Samenvatting
Metabolism Summary LST
- Vak
- Metabolism
- Instelling
- Rijksuniversiteit Groningen (RuG)
Notes from everything in the lectures and information from the book included
[Meer zien]Voorbeeld 4 van de 70 pagina's
Voorbeeld 4 van de 70 pagina's
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Voorbeeld van de inhoud
Metabolism Lecture 1 (Bakker)For the past 30 years, research in the biological sciences has been dominated by molecular biology
(1950s-60s). Otto Warburg investigated metabolism of tumors and respiration of cancer cells →
Nobel prize in 1931 for discovery of the nature and mode of action of the respiratory enzyme. Over
the past decades, biologists investigated the cellular systems but neglected the very basic function of
the cell: cell growth.
Metabolism is a tightly integrated network of reactions. Metabolism is constrained by the laws of
chemistry and physics: energy: the laws of thermodynamics. In healthy
metabolic network supply and demand of nutrients are balanced to support
growth or other vital functions: kinetics and regulation. ATP = the carrier of
Gibbs energy. ATP is adenosine triphosphate. Two of the phosphate bonds
contain a high energy. So, if you release one bond, you will release a lot of
Gibbs energy. Only the first two bonds are energy rich. 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. When you use ions
(with charge) → energy: electrical force creates a flow from right to
left.
Driving force of ATP hydrolysis → ADP + inorganic phosphate:
1. Negative charges on phosphate repel each other
2. Resonance stabilization of inorganic phosphate (Pi) = entropy effect
3. Two molecules are formed from one
4. ADP and Pi are stabilized by bound water molecules
Computing reaction Gibbs energy:
what makes ATP a good carrier of Gibbs energy:
- The phosphate in ATP is stabilized, but energy rich
- Because of the (high energy) phosphate groups in the ATP molecule
- It contains two energy-rich phosphates
- ATP hydrolysis: G0 = -30.5 KJ/mol;
- ATP hydrolysis has strong driving force hence ATP can drive uphill reactions
- There are reactions with even more negative delta G0. These are required to
recharge the carrier (drive the synthesis of ATP from ADP)
- ATP is stable in the absence of enzymes
ATP has a very high phosphoryl potential, that can be explained by its structure. Four
factors are important: Resonance stability, electrostatic repulsion, increase in entropy
and stabilization due to hydration of the end products. ATP hydrolysis is often catalyzed by a kinase.
Other carriers of Gibbs-energy = ATP, GTP, proton gradient and creatine phosphate (mostly present
in the muscle). Creatine-P + ADP → creatine + ATP. Creatine-P is a short-term storage from Gibb’s
energy in skeletal muscle (for initial 5-6 sec of a sprint). You learned in Chapter 8 that enzymes are
catalysts: they speed up the reaction by lowering its activation energy. An equally important function
of enzymes, however, is to couple thermodynamically infeasible reactions (endergonic reactions, i.e.
,with a positive deltaG) to an exergonic reaction (with a negative
deltaG). The overall process is feasible if the overall deltaG is
negative.
The hexokinase reaction:
Enzymes couple uphill and downhill reactions. ATP + glucose → ADP + glucose-6-
P. The production of glucose-6-P would be thermodynamically infeasible without
an enzyme to couple it to ATP hydrolysis.
Enzyme kinetics
This is all based on Chapter 8 and the course
“Molecules of Life”. When adding a competitive
inhibitor to a model, the Vmax is unchanged, and
the KM is increased. Here you see the Lineweaver-
Burk plot and the competitive inhibitor plot.
Glycolysis
Glycolysis can be divided into two stages. In the first
stage, there is no ATP converted, but only used. Glucose
is converted into fructose-1,6-biphosphate in three steps:
a phosphorylation, an isomerization and a second
phosphorylation. The glucose is trapped inside the cell
and is converted into a form that can be readily cleaved
into phosphorylated three-carbon units. In stage 2,
ATP is harvested when the three-carbon fragments
are oxidized to pyruvate. Conversion of CO2 to
pyruvate → ethanol (fermentation) or lactate or
complete oxidation. Glycolytic enzymes were the
first enzymes ever discovered. In 1860: Pasteur
proves that fermentation requires living cells. in
1897: Eduard Buchner proves that fermentation
takes place in yeast extracts without living cells.
