Bioenergetics and Biological Oxidation

Daniel D. Menorca, MD

July 14, 2015

BIOENERGETICS
INTRODUCTION
Bioenergetics- the biology of energy transformations and
energy exchanges within and between living things and their
environment.
I. LAWS OF THERMODYNAMICS
Thermodynamics- study of thermal processes which
transform heat energy into useful mechanical work and vice
versa
(1) Zeroth Law of Thermodynamics: The Thermal
Equilibrium
The law states that:
If two systems are each in thermal equilibrium with a third, they
are also in thermal equilibrium with each other.
(2) First Law of Thermodynamics: Law of Conservation of
Energy
The law states that:
Energy is neither created nor destroyed, although it can be
changed from one form to another
The total ENERGY of a system, including its surroundings,
REMAINS CONSTANT.
a) G = free energy; G = change in free energy
Gibbs Free energy (G)- energy associated with a chemical
reaction that can be used to do work.
b) Neither lost or gained
c) May be transferred or transformed into another form of
energy
1) Heat enegy/radiant energy chemical energy
2) Chemical energyheat energy/radiant energy

1ST SHIFTING

As a system approaches absolute zero, all processes cease

and the entropy of the system approaches a minimum value.

G=H-TS
where: H= change in heat (enthalpy)
T=absolute temperature
Enthalpy- the sum of the internal energy of a body or system
and the product of its volume multiplied by the pressure
In biochemical reactions, since H is approximately equal to
the total change in internal energy of the reaction (E), the
above relationship may be expressed in the following way:
G=E-TS
II. EXERGONIC/ENDERGONIC/IRREVERSIBLE/
EQUILIBRIUM
1. If G is negative, the reaction proceeds spontaneously with
loss of free energy = EXERGONIC REACTION
2. If the negative G is of great magnitude = IRREVERSIBLE
3. If G is positive, the reaction cannot proceed
spontaneously, unless G is supplied = ENDERGONIC
REACTION
4. If the positivity of G is very great = little or no reaction
5. If G is zero = the reaction is at EQULIBRIUM
III. EXOTHERMIC/ENDOTHERMIC/ ISOTHERMIC
1. Exothermic reaction = one form of exergonic reaction
2. Endothermic reaction = one form of endergonic reaction
3. Isothermic reaction = typical reactions in biological systems
that may be exergonic or endergonic, reversible or irreversible,
equilibrium or non-equilibrium
IV. STANDARD FREE ENERGY CHANGE (G)
Free energy change when the reactants are present in
concentrations of 1.0 mol/L occurring at pH 7.0

(3)Second Law of Thermodynamics: Entropy

Entropy- extent of disorder or randomness of a system
The law states that:
Whenever a spontaneous or irreversible process takes place, it
is accompanied by an increase in the total entropy of the
universe.
The total ENTROPY of a system MUST INCREASE if a
process is to occur SPONTANEOUSLY.
a. S (entropy)
b. S= the change in entropy of a system
(4) Third Law of Thermodynamics: Law of Enthalpy
-Combination of 1st & 2nd law
The law states that:

Santos,J., Sarte, Sijas

G=-RT ln Keq
where: R = gas constant

RESPIRATORY CONTROL IN METABOLISM

A. Catabolism = breakdown or oxidation of fuel molecules. An
exergonic reaction.
B. Anabolism = synthetic reactions that build up substances.
An endergonic reaction.
C. Metabolism = combined catabolic and anabolic processes.
D. Coupling (exergonic and endergonic reactions)

LOW AND HIGH-ENERGY PHOSPHATES ~(P), OTHER

HIGH ENERGY COMPOUNDS IN INTERMEDIARY
METABOLISM
A. Low-energy Phosphates
Ester phosphates
-Intermediates of glycolysis
-Their G is smaller than ATP
B. High-energy Phosphates
Anhydrides (e.g. 1,3 BPG); Enol phosphates (e.g. PEP);
Phosphoguanidines (e.g., Creatine-PO4)
-Their G is higher than ATP

Fig 1. Coupling of an exergonic to an endergonic reaction.

