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Lectures summary Metabolism
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A broad summary of all lectures of Metabolism, including some important features of the corresponding book.
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Metabolism 2020Introduction lecture
Understanding in metabolism can help tackling diseases (cancer, diabetes) and climate change.
In every cell: chemical reaction network that generates building blocks for new cells and generates
energy, from nutrients.
Cellular metabolism:
About 1000 reactions (enzyme‐catalysed)
About 800 intermediates (metabolites)
Metabolism is key for bio‐based economy. We can engineer cells to produce better waste-/by
products bioplastics, biofuel.
1920s-30s
Golden age of metabolism studies, metabolites and enzymes of key catabolic pathways identified.
1950s-60s
Not much learning in metabolism , double helix structure of DNA was discovered
2010
Rediscovery of importance of metabolism
Otto Warburg: investigated metabolism of tumors and respiration of cancer cells Warburg
effect
Over the past decades biologists investigated the “fancy” cellular systems but neglected the very
basic function of a cell: its growth (which is connected with metabolism).
Lecture 1
Metabolism is a tightly integrated network of reactions.
Basic principles:
Metabolism is constrained by the laws of chemistry and physics
o Energy: the laws of thermodynamics
In healthy metabolic network supply and demand of nutrients are balanced to support
growth or other vital functions
o Kinetics & Regulation (how are the rates of an enzyme)
We take a quantitative approach, but physical and chemical principles should always serve to
understand biological function
ATP is the carrier of Gibbs energy
It has 3 phosphate bonds, from which the first 2 are high-energy bonds.
Gibbs energy is the driving force
Second law of thermodynamics: in all spontaneous processes Gibbs energy is dissipated at constant
(environmental) temperature and pressure.
Entropy: probability creates a net flow from left to right (from high to low concentrations of glucose)
Example: glucose needs transport proteins to pass the selectively permeable membrane. The
transport occurs more frequently to the side with the lower glucose concentration. But it can also
happen in the other reaction
Energy: electrical force creates a flow from right to left (from positive to negative side when
compound is positively charged)
Example: sodium ions (positively charged) flow from positive to negative side, in the opposite side
of the entropy.
Gibbs energy balances energy and entropy.
1
,Gibbs energy of a biochemical reaction
ATP ADP + inorganic phosphate
Driving force of ATP hydrolysis:
Negative charges on phosphate repel each other. The repulsion is reduced when ATP is
hydrolysed.
Resonance stabilization of inorganic phosphate (Pi) entropy
Two molecules are formed from one (increase in entropy)
ADP and Pi are stabilized by bound water molecules
It is difficult to calculate ΔG from first principles.
When there is an equilibrium: ΔG=0
0'
∆ G =−RTln K eq
Why is ATP a good carrier of Gibbs energy?
ATP hydrolysis: G0’ = 30.5 kJ mol-1
ATP hydrolysis has strong driving force, hence ATP is capable of driving uphill reactions.
There are reactions with even more negative G0’. These are required to recharge the carrier,
i.e. drive the synthesis of ATP from ADP.
ATP is stable in the absence of enzymes
ATP has a high phosphoryl transfer potential. Some compounds have a higher phosphoryl-transfer
potential: PEP, 1,3-BPG and creatine phosphate can power ATP synthesis.
Other carriers of Gibbs energy: GTP, proton gradient and creatine phosphate
creatine-P + ADP creatine + ATP by creatine kinase
Creatine-P is a short-term storage form of Gibbs energy in skeletal muscle (for the initial 5-6 sec of a
sprint). Creatine-P can donate the P to ATP when there is no time to generate ATP in the usual way.
G and G0’ are additive
The production of glucose-6-P would be thermodynamically infeasible without an enzyme to couple
it to ATP hydrolysis.
An important function of enzymes is to couple thermodynamically infeasible reactions (endergonic
reactions, positive G) to an exergonic reaction (negative G). the overall process is feasible if the
total G is negative.
2
,A thermodynamically unfavorable reaction sequence can be converted into a favorable one by
coupling it to the hydrolysis of a sufficient number of ATP molecules in a new reaction.
Cancer cells use a lot of glucose to grow.
By inhibiting glycolysis cancer might be tackled.
Short and intense exercise depends primarily on glycolysis.
Glycolysis can be upregulated 400-fold during a 100 m sprint.
Kinase: transfers phosphate from ATP to an acceptor molecule.
Glycolysis
3
, Hexokinase
Induced fit: glucose wanders around and binds to the kinase
enzyme folds around glucose and ATP tight binding. ATP is
protected from water in its activated form.
Phosphoglucose isomerase
G-6P to open chain form double bond moves from first carbon
to second carbon F-6P, ring closes again.
Phosphofructokinase
F-6P + ATP F-1,6BP + ADP + H+
F-1,6BP is a symmetry molecule, important for the splitting of this
GAPDH G0’ = +6.3 kJ mol-1
PGK G0’ = -18.8 kJ mol-1
PGK pulls GAPDH over a ‘Gibbs-energy barrier’ by keeping the concentration of the instable 1,3-
bisphosphoglycerate low.
4
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