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Energy transformation in living cell
10-19-2015
Life needs energy!
食物分子中生命不能利用的化學能,經由細胞的代謝反應
轉變成生命可以利用的化學能
Two kinds of energy source in living
system:
1, ATP: hydrolysis of “high energy bond” to
generate energy
2, redox reaction: electron transfer
- electron donor (H2, H2S, NADH etc.)
- electron acceptor (Oxygen, S)
- energy released during the electron transfer.
Two kinds of energy source in living
system:
1, ATP: hydrolysis of “high energy bond” to
generate energy
2, redox reaction: electron transfer
- electron donor (H2, H2S, NADH etc.)
- electron acceptor (Oxygen, S)
- energy released during the electron transfer.
A very ancient invention (3.6 BY?): to save and
to convert reducing power into ATP!
Do you still remember the natural proton gradient in the
lost city may be the energy source of the origin of life?
Too large to be used!
• Dissecting glucose degradation into many steps.
• In some key steps, a relative constant amount of
energy will be released to generate one ATP or one
NADH.
• Energy stored in the structure of glucose is
transformed into common currency of life.
Activation of glucose by ATP?
The first step of glucose degradation (glycolysis)
Complete oxidation of one
mole of glucose will generate
686 kcal of heat or energy.
In the absence of oxygen,
glucose can only be degraded
into pyruvate (glycolysis).
One mole of glucose only
produce two mole of ATP
(7.3+7.3=14.6 kcal).
The efficiency of energy
preservation is only 2%.
Life needs more efficient energy production!
How energy (electric
potential) stored in NADH
can be utilized?
How does the product of
glycolysis (pyruvic acid) be
completely degraded?
Two new features for energy transformation are
invented: Krebs cycle and electron transport chain!
The degradation of
pyruvate through
Krebs cycle produces
large quantities of
high energy electron
(NADH and FADH2).
How the high energy electron is
utilized in the living cells?
粒腺體：細胞內的火力發電廠！
High energy electrons are transfer to oxygen in
mitochondria to produce ATP .
Electron donor: NADH/Electron acceptor: O2.
How?
• High energy chemical intermediate (X) is formed
during electron transfer from NADH to oxygen, then
compound X transfer its energy to synthesis ATP.
• You need to identify chemical nature of this putative
intermediate.
• This intermediate has never been found!
• The Chemiosmotic Theory.
The Chemiosmotic Theory (Nature 191, 144-148, 1961)
By Peter Mitchell who won Nobel Prize in Chemistry in 1978
Why life use proton gradient but not
chemical compound as energy source
to synthesize ATP?
Substrate phosphorylation is stoichiometrical:
Always one to one excahange!
The total free energy from the movement of 1
mole of protons cross mitochondria membrane:
50 kJ/mol is required for ATP synthesis in
mitochondria. Then you need translocate 3
protons in order to synthesize one ATP!
Advantage to use proton gradient as
energy storage for ATP synthesis
• 10 protons will translocate per electron pair
passed from NADH to O2.
• 3 protons consumed per ATP synthesized.
• (1 ATP/4 H+)/(10 H+/electron pair) = 2.5
ATP/electron pair.
• No energy will lost or waste!
High energy electron (NADH and FADH2) is converted to
ATP through electron transport chain and proton gradient!
X
When
oxygen is
not enough,
Krebs cycle
and ETC
will not
proceed!
If we want this pathway continue, what do we need?
Why cells want to further convert pyruvate
into lactate when oxygen is low?
X
Krebs
cycle and
ETC
If we want this pathway continue, what do we need?
We need supply of ADP and NAD!
For ADP: no problem, but for NAD….
For NAD+:
In exhausted muscle:
Not enough oxygen!
When the supply of
glucose is OK, even in
the presence of
oxygen, yeast still do
fermentation:
For NAD+:
In exhausted muscle:
Not enough oxygen!
When the supply of
glucose is OK, even in the
presence of oxygen, yeast
still do fermentation: Why?
(Metabolite suppression)
When LUCA left the lost city, they
need an alternative energy source
SUN LIGHT!
1, source of energy：photon from sun light
2, who absorbs the energy: chlorophyll molecule！
3, how? Exciting electron of chlorophyll to higher energy level！
4, who is the electron acceptor？Electron transport chain！
Water is abundant !
Chlorophyll: The most efficient
molecule on earth to absorb light!
Organization of
photosystems in the
thylakoid membrane:
How the energy
transfer is
unidirectional ？
Take two electrons from water and
release one oxygen and two protons
In green plant, two photosynthesis system
(PSII and PSI) are coupled
To generate proton gradient for ATP synthesis
Photosynthesis
1. Light reactions: transform light
(sunlight) energy into ATP and
biosynthetic reducing power, NADPH.
2. Dark reactions (Calvin cycle): use ATP
and NADPH to reduce CO2 to hexose
Net reaction of the Calvin cycle
6 CO2 + 18 ATP +12 NADPH +12 H2O 
C6H12O6 + 18 ADP + 18 Pi + 12 NADP+ + 6 H+
Incorporation of one CO2 into hexose uses 3 ATP and 2
NADPH (from light reaction)
Ribulose 1,5-bisphosphate carboxlase/oxygenase
(Rubisco): the most abundant protein on earth!
5C + 1C  2 x 3C
Structure of Rubisco.
Active site
Acceleration of photosynthesis by concentrating CO2.
PEP carboxylase vs
NADP+-linked malate dehydrogenase
Major site of photosynthesis
Metabolism and Diseases
Warburg effect: cancer cells produce
lactic acid from glucose even under
non-hypoxic conditions.
1883-1970
The shortest grand proposal!
Warburg effect: cancer cells produce lactic
acid from glucose even oxygen supply is high.
Why glucose does not go to TCA cycle in cancer cells ?
Defect in mitochondria function or ??
Science 324: 1029-1033; 2009
Pyruvate kinase (M1 and M2)
• the M1 isoform is expressed in most adult tissues; and the
M2 is a splice variant of M1 expressed during embryonic
development
• M1 is a constitutively active enzyme. M2 is a low activity
enzyme.
• Tumor tissues exclusively express the embryonic M2
isoform of pyruvate kinase.
• What is the functional significance of expression of M2 of
PK?
• How cancer cell switch its PK gene expression from M1 to
M2?
How cancer cell switch its PK gene
expression from M1 to M2:
Myc enhances PKM splicing to produce PKM2
exon 9 is skipped
From David et al. 2010 Nature 463, 364-368
What is the functional significance of expression of M2 of PK?
The therapeutic target of cancer cell
What message we learn so far:
• Life is all about electron (carbon based life).
• Life is all about proton!
• Life is all about economy.