C. Others
1. Thiol Esters
2. Acyl carrier protein
3. Amino acid esters
4. S-adenosyl methionine
5. UDP-glucose
6. Phosphoribosylpyrophosphate

So that there will be no loss of energy as heat, we can have:

A+CIB+D
Note: This type of system has a built-in mechanism for
biologic control at the rate of oxidative process since the
common obligatory intermediate (I) allows the rate of utilization
of the product of the synthetic path (D) to determine by mass
action the rate at which A is oxidized.

E. Compound with High Energy Potential, [~(E)]

Therefore, we can say that ATP has a G0 that is in the

intermediate position

HIGH-ENERGY PHOSPHATES ~(P) ACT AS THE ENERGY

CURRENCY OF THE CELL
Table 1. The standard free energy of hydrolysis of some
organophosphates (Low and High Energy) of Biochemical
importance

Phosphoenolpyruvate

kJ/mol
61.9

G'
kcal/mol
14.8

Carbamoyl phosphate

51.4

12.3

1,3-Bisphosphoglycerate

49.3

11.8

Creatine phosphate

43.1

10.3

ATP AMP + PPi

32.2

7.7

ATP ADP + Pi

30.5

7.3

Glucose 1-phosphate

20.9

5.0

PPi

19.2

4.6

Fructose 6-phosphate

-15.9

-3.8

Glucose 6-phosphate

-13.8

-3.3

Glycerol 3-phosphate

-9.2

-2.2

COMPOUND

Fig 2. Transfer of free energy from an exergonic to an endergonic

reaction via a high-energy intermediate compound (~E)

Note: The biological advantage of the compound with high

energy potential ~(E), unlike I, is that there is no need for ~(E)
to be structurally related to A, B, C, D. It therefore can
transduce energy from a wide range of exergonic and
endergonic reactions.
-energy
potential is adenosine triphosphate (ATP). Both the obligatory
intermediate I and the high-energy compound ~(E) supply a
basis for the concept of RESPIRATORY CONTROL.

Santos,J., Sarte, Sijas

Note: ATP is able to act as a donor of high-energy phosphate

to form those compounds below it in the table above. Likewise,
ADP can accept high-energy phosphate to form ATP from
those compounds above ATP.
In effect, an ATP/ADP CYCLE connect those processes that
generate ~(P) to those processes that utilize ~(P). This
phenomenon is called ENERGY CONSERVATION OR
ENERGY CAPTURE (following the 1st law of Thermodynamics)

OTHER NUCLEOSIDE TRIPHOSPHATES PARTICIPATE IN

THE TRANSFER OF HIGH-ENERGY PHOSPHATES

All of these triphosphates take part in phosphorylation in the

cell

BIOLOGICAL OXIDATION
TERMINOLOGIES

Fig 3. Role of ATP/ADP cycle in transfer of high-energy phosphate

Note: This occurs at a very rapid rate, since the total ATP/ADP
pool is extremely small and sufficient to maintain an active
tissue for only a few seconds.
Sources of ~(P) taking part in energy conservation or
capture:
1. OXIDATIVE PHOSPHORYLATION Greatest quantitative
source of ~(P) in aerobic organisms
2. GLYCOLYSIS a net formation of two ~(P) from the
formation of lactate from one molecule of glucose
3. CITRIC ACID CYCLE one ~(P) is generated directly from
CAC (at the succinate thiokinase step)

ATP ALLOWS THE COUPLING OF THERMODYNAMICALLY

UNFAVORABLE REACTIONS TO FAVORABLE
REACTIONS
A. Thermodynamically unfavorable (endergonic) reaction:

Glucose + Pi Glucose 6-PO4 + H2O

A Biological Oxidation
1. Oxidation-reduction reaction occurring in biochemical
systems.
2. Whereas oxidation is lost of electrons, reduction is gain of
electrons.
3. Therefore, oxidation of an electron donor is always coupled
with reduction of an electron acceptor.
4. This principle applies equally to biochemical systems.
B. Redox Reaction
1. Shortened term for oxidation-reduction reaction.
2. In the laboratory, reaction of hydrogen with oxygen will
produce this reaction:

Where: H2 is oxidized (electron donor)

O2 is reduced (electron acceptor)
3. In biochemical systems, the reaction of H2 with O2 is
controlled by enzymes and instead of dissipating heat, the
cells stores energy [~(P)] in the form of ATP.
C. Respiration (in biochemical systems)
1. The process by which cells derive energy in the form of ATP
from the controlled reaction of hydrogen with oxygen to
form water. Also known as cellular respiration

(G = +13.8 kJ/mol)
B. Thermodynamically favorable (exergonic) reaction:

ATP ADP + Pi
(G = -30.5 kJ/mol)
C. Coupling of the two reactions through ATP

The enzymes* involved in this respiratory process are the so

called Enzymes of Biologic Oxidation.

