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Chapter 27
Essential Question
Metabolic Integration and
Organ Specialization
• What principles underlie the integration of
catabolism and energy production with
anabolism and energy consumption?
• How is metabolism integrated in complex
organisms with multiple organ systems?
Biochemistry
by
Reginald Garrett and Charles Grisham
Outline
1. Can Systems Analysis Simplify the
Complexity of Metabolism?
2. What Underlying Principle Relates ATP
Coupling to the Thermodynamics of
Metabolism?
3. Can Cellular Energy Status Be Quantified?
4. How Is Metabolism Integrated in a
Multicellular Organism?
27.1 – Can Systems Analysis Simplify the
Complexity of Metabolism?
•
The metabolism can be portrayed by a
schematic diagram consisting of just three
interconnected functional block:
1. Catabolism
2. Anabolism
3. Macromolecular synthesis and growth
•
Catabolic and anabolic pathways, occurring
simultaneously, must act as a regulated, orderly,
responsive whole
Figure 27.1
Block diagram of
intermediary metabolism.
• Catabolism:
–
–
–
–
Foods are oxidized to CO2 and H2O
The formation of ATP
Reduce NADP+ to NADPH
The intermediates serve as substrates for
anabolism
Glycolysis
The citric acid cycle
Electron transport and oxidative phosphorylation
Pentose phosphate pathway
Fatty acid oxidation
• Anabolism:
– The biosynthetic reactions
– The chemistry of anabolism is more complex
– Metabolic intermediates in catabolism are the
precursor for anabolism
– NADPH supplies reducing power
– ATP is the coupling energy
• Macromolecular synthesis and growth
– Creating macromolecules
– Macromolecules are the agents of biological
function and information
– Growth can be represented as cellular
accumulation of macromolecules
• Just a few intermediates connect major systems
– Sugar-phosphates (triose-P, tetraose-P, pentose-P, and
hexose-P)
− α-keto acids (pyruvate, oxaloacetate, and αketoglutarate)
– CoA derivs (acetyl-CoA and suucinyl-CoA)
– PEP
• ATP & NADPH couple catabolism & anabolism
• Phototrophs also have photosynthesis and CO2
fixation systems
27.2 – What Underlying Principle Relates
ATP Coupling to the Thermodynamics of
Metabolism?
Three types of stoichiometry in biological systems
1. Reaction stoichiometry - the number of each
kind of atom in a reaction
2. Obligate coupling stoichiometry - the required
coupling of electron carriers
3. Evolved coupling stoichiometry - the number
of ATP molecules that pathways have evolved
to consume or produce - a number that is a
compromise, as we shall see
1. Reaction stoichiometry
The number of each kind of atom in any
chemical reaction remains the same, and
thus equal numbers must be present on
both sides of the equation
C6H12O6 + 6 O2 → 6 CO2 + 6 H2O
2. Obligate coupling stoichiometry
3. Evolved coupling stoichiometry
Cellular respiration is an oxidation-reduction
process, and the oxidation of glucose is
coupled to the reduction of NAD+ and
FAD
(a) C6H12O6 + 10 NAD+ + 2 FAD + 6 H2O →
6 CO2 + 10 NADH + 10 H+ + 2 FADH2
(b) 10 NADH + 10 H+ + 2 FADH2 + 6 O2 →
12 H2O + 10 NAD+ + 2 FAD
•
The coupled formation of ATP by oxidative
phosphorylation
C6H12O6 + 6 O2 + 38 ADP + 38 Pi →
6 CO2 + 38 ATP + 44 H2O
•
•
Prokaryotes: 38 ATP
Eukaryotes: 32 or 30 ATP
ATP coupling stoichiometry determines
the keq for metabolic sequence
ATP has two metabolic roles
1. ATP is the energy currency of the cells
• The energy release accompanying ATP
hydrolysis is transmitted to the unfavorable
reaction so that the overall free energy for the
coupled process is negative (favorable)
• The cell maintains a very high
[ATP]/([ADP][Pi]) ratio so that ATP hydrolysis
can serve as the driving force for virtually all
biochemical events
27.3 – Can Cellular Energy Status
Be Quantified?
‘Energy Charge’
• Adenylates provide phosphoryl groups to
drive thermodynamically unfavorable
reactions
• Adenylate kinase interconverts ATP, ADP,
and AMP
ATP + AMP ↔ 2 ADP
• Adenylate pool
–
–
To establish large equilibrium constant
To render metabolic sequence
thermodynamically favorable
2. An important allosteric effector in the
kinetic regulation of metabolism
• Energy charge is an index of how fully
charged adenylates are with phosphoric
anhydrides
Energy charge =
[ATP] + ½ [ADP]
[ATP] + [ADP] + [AMP]
• If [ATP] is high, E.C.→1.0
• If [ATP] is low, E.C.→ 0
• Key enzymes are regulated by Energy
charge
• Regulatory enzymes in energy-producing
catabolic pathways show greater activity at
low energy charge
– PFK and pyruvate kinase
• Regulatory enzymes of anabolic pathways
are not very active at low energy charge
– Acetyl-CoA carboxylase
Figure 27.2
Relative concentrations of AMP, ADP, and ATP as a function of energy charge. (This graph
was constructed assuming that the adenylate kinase reaction is at equilibrium and that ΔG°'
for the reaction is -473 J/mol; Keq = 1.2.)
