport Nutrition 6:272–284.
Hargreaves, M., 1997 Interactions between muscle glycogen and blood
glucose during exercise Exercise and Sport Science Reviews 25:21–39.
Horton, E S., and Terjung, R L., 1988 Exercise, Nutrition and Energy
Me-tabolism New York: Macmillan.
Rhoades, R., and Pflanzer, R., 1992 Human Physiology Philadelphia:
Saunders College Publishing
Glucose Homeostasis
Dalsgaard, M K., 2006 Fuelling cerebral activity in exercising man
Jour-nal of Cerebral Blood Flow and Metabolism 26:731–750.
Dalsgaard, M K., and Secher, N H., 2007 The brain at work: A cerebral
metabolic manifestation of central fatigue? Journal of Neuroscience
Re-search 85:3334–3339.
Feinman, R D., and Fine, E J., 2007 Nonequilibrium thermodynamics
and energy efficiency in weight loss diets Theoretical Biology and
Med-ical Modelling 4:1–13.
Huang, S., and Czech, M P., 2007 The GLUT4 glucose transporter Cell
Metabolism 5:237–252.
Watson, R T., and Pessin, J E., 2006 Bridging the GAP between insulin
signaling and GLUT4 translocation Trends in Biochemical Sciences
31:215–222
Glycogen Metabolism
Browner, M F., and Fletterick, R J., 1992 Phosphorylase: A biological
transducer Trends in Biochemical Sciences 17:66–71.
Delibegovic, M., Armstrong, C J., et al., 2003 Disruption of the striated muscle glycogen targeting subunit PPP1R3A of protein phos-phatase 1 leads to increased weight gain, fat deposition, and
devel-opment of insulin resistance Diabetes 52:506–604.
Foster, J D., and Nordlie, R C., 2002 The biochemistry and molecular
biology of the glucose-6-phosphatase system Experimental Biology
and Medicine 227:601–608.
Horcajada, C., Guinovart, J J., et al., 2006 Crystal structure of an archaeal
glycogen synthase Journal of Biological Chemistry 281:2923–2931.
Hurley, T D., Stout, S., et al., 2005 Requirements for catalysis in
mam-malian glycogenin Journal of Biological Chemistry 280:23892–23899.
Johnson, L N., 1992 Glycogen phosphorylase: Control by
phosphory-lation and allosteric effectors FASEB Journal 6:2274–2282.
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Jope, R S., Yuskaitis, C., et al., 2007 Glycogen synthase kinase-3 (GSK3):
Inflammation, diseases, and therapeutics Neurochemical Research
32:577–595
Kerkela, R., Woulfe, K., et al., 2007 Glycogen synthase kinase-3:
Ac-tively inhibiting hypertrophy Trends in Cardiovascular Medicine 17:
91–96
Kotova, O., Al-Khalili, L., et al., 2006 Cardiotonic steroids stimulate
glycogen synthesis in human skeletal muscle cells via a Src- and
ERK1/2-dependent mechanism Journal of Biological Chemistry 281:
20085–20094
Larner, J., 1990 Insulin and the stimulation of glycogen synthesis: The
road from glycogen structure to glycogen synthase to cyclic
AMP-dependent protein kinase to insulin mediators Advances in
Enzy-mology 63:173–231.
Lerin, C., Montell, E., et al., 2003 Regulation and function of the
mus-cle glycogen-targeting subunit of protein phosphatase-1 (GM) in
hu-man muscle cells depends on the COOH-terminal region and
glyco-gen content Diabetes 52:2221–2226.
Montori-Grau, M., Guitart, M., et al., 2007 Expression and glycogenic effect of glycogen-targeting protein phosphatase 1 regulatory sub-unit GLin cultured human muscle Biochemical Journal 405:107–113.
Ozen, H., 2007 Glycogen storage diseases: New perspectives World
Jour-nal of Gastroenterology 13:2541–2553.
Paterson, J., Kelsall, I R., et al., 2008 Disruption of the striated mus-cle glycogen-targeting subunit of protein phosphatase 1: Influence
of the genetic background Journal of Molecular Endocrinology 40:
47–59
Saeed, Y A., and Barger, S W., 2007 Glycogen synthase kinase-3 in
neu-rodegeneration and neuroprotection: Lessons from lithium
Cur-rent Alzheimer Research 4:21–31.
Stalmans, W., Cadefau, J., et al., 1997 New insight into the regulation of
liver glycogen metabolism by glucose Biochemical Society Transactions
25:19–25
Yamamoto-Honda, R., Honda, Z., et al., 2000 Overexpression of the glycogen targeting (GM) subunit of protein phosphatase-1
Biochem-ical and BiophysBiochem-ical Research Communications 275:859–864.