(G = -16.7 kJ/mol)

Santos,J., Sarte, Sijas

D. Redox Potential (E0)

1. The tendency of reactions in redox reaction to donate or
accept electrons.
2. Proportionate to G (1st Law of Thermodynamics)
Where G = standard free energy change
E0 = standard redox potential.
E0 is normally expressed at pH 7.0 where the electrode
potential of hydrogen electrode is 0.42 volts [heat energy (kJ)
is transformed to electrical energy (volts), consistent with the
1st Law of Thermodynamics].

SOME REDOX POTENTIALS OF SPECIAL INTEREST IN

MAMMALIAN OXIDATION SYSTEM
System

E0 Volts

H+/H2

0.42

NAD+/NADH

0.32

Lipoate; ox/red

0.29

Acetoacetate/3-hydroxybutyrate

0.27

Pyruvate/lactate

0.19

Oxaloacetate/malate

0.17

Fumarate/succinate

0.03

Cytochrome b; Fe3+/Fe2+

0.08

Ubiquinone; ox/red

0.1

Cytochrome c1; Fe3+/Fe2+

0.22

Cytochrome a; Fe3+/Fe2+

0.29

Oxygen/water

0.82

The relative position of redox systems in the table allow

prediction of the direction of flow of electrons from one redox
couple to another.

Enzymes of Biologic Oxidation

A. Oxidases
1. Catalyze the removal of hydrogen from a substrate using
oxygen as hydrogen acceptor.
2. They form H2O or H2O2 as reaction product.
3. Some are hemoproteins (e.g., cytochrome oxidase)
4. Some are flavoproteins
a. FMN-linked (e.g. L-amino acid oxidase)
b. FAD-linked (e.g. aldehyde dehydrogenase)

B. Dehydrogenase
1. Cannot use oxygen as hydrogen acceptor. Perform two
functions:
a. Transfer hydrogen from one substrate to another in
a coupled oxidation-reduction reaction.
b. Component of respiratory chain for electron
transport from substrate to oxygen.
2. Many depend on Nicotinamide Coenzymes
a. NAD-linked catalyze redox reaction in the
oxidative pathways of metabolism
i. Glycolysis
ii. CAC

Santos,J., Sarte, Sijas

iii. Respiratory Chain

b. NADP-linked found characteristically in reductive
syntheses
i. Extramitochondrial fatty acid synthesis
ii. Pentose Phosphate Pathway
iii. Steroid synthesis
3. Others depend on Riboflavin
a. Electron transport in the respiratory chain
i. NADH dehydrogenase
ii. Succinate DH, Acyl CoA DH, Glycerol-3PO4 DH
b. Dehydrogenation of reduced lipoate
i. Diphydrolipoyl dehydrogenase
ii. Oxidative decarboxylation of pyruvate and
alpha-ketoglutarate
c. Intermediate carrier of electrons between AcylCoA
DH and the respiratory chain
i. Electron Transferring Flavoprotein (ETF)
4. Cytochromes may also be regarded as dehydrogenases
a. Iron-containing hemoproteins in which the iron
atoms oscillate between Fe3+ and Fe2+ during redox
reaction
b. In the respiratory chain, they are involved as
carriers of electrons from flavoproteins to cytochrome
oxidase
c. Aside from the respiratory chain (Cyt b, c, c, c1 and
Cytochrome oxidase), some are located in the
endoplasmic reticulum (Cyt P450 and Cyt b5), plant
cells, bacteria and yeasts. (note: Cyt oxidase is an
oxidase while Cyt P450 is a monooxygenase)

