Chapter 28

Biochemistry 2/e - Garrett & Grisham
Copyright © 1999 by Harcourt Brace & Company
Chapter 28
Metabolic Integration and
Unidirectionality of Pathways
to accompany
Biochemistry, 2/e
by
Reginald Garrett and Charles Grisham
All rights reserved. Requests for permission to make copies of any part of the work
should be mailed to: Permissions Department, Harcourt Brace & Company, 6277
Sea Harbor Drive, Orlando, Florida 32887-6777

Outline
• 28.1 A Systems Analysis of Metabolism
• 28.2 Metabolic Stoichiometry
• 28.3 Unidirectionality
• 28.4 Metabolism in a Multicellular
Organism

Systems Analysis of Metabolism
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

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

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!

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

The ATP Equivalent
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

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!

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

Solvent Capacity of the Cell
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

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!

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!

‘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

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 β-
hydroxybutyrate (from fatty acids),
converting it to acetyl-CoA in TCA
• This allows brain to use fat as fuel!

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

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

Chapter 28

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