Trang 523 Fatty Acid Catabolism
23.1 How Are Fats Mobilized from Dietary Intake and
Adipose Tissue?
Modern Diets Are Often High in Fat
Fatty acids are acquired readily in the diet and can also be made from carbohydrates
and the carbon skeletons of amino acids Fatty acids provide 30% to 60% of the
calo-ries in the diets of most Americans For our caveman and cavewoman ancestors, the
figure was probably closer to 20% Dairy products were apparently not part of their
diet, and the meat they consumed (from fast-moving animals) was low in fat In
con-trast, modern domesticated cows and pigs are actually bred for high fat content (and
better taste) However, woolly mammoth burgers and saber-toothed tiger steaks are
hard to find these days—even in the gourmet sections of grocery stores—and so, by
default, we consume (and metabolize) large quantities of fatty acids.
Triacylglycerols Are a Major Form of Stored Energy in Animals
Although some of the fat in our diets is in the form of phospholipids,
triacylglyc-erols are a major source of fatty acids Triacylglyctriacylglyc-erols are also our principal stored
energy reserve As shown in Table 23.1, the energy available in stores of fat in the
average person far exceeds the energy available from protein, glycogen, and
glu-cose Overall, fat accounts for approximately 83% of available energy, partly because
more fat is stored than protein and carbohydrate and partly because of the
sub-stantially higher energy yield per gram for fat compared with protein and
carbohy-drate Complete combustion of fat yields about 37 kJ/g, compared with about 16 to
17 kJ/g for sugars, glycogen, and amino acids In animals, fat is stored mainly as
tri-acylglycerols in specialized cells called adipocytes or adipose cells As shown in
Fig-ure 23.1, triacylglycerols, aggregated to form large globules, occupy most of the
vol-ume of adipose cells Much smaller amounts of triacylglycerols are stored as small,
aggregated globules in muscle tissue.
Hormones Trigger the Release of Fatty Acids from Adipose Tissue
The pathways for liberation of fatty acids from triacylglycerols, either from adipose
cells or from the diet, are shown in Figures 23.2 and 23.3 Fatty acids are mobilized
from adipocytes in response to hormone messengers such as adrenaline, glucagon,
and adrenocorticotropic hormone (ACTH) These signal molecules bind to
re-ceptors on the plasma membrane of adipose cells and lead to the activation of
The hummingbird’s tremendous capacity to store and use fatty acids enables it to make migratory journeys
of remarkable distances
The fat is in the fire.
John Heywood
Proverbs (1497–1580)
KEY QUESTIONS
23.1 How Are Fats Mobilized from Dietary Intake and Adipose Tissue?
23.2 How Are Fatty Acids Broken Down?
23.3 How Are Odd-Carbon Fatty Acids Oxidized?
23.4 How Are Unsaturated Fatty Acids Oxidized?
23.5 Are There Other Ways to Oxidize Fatty Acids?
23.6 What Are Ketone Bodies, and What Role
Do They Play in Metabolism?
ESSENTIAL QUESTIONS
Fatty acids represent the principal form of stored energy for many organisms There
are two important advantages to storing energy in the form of fatty acids (1) The
car-bon in fatty acids (mostly OCH2O groups) is almost completely reduced compared
to the carbon in other simple biomolecules (sugars, amino acids) Therefore, oxidation
of fatty acids will yield more energy (in the form of ATP) than any other form of
carbon (2) Fatty acids are not generally as hydrated as monosaccharides and
polysac-charides are, and thus they can pack more closely in storage tissues.
How are fatty acids catabolized, and how is their inherent energy captured by
organisms?
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Trang 6698 Chapter 23 Fatty Acid Catabolism
Energy Dry Weight Available Energy
Sources: Owen, O E., and Reichard, G A., Jr., 1971 Fuels consumed by man: The interplay between carbohydrates and fatty
acids Progress in Biochemistry and Pharmacology 6:177; and Newsholme, E A., and Leech, A R., 1983 Biochemistry for the
Medical Sciences New York: Wiley.
