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Biochemistry 2/e - Garrett & Grisham
Chapter 28
Metabolic Integration and
Unidirectionality of Pathways
to accompany
Biochemistry, 2/e
by
Reginald Garrett and Charles Grisham
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Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Outline
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28.1 A Systems Analysis of Metabolism
28.2 Metabolic Stoichiometry
28.3 Unidirectionality
28.4 Metabolism in a Multicellular
Organism
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Biochemistry 2/e - Garrett & Grisham
Systems Analysis of Metabolism
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Catabolic and anabolic pathways, occurring
simultaneously, must act as a regulated, orderly,
responsive whole
See Figure 28.1 - catabolism, anabolism and
macromolecular synthesis
Just a few intermediates connect major systems sugar-Ps, alpha-keto acids, CoA derivs, and PEP
ATP & NADPH couple catabolism & anabolism
Phototrophs also have photosynthesis and CO2
fixation systems
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
28.2 Metabolic Stoichiometry
Three types of stoichiometry in biological
systems
• Reaction stoichiometry - the number of each
kind of atom in a reaction
• Obligate coupling stoichiometry - the
required coupling of electron carriers
• 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
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Biochemistry 2/e - Garrett & Grisham
The Significance of 38 ATPs
The "ATP stoichiometry" has a large effect on the
Keq of a reaction
• Consider the Keq for glucose oxidation (page
932)
• If 38 ATP are produced, cellular G is -967
kJ/mol and Keq = 10170, a very large number!
• If G = 0, 58 ATP could be made, but the
reaction would come to equilibrium with only half
as much glucose oxidized as we could have had
• So the number of 38 is a compromise!
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Biochemistry 2/e - Garrett & Grisham
Significance of large Keq
The more ATP obtained, the lower the
equilibrium constant, and the higher the level
of glucose required
• If [glucose] is below this value, it won't be
effectively utilized
• Large Keq means that this threshold level of
glucose will be be very low
• Large Keq also means that the reaction will be
far from equilibrium and can thus be regulated
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Biochemistry 2/e - Garrett & Grisham
The ATP Equivalent
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What is the "coupling coefficient" for ATP
produced or consumed?
Coupling coefficient is the moles of ATP
produced or consumed per mole of substrate
converted (or product formed)
Cellular oxidation of glucose has a coupling
coefficient of 30-38 (depending on cell type)
Hexokinase has a coupling coefficient of -1
Pyruvate kinase (in glycolysis) has a coupling
coefficient of +1
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Biochemistry 2/e - Garrett & Grisham
The ATP Value of NADH vs
NADPH
• The ATP value of NADH is 2.5-3
• The ATP value of NADPH is higher
• NADPH carries electrons from catabolic
pathways to biosynthetic processes
• [NADPH]>[NADP+] so NADPH/NADP+ is
a better e- donating system than
NADH/NAD
• So NADPH is worth 3.5-4 ATP!
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Biochemistry 2/e - Garrett & Grisham
Nature of the ATP Equivalent
A different perspective
 G for ATP hydrolysis says that at equilibrium
the concentrations of ADP and Pi should be
vastly greater than that of ATP
• However, a cell where this is true is dead
• Kinetic controls over catabolic pathways ensure
that the [ATP]/[ADP][Pi] ratio stays very high
• This allows ATP hydrolysis to serve as the
driving force for nearly all biochemical
processes
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Biochemistry 2/e - Garrett & Grisham
Solvent Capacity of the Cell
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The capacity to keep all metabolites solvated
What is the role of ATP in solvent capacity?
Consider phosphorylation of glucose
If done by Pi, the concentration of Pi would have
to be 2700 M
However, using ATP, and if [ATP] and [ADP] are
equal, [G-6-P]/[G] is maintained at 850
ATP, an activated form of phosphate, makes it
possible for cell to carry out reactions while
keeping concentrations of metabolites low
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Substrate Cycles
If ATP c.c. for a reaction in one direction differs from
c.c. in the other, the reactions can form a
substrate cycle
• See Figure 28.2
• The point is not that ATP can be consumed by
cycling
• But rather that the difference in c.c. permits both
reactions (pathways) to be thermodynamically
favorable at all times
• Allosteric effectors can thus choose the direction!
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Unidirectionality of Pathways
A "secret" role of ATP in metabolism
• Both directions of any pair of opposing
pathways must be favorable, so that
allosteric effectors can control the
direction effectively
• The ATP coupling coefficient for any such
sequence has evolved so that the overall
equilibrium for the conversion is highly
favorable
• See Figure 28.4 for an illustration!
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
‘Energy Charge’
• Adenylates provide phosphoryl groups
to drive thermodynamically unfavorable
reactions
• Energy charge is an index of how fully
charged adenylates are with phosphoric
anhydrides
• If [ATP] is high, E.C.1.0
• If [ATP] is low, E.C. 0
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Fueling the Brain
• Brain has very high metabolism but has
no fuel reserves
• This means brain needs a constant
supply of glucose
• In fasting conditions, brain can use hydroxybutyrate (from fatty acids),
converting it to acetyl-CoA in TCA
• This allows brain to use fat as fuel!
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Creatine Kinase in Muscle
• Muscles must be prepared for rapid
provision of energy
• Creatine kinase and phosphocreatine
act as a buffer system, providing
additional ATP for contraction
• Glycogen provides additional energy,
releasing glucose for glycolysis
• Glycolysis rapidly lowers pH, causing
muscle fatigue
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Muscle Protein Degradation
• During fasting or high activity, amino
acids degrade to pyruvate, which can
be transaminated to alanine
• Alanine circulates to liver, where it is
converted back to pyruvate - food for
gluconeogenesis
• This is a fuel of last resort for the fasting
or exhausted organism
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Copyright © 1999 by Harcourt Brace & Company
Biochemistry 2/e - Garrett & Grisham
Copyright © 1999 by Harcourt Brace & Company