0.85 - 0.88
Figure 27.3
Responses of regulatory enzymes to variation in energy charge. Enzymes
in catabolic pathways have as their ultimate metabolic purpose the
regeneration of ATP from ADP. Such enzymes show an R pattern of
response to energy charge. Enzymes in biosynthetic pathways utilize ATP
to drive anabolic reactions; these enzymes follow the U curve in response
to energy charge.
Figure 27.4
The oscillation of energy charge (E.C.) about a steady-state value as a consequence of the
offsetting influences of R and U processes on the production and consumption of ATP. As
E.C. increases, the rates of R reactions decline, but U reactions go faster. ATP is consumed,
and E.C. drops. Below the point of intersection, R processes are more active and U
processes are slower, so E.C. recovers. Energycharge oscillates about a steady-state value
determined by the intersection point of the R and U curves.
27.4 – How Is Metabolism Integrated
in a Multicellular Organism?
Figure 27.5
Metabolic
relationships
among the major
human organs:
brain, muscle,
heart, adipose
tissue, and liver.
Fueling the Brain
•
The major fuel depots:
–
–
–
•
Triacylglycerol
Glycogen
Protein
Brain has two remarkable metabolic features
1. very high respiratory metabolism
20 % of oxygen consumed is used by the brain
2. but no fuel reserves
Uses only glucose as a fuel and is dependent on the blood
for a continuous incoming supply (120g per day)
Brain
• In fasting conditions, brain can use βhydroxybutyrate (from fatty acids),
converting it to acetyl-CoA for the energy
production via TCA cycle
• Generate ATP to maintain the membrane
potentials essential for transmission of nerve
impulses
Figure 27.6
The structure of
β-hydroxybutyrate
and its conversion
to acetyl-CoA for
combustion in the
citric acid cycle.
Muscle
• Skeletal muscles is responsible for about
30% of the O2 consumed by the human
body at rest
• Muscle can utilize a variety of fuels -glucose, fatty acids, and ketone bodies
• Muscle contraction occurs when a motor
never impulse causes Ca+2 release from
endomembrane compartments
Creatine Kinase in Muscle
• About 4 second exertion, phosphocreatine
and glycogen provide enough ATP for
contraction
• During strenuous exertion, once
phosphocreatine is depleted, muscle relies
solely on its glycogen reserves
• Glycolysis is capable of explosive bursts of
activity
• Glycolysis rapidly lowers pH (lactate
accumulation), causing muscle fatigue
Figure 27.7
Phosphocreatine serves as a reservoir of ATP-synthesizing potential. When
ADP accumulates as a consequence of ATP hydrolysis, creatine kinase
catalyzes the formation of ATP at the expense of phosphocreatine. During
periods of rest, when ATP levels are restored by oxidative phosphorylation,
creatine kinase acts in reverse to restore the phosphocreatine supply.
Muscle Protein Degradation
• During fasting or high activity, amino acids
are degraded to pyruvate, which can be
transaminated to alanine
• Alanine circulates to liver, where it is
converted back to pyruvate – a substrate for
gluconeogenesis
• This is a fuel of last resort for the fasting or
exhausted organism
Figure 27.8
The transamination of pyruvate to alanine by glutamate:alanine aminotransferase.
Heart
• The activity of heart muscle is constant and
rhythmic
• The heart functions as a completely aerobic
organ and is very rich in mitochondria
• Prefers fatty acid as fuel
• Continually nourished with oxygen and free
fatty acid, glucose, or ketone bodies as fuel
Adipose tissue
• Amorphous tissue widely distributed about
the body
• Consist of adipocytes
• ~65% of the weight of adipose tissue is
triacylglycerol
• continuous synthesis and breakdown of
triacylglycerols, with breakdown controlled
largely via the activation of hormonesensitive lipase
• Lack glycerol kinase; cannot recycle the
glycerol of TAG
Liver
Brown fat
• In newborn and hibernating animals
• Rich in mitochondria
• Thermogenin, uncoupling protein-1,
permitting the H+ ions to reenter the
mitochondria matrix without generating
ATP
• Is specialized to oxidize fatty acids for heat
production rather than ATP synthesis
Figure 27.9
Metabolic conversions
of glucose-6-phosphate
in the liver.
• The major metabolic processing center in
vertebrates
• Glucose-6-phosphate
– From dietary carbohydrate, degradation of
glycogen, or muscle lactate
– Converted to glycogen, NADPH….
•
•
•
•
Buffering the blood glucose – glucokinase
Fatty acid turnover
Cholesterol synthesis
Detoxification organ
Are you hungry
•
•
•
The hormones control eating behavior
Produced in the stomach, liver….; move
to brain and act on neurons
The hormones are divided into
1. Short-term regulator: determine individual
meal
2. Long-term regulator: act as stabilize the levels
of body fat deposit
•
Two subset neurons
1. NPY/ AgRP producing neurons -- stimulating
2. Melanocortin producing neurons-- inhibiting