TABLE 23.1 Stored Metabolic Fuel in a 70-kg Person
FIGURE 23.1 Scanning electron micrograph of an
adi-pose cell (fat cell) Globules of triacylglycerols occupy
most of the volume of such cells
P
P
P
Adenylyl cyclase Receptor
cAMP Hormone
Protein kinase (inactive)
Protein kinase (active)
Triacylglycerol lipase (inactive) Triacylglycerol
lipase (active)
Phosphatase
P
Triacylglycerol
Diacylglycerol
Monoacylglycerol
Glycerol
MAG lipase
DAG lipase
Fatty acid
Fatty acid
Adipose cell
Plasma membrane
Fatty acid ADP
ATP
ATP
FIGURE 23.2 Liberation of fatty acids from
triacylglyc-erols in adipose tissue is hormone-dependent
Trang 7O C
H
CH2
H2C
CO CO CO
O C
H
CH2
H2C
CO
CO CO
O–
+ O
C
H
CH2
H2C
CO CO
O–
+
CO O–
+
O C
H
CH2
H2C
CO CO
CO O–
+
Triacylglycerol
Pancreatic lipase
Pancreatic lipase
Pancreatic lipase
Diacylglycerol
2 fatty acid 2 CoA
2 fatty acyl CoA Monoacylglycerol
Triacylglycerol
Chylomicrons Lymph duct
Epithelial cells
of intestinal wall
Pancreatic duct
Entry of pancreatic juice
into duodenum
Small intestine
Large intestine Pancreas
Stomach
Duodenum
Food containing triacylglycerols
(b) (a)
FIGURE 23.3 (a) The pancreatic duct secretes digestive fluids into the duodenum, the first portion of the small
intestine (b) Hydrolysis of triacylglycerols by pancreatic and intestinal lipases Pancreatic lipases cleave fatty
acids at the C-1 and C-3 positions Resulting monoacylglycerols with fatty acids at C-2 are hydrolyzed by
intesti-nal lipases Fatty acids and monoacylglycerols are absorbed through the intestiintesti-nal wall and assembled into
lipoprotein aggregates termed chylomicrons (discussed in Chapter 24)
Trang 8700 Chapter 23 Fatty Acid Catabolism
adenylyl cyclase, which forms cyclic AMP from ATP (Second messengers and hor-monal signaling are discussed in Chapter 32.) In adipose cells, cAMP activates
pro-tein kinase A, which phosphorylates and activates a triacylglycerol lipase (also termed hormone-sensitive lipase) that hydrolyzes a fatty acid from C-1 or C-3 of triacylglycerols Subsequent actions of diacylglycerol lipase and monoacylglycerol lipase yield fatty acids and glycerol The cell then releases the fatty acids into
the blood, where they are bound to serum albumin (the most abundant protein in
blood serum) Serum albumin transports free fatty acids to sites of utilization.
Degradation of Dietary Fatty Acids Occurs Primarily in the Duodenum
Dietary triacylglycerols are degraded to a small extent (via fatty acid release) by lipases in the low-pH environment of the stomach, but mostly they pass untouched into the duodenum Alkaline pancreatic juice secreted into the duodenum (Figure 23.3a) raises the pH of the digestive mixture, allowing hydrolysis of the triacylglyc-erols by pancreatic lipase and by nonspecific esterases, which hydrolyze the fatty acid ester linkages Pancreatic lipase cleaves fatty acids from the C-1 and C-3 positions of triacylglycerols, and other lipases and esterases attack the C-2 position (Figure
23.3b) These processes depend upon the presence of bile salts, a family of
car-boxylic acid salts with steroid backbones (see also Chapter 24) These agents act as detergents to emulsify the triacylglycerols and facilitate the hydrolytic activity of the lipases and esterases Short-chain fatty acids (ten or fewer carbons) released in this way are absorbed directly into the villi of the intestinal mucosa, whereas long-chain fatty acids, which are less soluble, form mixed micelles with bile salts and are carried
in this fashion to the surfaces of the epithelial cells that cover the villi (Figure 23.4) The fatty acids pass into the epithelial cells, where they are condensed with glycerol
to form new triacylglycerols These triacylglycerols aggregate with lipoproteins to
form particles called chylomicrons, which are then transported into the lymphatic
system and on to the bloodstream, where they circulate to the liver, lungs, heart, muscles, and other organs (see Chapter 24) At these sites, the triacylglycerols are
microvilli or the
lymphatic system, tissues throughout the body
FIGURE 23.4 In the small intestine, fatty acids combine
with bile salts in mixed micelles, which deliver fatty
acids to epithelial cells that cover the intestinal villi
Tri-acylglycerols are formed within the epithelial cells
Trang 9hydrolyzed to release fatty acids, which can then be oxidized in a highly exergonic
metabolic pathway known as -oxidation.
23.2 How Are Fatty Acids Broken Down?
Knoop Elucidated the Essential Feature of -Oxidation
The earliest clue to the secret of fatty acid oxidation and breakdown came in the
early 1900s, when Franz Knoop carried out experiments in which he fed modified
fatty acids to dogs Knoop’s experiments showed that fatty acids must be degraded
by oxidation at the -carbon (Figure 23.5), followed by cleavage of the COCbond.
Repetition of this process yielded two-carbon units, which Knoop assumed must be
acetate Much later, Albert Lehninger showed that this degradative process took
place in the mitochondria, and F Lynen and E Reichart showed that the
two-carbon unit released is acetyl-CoA, not free acetate Because the entire process
be-gins with oxidation of the carbon that is “ ” to the carboxyl carbon, the process has
come to be known as -oxidation.
