1. Berg • Tymoczko • Stryer
Biochemistry
Sixth Edition
Chapter 27
The Integration of Metabolism
Copyright © 2007 by W. H. Freeman and Company

3. Integration of Metabolism and
Hormone Action
 Metabolic process in single cells
 Whole organism
 Hormonal signals integrate and coordinate the
metabolic activities of different tissues and
bring about optimal ALLOCATION of fuels and
precursors to each organ.
 Our focus:
– The specialized metabolism of major organs
– Some tissues are energy suppliers, others are energy
consumers, and some are both.
Question: How do these tissues communicate to
each other?
» Answer: Hormones.

4. Metabolism has highly
interconnected pathways
 Central themes:
– ATP is universal currency of energy
– ATP is made by the oxidation of Glc, fa’s and aa’s
• The common intermediate is AcetylCoA
– NADPH is the major electron donor in reductive
biosynthesis
– Biomolecules are made from building blocks.
– Biosynthetic and degradative pathways are almost
always distinct!
• They could be easily controlled
• They become thermodynamically favorable at all times

20. Recurring motifs in regulation
1. Allosteric interaction
2. Covalent modification
3. Adjustment of enzyme levels
4. Compartmentation
5. Metabolic specializations of organs

23. Major metabolic pathways
and control sites
1. Glycolysis
 PFK is the most important control point
 In the liver, the most important regulator is F-2,6 BP.
– When blood Glc goes down, a glucagon-triggered cascade
leads to the activation of the phosphatase and the inhibition
of the kinase in the liver.
• F-2,6BiP decreases
• PFK decreases
 Glycolysis slows down

25. Major metabolic pathways
and control sites
2. TCA cycle and Oxidative Phosphorylation
 Takes place inside mitochondria
 The rate of the TCA cycle matches the need for
ATP.
– High ATP levels decrease the activities of 2 enzymes:
• Isocitrate dehydrogenase
• α-ketoglutarate dehydrogenase

26. Major metabolic pathways
and control sites
3. Pyruvate dehydrogenase complex
 Takes place inside mitochondria

27. Major metabolic pathways
and control sites
4. Pentose phosphate pathway
 Takes place in the cytosol in two stages:
– Oxidative decarboxylation of G-6-Phosphate
– Nonoxidative, reversible metabolism of 5C phosphosugars
into phospharylated 3C and 6C glycolitic intermediates

29. Major metabolic pathways
and control sites
5. Gluconeogenesis
 Glc can be made by the liver from noncarbohydrates
 The major entry point of this pathway is pyruvate,
which is carboxylated to OAA in mitochondria.
 Gloconeogenesis and glycolysis are usually
reciprocally regulated so one pathway is minimally
active while the other one is highly active.
– If F-2,6BiP increases, gluconeogenesis is inhibited and
glycolysis is activated.

31. Major metabolic pathways
and control sites
6. Glycogen synthesis and degradation
 Glycogen synthesis and degradation are
coordinately controlled by a hormone-triggered
cascade so there is no misunderstanding
 Enzymes to remember:
– Phosphorylase
– Glycogen synthase

33. Major metabolic pathways
and control sites
7. Fa synthesis and degradation
 Fa’s are made in the cytosol
– 2C units are added to a growing chain on an acyl carrier
protein.
• Acetyl groups are carried from mitochondria to the cytosol as
CITRATE
• Citrate increases the activity of acetyl CoA carboxylase which
increases fa synthesis
– Malonyl CoA is formed by the carboxylation of acetyl CoA.
 Beta oxidation is in mitochondria
– Acylcarnitine formation is important
– ATP need is important
– If there is too much malonyl CoA, fa degradation is inhibited.

36. Key junctions
 There are 3 metabolic junctions
– Glc-6-P
– Pyruvate
– AcetylCoA

39. Metabolic
pathways
for G-6-P
in the liver

40. Metabolism of
amino acids in
the liver

41. Metabolism
of fatty acids
in the liver

42. Each organ has a unique metabolic profile
 Brain
 Muscle
 Adipose tissue
 The kidney
 Liver

43. Brain
 Glc is virtually the sole fuel for the human brain,
except during prolonged starvation
 It consumes 120 g glc per day
 No glycogen strores in the brain
 During prolonged starvation, acetaacetate is
used
 Fas do not serve as fuel in the brain because
– They are bound to albumin in plasma; therefore, they
cannot pass the blood brain barrier.
– In essence, ketone bodies are transported equivalents
of fa’s

47. Muscle
 Muscle differs from brain in that muscle has a
large store of glycogen
– 75% of glycogen is in muscle.
– The energy consumption increases with muscle
activity
– CORI cycle
• In actively contracting skeletal muscle, the rate of glycolysis
far exceeds that of the citric acid cycle, and much of the
pyruvate formed is reduced to lactate.
• Lactate goes to liver and is converted to glc again

54. Heart muscle
 For reasons that are not clear, the heart
relies mainly on fatty acids.
– One possibility is that fatty acid supply is more
reliable than the fluctuating carbohydrate supply.
– Most organisms have a very extensive supply of
fa’s; thus the functioning of the heart muscle is
protected

55. Adipose tissue
 The TAGs are stored here.
– They are enormous reservoir of fuel.
 Adipose cells need glucose for the synthesis of
TAGs
 The glucose level inside adipose cells is a major
factor in determining whether fatty acids are
released into the blood.
– If too much food, then FFA is stored.
– If Glc and glycogen are NOT enough, then TAG is
converted to FFA with the excess re-esterified in the liver
to form TAG.

