Transcript CHAPTER 6

Chapter 27
Metabolic Integration and
Organ Specialization
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. Is there a good index of cellular energy status?
4. How is overall energy balance regulated in
cells?
5. How is metabolism integrated in a multicellular
organism?
6. What regulates our eating behavior?
7. Can you really live longer by eating less?
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
• Only a few intermediates interconnect the major
metabolic systems
– Sugar-phosphates (triose-P, tetraose-P, pentose-P, and
hexose-P)
 a-keto acids (pyruvate, oxaloacetate, and aketoglutarate)
– 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
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
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
3. Evolved coupling stoichiometry
•
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
• 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 involvement of ATP alters the free energy change
for a reaction
– the role of ATP is to change the equilibrium ratio of
[reactants] to [products] for a reaction
• The cell maintains a very high [ATP]/([ADP][Pi])
ratio
• The cell maintains a very high [ATP]/([ADP][Pi])
ratio
– ATP hydrolysis can serve as the driving force for
virtually all biochemical events
– Living cells break down energy-yielding nutrient
molecules to generate ATP
ATP has two metabolic roles
1. ATP is the energy currency of the cells
–
–
To establish large equilibrium constant for
metabolic conversions
To render metabolic sequence
thermodynamically favorable
2. An important allosteric effector in the
kinetic regulation of metabolism
•
•
PFK in glycolysis
FBPase in gluconeogenesis
27.3 – Is there a good index of
cellular energy status??
• Energy transduction and energy storage in the
adenylate system – ATP, ADP, and AMP – lie at
the very heart of metabolism
– The regulation of metabolism by adenylates in turn
requires close control of the relative concentrations
of ATP, ADP, and AMP
– ATP, ADP, and AMP are all important effectors in
exerting kinetic control on regulated enzymes
• Adenylate kinase interconverts ATP, ADP,
and AMP
ATP + AMP  2 ADP
• Adenylate kinase provides a direct
connection among all three members of the
adenylate pool
• Adenylate pool: [ATP] + [ADP] + [AMP]
• Adenylates provide phosphoryl groups to
drive thermodynamically unfavorable
reactions
Energy Charge Relates the ATP Levels to the
Total Adenine Nucleotide Pool
• Energy charge is an index of how fully
charged adenylates are with phosphoric
anhydrides
[ATP] + ½ [ADP]
Energy charge =
[ATP] + [ADP] + [AMP]
• If [ATP] is high, E.C.1.0
• If [ATP] is low, E.C. 0
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 DG°'
for the reaction is -473 J/mol; Keq = 1.2.)
Key enzymes are regulated by Energy charge
• Regulatory enzymes typically respond in
reciprocal fashing to adenine nucleotides
– For example, phosphofructokinase is stimulated
by AMP and inhibited by ATP
• 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
0.85 - 0.88
Figure 27.3 Responses of regulatory enzymes to variation in
energy charge.
27.4 – How is Overall Energy Balance
Regulated in Cells?
• AMP-activated protein kinase (AMPK) is the
cellular energy sensor
– Metabolic inputs to this sensor determine whether its
output (protein kinase activity) takes place
– When ATP is high, AMPK is inactive
– When ATP is low, AMPK is allosterically activated
and phosphorylates many targets controlling cellular
energy production and consumption
– The competition between ATP and AMP for binding
to the AMPK allosteric sites determines the activity
of AMPK
• AMPK is an abg heterotrimer; the a-subunit is the
catalytic subunit and the g-subunit is regulatory
• The b-subunit has an ag-binding domain that brings
a and g together
Figure 27.4 Domain
structure of the AMPactivated protein
kinase (AMPK)
subunits.
