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Chemical Logic of Metabolism

Chapter 12

- Catabolism: complex substances are degraded into simpler molecules, accomplied by net release of chemical energy.
- Anabolism: synthesis of complex organic molecules, requires net input of chemical energy.

Metabolism
Catabolism

12.1

Anabolism

complex

ADP + Pi

complex

simple

ATP

simple

Catabolic and anabolic pathways


between a given precursor and product
not reverse of each other:

committed step - essentially


irreversible makes entire
pathway unidirectional

12.1

pathway taken for catabolism


energetically impossible for
anabolism

Advantage = independently regulated pathways:


1. often take place in different compartments of cell
2. Repression/induction of enzyme synthesis
3. modulation of enzyme activity - often of enzyme
catalyzing committed step:
feedback inhibition by product
allosteric regulation
covalent modification

Bioenergetics and ATP


1. Living systems obtain most of the energy
needed to drive biosynthetic reactions from
the oxidation of organic substrates.
2. G depends only on the difference between
free energy of the products and free energy of
reactants. It is independent of the pathway
taken G is the same whether occurs in 1
step or many.

- ATP serves as immediate donor of free energy, continuously formed and consumed.

ATP as a Free Energy Currency

ATP + H2O ! ADP + Pi = -30.5 kJ/mol

Go for

Calculate Keq:

G = RT lnK'eq
o

(eqn 3.27)

-30,500 J/mol = -(8.315 J/molK)(298K)lnKeq


lnKeq = 12.3
Keq = 2.22 x

105

[ADP][Pi ]
[ATP]

Standard free energy changes of chemical rxns are


additive in any sequence of consecutive rxns =
coupled:
A

G1

G2

G3

sum of rxns = A ! D
GS = G1 + G2 + G3

3 types of Metabolic stoichiometry:


A. Reaction stoichiometry: simple chemical stoichiometry
C6H12O6 + 6O2 ! 6CO2 + 6H2O

G= -2870 kJ/mol

glucose combustion

B. Obligate coupling stoichiometry: e.g. oxidation-reduction


processes - biological oxidation of glucose removes 12 epairs, creating obligate requirement for 12 e- pair acceptors
(NAD, FAD) to transfer e- to oxygen.
C6H12O6 + 10NAD+ + 2FAD + 6H2O ! 6CO2 + 10NADH + 10H+ + 2FADH2
10NADH + 10H+ + 2FADH2 + 6O2 ! 10NAD+ + 2FAD + 12H2O
C6H12O6 + 6O2 ! 6CO2 + 6H2O

3 types of Metabolic stoichiometry:


C. Evolved coupling stoichiometry: not fixed by chemical
necessity, but rather a consequence of evolutionary design or
selection.
C6H12O6 + 6O2 + 38 ADP + 38 Pi ! 6CO2 + 38 ATP + 44H2O

Fundamental biological purpose of ATP as an energycoupling reagent is to drive thermodynamically


unfavorable reactions.
coupling coefficient = # moles ATP produced or consumed per
mole substrate converted.
glucose + 38 ADP --> 38 ATP + CO2

+38

Coupling ATP hydrolysis to a process changes equilibrium


ratio of [reactants]/[products] by a factor of 108!

The energetics of ATP is crucial to solvent capacity of


the cell: capacity to keep all essential metabolites
and macromolecules at low concentrations. This is
important because:
1. for so many solutes to exist in same solution,
individual concentrations must be low
2. decreases probability of unwanted side reactions:
Non-enzymatic reaction: A + B ! C

(1st order wrt both [A] and [B])

Scenario 1: [A] = [B] = 1 M


Scenario 2: [A] = [B] = 10-5 M

v = k[A][B]

The quantity of C produced in 1 sec under Scenario 1 would take ~317 years
to produce under Scenario 2

How does ATP help avoid high metabolite


concentrations? Go back to previous example:

Substrate cycles (opposing pathways):


fructose-6-P + ATP ! fructose-1,6-bisP + ADP

Go

Keq

-14.2

308

-16.3

719

PFK

fructose-1,6-bisP + H2O ! fructose-6-P + Pi


FBPase

Net: ATP + H2O ! ADP + Pi


For FBPase rxn, at physiological [Pi] = 1 mM, equilibrium ratio
[F 6 P]
719,000
[FBP]

[FBP]
0.0000014
[F 6 P]

i.e. under virtually any cellular condition, FBPase rxn is thermodynamically


favorable in direction of F-6-P

For PFK rxn, at physiological conditions of [ATP] = [ADP],


equilibrium ratio
[FBP]
[F 6 P]

308

i.e. rxn is favorable in direction of


FBP until [FBP] > 310 X [F6P]

Why is it so important that both pathways be thermodynamically


favorable under all conditions? Regulation can be imposed only
on reactions displaced far from equilibrium:
Lake
Travis

vs.

p. 495

Open floodgates, what happens?

Lake
Austin

Although opposing pathways may share a # of steps in common


(e.g. glycolysis vs. gluconeogenesis), the overall pathways are
unidirectional due to a few unique reactions (e.g. PFK vs. FBPase).
The evolved coupling ATP stoichiometry that produces unidirectional
pathways is the most important metabolic role of ATP.
The second most important role of ATP is its role as allosteric
effector in the kinetic regulation of these unidirectional pathways.

p. 495

Gibbs free energy as a


function of displacement
from equilibrium

Oxidation of glucose:

Q
G = RT ln (eqn 3.33)
K
Q
=e
K

RT

=e

1300 10 3 J/mol
8.315 J/moliK ( 298 K )
)
(

10 228

[A] high [B] low, Q/K<1, rxn goes to right


[A] low, [B] high, Q/K>1, rnx goes to left

12.10

Most regulatory enzymes of energy metabolism are allosterically


modulated by adenine nucleotides (ATP, ADP, AMP).

adenylate kinase

ATP + AMP ! 2 ADP

[ATP]
[ADP] + [AMP]

= energy charge

Role of AMP and pyrophosphate:


in some rxns, 2 terminal phosphate groups enzymatically
removed as pyrophosphate (PPi), leaving AMP:

ATP + H2O " AMP + PPi G' = -45.6 kJ/mol


PPi + H2O " 2Pi

G' = -19.2 kJ/mol

Standard free energy change vs. reversibility in cell:

[Products]
G = G + RT ln
[Reactants]
o

Q = mass-action ratio

Glycolysis

12.3

Oxidative
metabolism

12.4

Carbohydrate
anabolism

12.5

Photosynthesis

12.6

NAD+, NADP+ in catabolism and


biosynthesis

12.9