C. Hydroperoxidases
1. Protect the body against harmful peroxidase
2. Two enzymes fall into this category:
a. Peroxidases
b. Catalase
3. In regard to peroxidase:
a. Found in milk, leukocytes, platelets and other
tissues involved in eicosanoid metabolism

(eicosanoids are signaling molecules made from

metabolism of fatty acids, they serve their
functions in inflammatory and other immune
responses.)
b. Hydrogen peroxidase is reduced at the expense of
several substances that will act as electron acceptors
such as ascorbate, quinones, and cytochrome c.

peroxidase

H2O2 + AH2

2H2O + A

c. In Red Blood Cells, there is the enzyme

glutathione peroxidase that utilizes reduced
glutathione.
Glutathione Peroxidase

H2O2 + 2GSH

2H2O + GS-SG

4. In regard to catalases:
a. It is a hemoprotein containing four heme groups
b. Uses H2O2 as both electron donor and electron
acceptor

Catalase
2H2O2

2H2O + O2
4

c. Found in blood, bone marrow, mucuos membrane,

kidney and liver

4. Reoxidized by substrates in a series of

reaction known as HYDROXYLASE CYCLE

D. Oxygenases
1. Catalyze the direct transfer and incorporation of oxygen into
a substrate molecule
2. Divide into two subgroups:
a. Dioxygenases
b. Monooxygenases
DIOOXYGENASES
a. They incorporate both atoms of molecular oxygen into the
substrate. [A + O2 AO2]
b. Examples:
i. Homogentisate dioxygenase
ii. 3-OH anthranilate dioxygenase
iii. L-Tryptophan dioxygenase
MONOOXYGENASES:
a. They incorporate only one atom of molecular oxygen into the
substrate. [A-H + O2 + ZH2 A-OH + H2O + Z]
b. Examples include:
i. Cytochrome P450
1. Heme-containing monooxygenase
2. Location and function
LOCATION
Endoplasmic reticulum of
hepatocytes
Mitochondria of the adrenal
cortex, testis, ovary and placenta
Renal cells

FUNCTION
Detoxification of substrates
and bile synthesis
Biosynthesis of steroid
hormones from cholesterol
Vit. D metabolism

3. Both NADH and NADPH donate reducing

equivalents for its reduction

Fig 5. Cytochrome P450 hydroxylase cycle.

E. Superoxide Dismutase
- an enzyme responsible for the removal of O2 in all
aerobic organisms (although not in obligate anaerobes)
indicate that the potential toxicity of oxygen is due to its
conversion to superoxide.
A. Transfer of a single electron to O2 generates the potentially
damaging superoxide anion free radical (O2-).
B. The destructive effect of this free radical can be amplified by
a side chain reaction
1. Initiation

ROOH + Metal(n)+
X- + RH
R- + XH

ROO+ Metal(n-1)+ + H+

2. Propagation

R- + O2 ROOROO- + RH ROOH + R, etc.

3. Termination
Fig 4. Electron transport chain in the endoplasmic reticulum.
Cyanide (CN ) inhibits the indicated step.

ROO- + ROOROOR + O2
ROO- + RROOR
R - + RRR
C. In vivo, the principal chain-breaking antioxidants are
superoxide dismutase, which acts in the aqueous phase to trap
superoxide free radicals (O2-) urate and vitamin C, which acts
in the lipid phase to trap ROO radicals.
D. Superoxide can reduce oxidized cytochrome c or be
removed by superoxide dismutase.
O2- + Cyt c(Fe3+)

O2+ Cyt c (Fe2+)

In this reaction, superoxide acts as both oxidant and reductant.

Thus, superoxide dismutase protects aerobic organisms
against the potential deleterious effects of superoxide.

Santos,J., Sarte, Sijas

E. This enzyme occurs in all major aerobic tissues in the

mitochondria and cytosol.
F. Although exposure of animals to an atmosphere of 100%
oxygen causes an adaptive increase in superoxide dismutase,
prolonged exposure to 100% oxygen leads to lung damage
and death.

*Antioxidants, eg, -tocopherol (vitamin E), act as

scavengers of free radicals and reduce the toxicity of
oxygen

Santos,J., Sarte, Sijas