• AMPK targets key enzymes in energy
production and consumption
– Activation of AMPK leads to phosphorylation of
many key enzymes in energy metabolism
– Include phosphorylation of PFK-2 (in liver);
glycogen synthase; ACC; HMG-CoA reductase
– Phosphorylation of transcription factors diminishes
expression of gene encoding biosynthetic enzymes
• AMPK controls whole-body energy
homeostasis
Figure 27.6 AMPK regulation of
energy production and
consumption in mammals.
27.5 – How Is Metabolism Integrated
in a Multicellular Organism?
• Organ systems in complex multicellular organisms
have arisen to carry out specific physiological
functions
• Such specialization depends on coordination of
metabolic responsibilities among organs so that the
organism as a whole can thrive
• Organs differ in the metabolic fuels they prefer as
substrates for energy production (see Figure 27.7)
Figure 27.7 Metabolic
relationships among the major
human organs.
27.5 – How Is Metabolism Integrated
in a Multicellular Organism?
• The major fuel depots in animals are glycogen in live
and muscle; triacylglycerols in adipose tissue; and
protein, mostly in skeletal muscle
• The usual order of preference for use of these is
glycogen > triacylglycerol > protein
• The tissues of the body work together to maintain
energy homeostasis
Brain
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)
In fasting conditions, brain can use bhydroxybutyrate (from fatty acids in liver),
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 27.8
Ketone bodies
such as βhydroxybutyrate
provide the brain
with a source of
acetyl-CoA when
glucose is
unavailable.
Muscle
• Skeletal muscles is responsible for about 30%
of the O2 consumed by the human body at rest
• Muscle contraction occurs when a motor never
impulse causes Ca+2 release from
endomembrane compartments
• Muscle can utilize a variety of fuels --glucose,
fatty acids, and ketone bodies
• Rest muscle contains about 2% glycogen and
0.08% phoshpocreatine
Creatine Kinase in Muscle
• About 4 seconds of exertion, phosphocreatine
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, and the flux of glucose-6-P through
glycolysis can increase 2000-fold almost
instantaneously
• Glycolysis rapidly lowers pH (lactate
accumulation), causing muscle fatigue
Creatine Kinase and Phosphocreatine
Provide an Energy Reserve in Muscle
Figure 27.9 Phosphocreatine
serves as a reservoir of ATPsynthesizing potential.
Muscle Protein Degradation
• During fasting or excessive 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 27.10 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
Brown fat
• A specialized type of adipose tissue, is
found 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
Liver
• The major metabolic processing center in
vertebrates, except for triacylglycerol
• Most of the incoming nutrients that pass
through the intestines are routed via the portal
vein to the liver for processing and distribution
• Liver activity centers around glucose-6phosphate
• Glucose-6-phosphate
– From dietary carbohydrate, degradation of
glycogen, or muscle lactate
– Converted to glycogen
– released as blood glucose,
– used to generate NADPH and pentoses via the
pentose phosphate pathway,
– catabolized to acetyl-CoA for fatty acid synthesis
or for energy production in oxidative
phosphorylation
• Fatty acid turnover
• Cholesterol synthesis
• Detoxification organ
Figure 27.11
Metabolic conversions
of glucose-6-phosphate
in the liver.
27.6 What Regulates Our Eating
Behavior?
• Approximately two-thirds of American are
overweight
• One-third of Americans are clinically obese
• Obesity is the most important cause of type 2
diabetes
• Research into the regulatory controls on feeding
behavior has become a medical urgency
• The hormones that control eating behavior come
from many different tissues
Are you hungry
•
The hormones control eating behavior
–
–
•
Produced in the stomach, liver,….
Move to brain and act on neurons within the
arcuate nucleus region of the hypothalamus
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
Figure 27.12 The regulatory
pathways that control eating.