In mammalian cells, -oxidation take place primarily in mitochondria, but a
simi-lar pathway occurs in peroxisomes In yeast and other lower eukaryotes, -oxidation
is confined exclusively to peroxisomes Mitochondrial -oxidation provides energy
to the organism (Figure 23.6), whereas peroxisomal -oxidation is responsible for
O
C
H2
H2 C C
H2
H2 C C
H2
H2 C C
H2
H2 C C
H2
H2 C C
H2
H2 C
C
H2
H2 C C
O O
C
H2
H2 C C
H2
H2 C C
H2
H2 C C
H2
H2 C C
H2
H2 C C
H2
H2 C
C
H2 C C
+ H3C C SCoA O
O C
H2
H2 C C
H2
H2 C C
H2
H2 C C
H2
H2 C C
H2
H2 C C
H2
H2 C C
[FAD], NAD+
[FADH2], NADH + H+
CoASH
FIGURE 23.5 Fatty acids are degraded by repeated cy-cles of oxidation at the -carbon and cleavage of the
COCbond to yield acetate units, in the form of acetyl-CoA Each cycle of -oxidation yields four
elec-trons, captured as FADH2and NADH, which drive elec-tron transport and oxidative phosphorylation pathways
to produce ATP
O
+31.5 –0.8
=
=
=
P P
P P
P P
ATP ATP
CoASH AMP
AMP kJ
mol kJ mol kJ mol
ΔG' for
ΔG' for acyl-CoA synthesis
H2O
kJ mol
FIGURE 23.6 The acyl-CoA synthetase reaction activates fatty acids for -oxidation.The reaction is driven by
hydrolysis of ATP to AMP and pyrophosphate and by the subsequent hydrolysis of pyrophosphate
Trang 10702 Chapter 23 Fatty Acid Catabolism
shortening long-chain fatty acids that are poor substrates for mitochondrial
-oxidation Such shortened fatty acids then become substrates for mitochondrial
-oxidation.
Coenzyme A Activates Fatty Acids for Degradation
The process of -oxidation begins with the formation of a thiol ester bond between
the fatty acid and the thiol group of coenzyme A This reaction, shown in Figure
23.6, is catalyzed by acyl-CoA synthetase, which is also called acyl-CoA ligase or fatty acid thiokinase. This condensation with CoA activates the fatty acid for reaction in the -oxidation pathway For long-chain fatty acids, this reaction normally occurs at
the outer mitochondrial membrane in higher eukaryotes before entry of the fatty acid into the mitochondrion, but it may also occur at the surface of the endoplas-mic reticulum Short- and medium-length fatty acids undergo this activating reac-tion in the mitochondria In all cases, the reacreac-tion is accompanied by the hydroly-sis of ATP to form AMP and pyrophosphate As shown in Figure 23.6, the overall reaction has a net G° of about 0.8 kJ/mol, so the reaction is favorable but
eas-ily reversible However, there is more to the story As we have seen in several similar cases, the pyrophosphate produced in this reaction is rapidly hydrolyzed by inor-ganic pyrophosphatase to two molecules of phosphate, with a net G° of about
33.6 kJ/mol Thus, pyrophosphate is maintained at a low concentration in the cell (usually less than 10
mechanism of the acyl-CoA synthetase reaction is shown in Figure 23.7 and involves
attack of the fatty acid carboxylate on ATP to form an acyladenylate intermediate, which
is subsequently attacked by CoA, forming a fatty acyl-CoA thioester.
Carnitine Carries Fatty Acyl Groups Across the Inner Mitochondrial Membrane
All of the other enzymes of the -oxidation pathway are located in the
mitochon-drial matrix Short-chain fatty acids, as already mentioned, are transported into the matrix as free acids and form the acyl-CoA derivatives there However, long-chain fatty acyl-CoA derivatives cannot be transported into the matrix directly These
long-O O
O–
O–
P
O
O–
P O
O–
P
O
Adenosine
O–
C O
O O–
P
O –O
O–
P O
C O
R
O
O–
O Adenosine H
S
O
O–
O–
O O
Adenosine C
S
R C
R
O
O–
O Adenosine
CoA
CoA CoA
Fatty acid
Pyrophosphate
Enzyme-bound acyl-adenylate intermediate
Fatty acyl-CoA AMP
ATP
Transient tetrahedral intermediate
ANIMATED FIGURE 23.7 The mechanism of the acyl-CoA synthetase reaction involves fatty acid carboxylate attack on ATP to form an acyl-adenylate intermediate The fatty acyl CoA thioester product is
formed by CoA attack on this intermediate See this figure animated at www.cengage.com/login.