57. The kidney
 Major role: to make urine
– The blood plasma is filtered nearly 60 times
each day in the renal tubules.
 During starvation, the kidney becomes an
important site of gluconeogenesis and may
contribute as much as half of the blood
glucose!

58. Liver
 The liver serves as the body’s distribution center,
detoxification center, and central clearing house.
– Metabolic hub
– The liver plays an essential role in the integration of
metabolism.
 Liver removes 2/3 of the glucose from the blood.
– The absorbed Glc is converted into G-6-P.
– G-6-P has many fates
• Fa, cholesterol, or bile synthesis
• Glycogen synthesis
• PPP

59. liver
 When fuels are increased, fa’s are derived from the
diet or synthesized by the liver as TAGs
– They are secreted into the blood in the form of VLDL
 During fasting, the liver converts fa’s into ketone
bodies
 The liver also plays an essential role in amino acid
metabolism
– It secretes 20-30 g urea/day
 Liver meets its own energy by using α-ketoacids.

60. Food intake and starvation
induce metabolic changes
Starved-fed cycle
 Nightly starved-fed cycle has 3 stages:
• Postabsorbtive state
• Early fasting during the night
• The refed state after breakfast
 Main goal is to maintain glc homeostasis!

61. Food intake and starvation
induce metabolic changes
The well-fed state
 After the consumption
– Glc, aa’s and lipids are transported to the blood.
– The secretion of insulin increases.
– Insulin increases the uptake of Glc into the liver by GLUT2
– Insulin also increases the uptake of Glc by muscle and
adipose tissue

63. Early fasting state
 The blood Glc decreases several hours after a meal
– Insulin decreases
– Glucagon increases
• Glucagon signals the starved state
• It mobilizes the glycogen by cAMP pathway
• The main target organ of glucagon is the liver.
– Net result: Increase glucose in blood

64. The refed state
 Fat process same as fed state
 The liver does not initially absorb glc from the
blood, but rather leaves it for the peripheral tissues
 Liver stays in gluconeogenic mode
 Newly made Glc is used to make glycogen
 As blood Glc increases, the liver completes the
replenishment of its glycogen stores

65. Metabolic adaptation in prolonged starvation
minimize protein degradation
What are the adaptations if fasting is prolonged
to the point of starvation?
– 70 kg man has fuel reserve ~ 161,000 kcal
– The energy need for a 24 hr cycle is 1600-6000 kcal
– So, fuels are ok for 1-3 months!
 The very first priority of metabolism in starvation
– Providing Glc to the brain and other tissues
 The second priority of metabolism in starvation is to
preserve protein, which is accomplished by shifting
from glc to fa’s

70. After 3 days of starvation
 Liver forms keton bodies
 Their synthesis from AcetylCoA is increased
because TCA is not running(gluconeogenesis
depletes the supply of oxaloacetate)
 So, liver makes lots of KBs
 The brain begins to use acetoacetate
 After 3 days, 1/3 of the energy comes from KBs
for the brain
 The heart also uses KBs

78. Obesity
 It is an epidemic.
– Nearly 30% of the adults are obese in the US.
 It is a risk factor for
– Diabetes
– Hypertension
– Cardiovascular diseases
 Cause is simple:
– More food taken than needed
 Two important signal molecules:
– Insulin
– Leptin

90. Diabetes
 Incidence: 5% of the population
 Most common metabolic disorder
 Type I
– Insulin-Dependent Diabetes Mellitus – IDDM
– No insulin formed
– The diabetic person is in biochemical starvation mode despite
a high concentration of blood glucose. Because insulin
deficient, and the entry of glucose into adipose and muscle
cells is impaired.
 Type II
– Non-Insulin-Dependent Diabetes Mellitus – NIDDM
– Accounts for more than 90% of the diabetes cases
– Insulin production is normal or higher than normal.

97. Metabolic changes during exercise
 Sprinting and marathon running are powered by
different fuels to maximize power output
– A 100 meter sprinter uses:
• Stored ATP
• CP
• Anaerobic glycolysis of muscle glycogen
– A 1000 meter runner
• Oxidative phosphorylation starts.
– Marathon requires a different selection of fuels
• A nice cooperation between muscle, liver, and adipose tissue
• Total glycogen stores (103 mol of ATP) are insufficient to
provide 150 mol of ATP.
• Fat breakdown is needed.

101. Ethanol alters energy metabolism in the liver
 EtOH causes many health problems
 Liver damage takes place in 3 stages
– Fatty liver
– Alcoholic hepatitis
– Cirrhosis (fibrous structure and scar tissue around
dead cells)