•
AgRP (agouti-related peptide)
–
•
Melanocortin
–
–
•
Block the activity of melanocortin-producing
neurons
Inhibit the neurons initiating eating behavior
Including a- and b-MSH (melanocyte-stimulating
hormone)
Ghrelin and cholecytokinin are short-term
regulators of eating behavior
–
–
Ghrelin is an appetite-stimulating peptide
hormone produced in the stomach
Cholecytokinin signal satiety and tends to curtail
further eating
•
Insulin and leptin are long-term regulators of
eating behavior
–
–
Insulin is produced in the b-cells of the pancreas
when blood glucose level raiseinsulin
Insulin stimulates fat cells to make leptin
•
•
–
Leptin is an anorexic (appetite-suppressing) agent
NPY is a orexic (appetite-stimulating) hormone
PYY3-36 inhibits eating by acting on the
NPY/AgRP-producing neurons
•
AMPK mediates many of the hypothalamic
responses to these hormones
–
–
–
The actions of leptin, gherlin, and NPY converge
at AMPK
Leptin inhibits AMPK
Gherlin and NPY activate hypothalamic AMPK
•
•
•
•
The effects of AMPK may be mediated through
changes in malonyl-CoA levels
AMPK phosphorylates ( inhibits) acetyl-CoA
carboxylase
malonyl-CoA levels decreased
Low [malonyl-CoA] is associated with increased food
intake
27.7 Can You Really Live Longer by
Eating Less?
Caloric restriction leads to longevity
• For most organisms, caloric restriction results in
–
–
–
–
–
lower blood glucose levels
declines in glycogen and fat stores
enhanced responsiveness to insulin
lower body temperature
diminished reproductive capacity
• Caloric restriction also diminishes the likelihood
for development of many age-related diseases,
including cancer, diabetes, and atherosclerosis
Mutations in the SIR2 Gene Decrease Life
Span
• Deletion of a gene termed SIR2 (silent information
regulator 2) abolishes the ability of caloric restriction to
lengthen life in yeast and roundworms
– This implicates the SIR2 gene product in longevity
• The human gene analogous to SIR2 is SIRT1, for sirtuin 1
• Sirtuins are NAD+-dependent protein deacetylases
– The tissue NAD+/NADH ratio controls sirtuin protein
deacetylase activity
– Nicotinamide and NADH are inhibitors of the deacetylase
reaction
– Oxidative metabolism, which drives conversion of NADH to
NAD+, enhances sirtuin activity
Figure 27.13 The NAD+-dependent protein deacetylase reaction of sirtuins.
SIRT1 is a Key Regulator in Caloric Restriction
• SIRT1 connects nutrient availability to the expression
of metabolic genes
– A striking feature of CR is the loss of fat stores and reduction
of WAT (white adipose tissue)
– SIRT1 participates in the transcriptional regulation of
adipogenesis through interaction with PPARg (peroxisome
proliferator-activator receptor- g)
– PPARg is a nuclear hormone receptor that activates
transcription of genes involved in adipogenesis and fat
storage
• SIRT1 binding to PPARg represses transcription of
these genes, leading to loss of fat stores.
• Because adipose tissue functions as an endocrine organ,
this loss of fat has significant hormonal consequences
SIRT1 is a Key Regulator in Caloric Restriction
• SIRT1 connects nutrient availability to the expression of
metabolic genes
• SIRT1 participates in the transcriptional regulation of
adipogenesis through interaction with PPARg (peroxisome
proliferator-activator receptor- g)
• PPAR g is a nuclear hormone receptor that activates
transcription of genes involved in adipogenesis and fat
storage
• SIRT1 binding to PPAR g represses transcription of these
genes, leading to loss of fat stores.
• Because adipose tissue functions as an endocrine organ,
this loss of fat has significant hormonal consequences for
energy metabolism
Resveratrol in Red Wine is a Potent Activator
of Sirtuin Activity
French people enjoy longevity despite a high-fat diet.
Resveratrol may be the basis of this “French paradox”.
Figure 27.14 Resveratrol, a phytoalexin, is a
member of the polyphenol class of natural
products. It is a free-radical scavenger, which
may explain its cancer preventive properties.