1909-1942: identification and purification of
glycolytic enzymes. Glycolysis in cancer research:
highly glycolytic tumour lesions. Short and intense
exercise depends primarily on glycolysis. Glycolysis
can be upregulated 400-fold during a 100 m sprint.
Glycolysis is the first phase of glucose catabolism.
Major reactions that occur are isomerization, group
transfers and redox reactions. The investment is 2 ATP. Microorganism have many variants of the
canonical Emden-Meyerhof-Parnas pathway (= glycolysis).
Types of chemical reactions in metabolism:
- Oxidation-reduction: electron transfer
- Ligation requiring ATP cleavage: formation of covalent bonds (carbon-carbon bond)
- Isomerization: rearrangement of atoms to form isomers
- Group transfer: transfer of a functional group from one molecule to another
, - Hydrolytic: cleavage of bonds by the addition of water
- Carbon bond cleavage by means other than hydrolysis or oxidation: two substrates yielding
one product or vice versa. When H2O or CO2 are a product, a double bond is formed.
Enzyme names often reveal the reaction type.
Hexokinase: is for the reaction of Glucose and ATP to Glucose-6-
phosphate. Kinase: a transferase that transfers phosphate from
ATP to an acceptor molecule, so there is always ATP needed. The
induced fit: bind their substrate precisely → only 6-C of glucose
can bind with ATP. The active site closes around glucose and ATP.
ATP in its activated form is protected from water.
Glucose 6-phosphate isomerase: glucose 6-phosphate to
fructose 6-phosphate. Isomerase = identical atomic composition
of product and substrate
Phosphofructokinase: fructose 6-phosphate with ATP to fructose
1,6-biphosphate (which is really symmetrical → important for the
next reaction = splitting reaction). Also, a kinase, so phosphate
transfer from ATP.
Aldolase splits hexose (C6) into two C3 compounds:
dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (GAP). Aldolase is a lyase:
carbon bond cleavage, forming a double bond elsewhere, so splitting a compound.
Triose-phosphate isomerase: transformation between dihydroxyacetone phosphate to
glyceraldehyde 3-phosphate. The reaction is rapid and reversible → close to chemical equilibrium. At
equilibrium, 96% is dihydroxyacetone.
Glyceraldehyde 3-phosphate dehydrogenase = GADPDH: transformation between glyceraldehyde 3-
phosphate (GAP) and 1,3-Biphosphoglycerate (1,3-BPG), this reaction is reversible. GADPDH catalyzes
a redox reaction. Glyceraldehyde 3-phosphate + Pi → 1,3-biphosphoglycerate + 2H+ + 2e. NAD+ + H+
+ 2e → NADH. Dehydrogenase = catalyse electron transfer to NAD+ with concomitant extraction of
hydrogen.
Electron carriers: biochemical redox reactions involve a limited number of electron carriers: NAD+
and FAD. They have an aromatic ring structures and have the reactive site also in this ring. As soon
as you get extra electrons, other electrons have to leave, and in a ring they can move easily. The
reduction of FAD is analogous to the reduction of NAD+. In both cases the double bonds allow
sequential displacement of electron pairs to accommodate the extra electron pair. Two electrons
come with a proton (H+ + 2e-). Each bond represents a pair of electrons. Cofactors are derived from
vitamins. The vitamins are then the precursors of the coenzymes.
, Phosphoglycerate kinase (PGK): transformation between 1,3-Biphosphoglycerate and 3-
Phosphoglycerate. The first ATP is harvested from the Gibbs-energy-rich phosphate bond of 1,3-
biphosphoglycerate → substrate-level phosphorylation. 1,3-bisphosphoglycerate has a high-energy
phosphate bond. The product 3-phosphoglycerate has a much lower Gibbs energy, since it is
stabilized by its resonance structures. Thus, the PGK reaction has a large negative G.
The PGK reaction is an example of substrate-level phosphorylation, since the phosphate donor is a
substrate with a high-energy phosphate bond. Substrate-level phosphorylation contrasts with
oxidative phosphorylation. PGK pulls GAPDH over a Gibbs-energy barrier by keeping the
concentration of the instable 1,3-biphosphoglycerate low.
GAPDH and PGK are strongly dependent on each other. GAPDH has a positive energy, and the PGK
has a negative. PGK pulls GAPDH over a Gibbs-energy barrier by keeping the concentration of the
instable 1,3-biphosphoglycerate low. The G of GAPDH must be negative. This can only be the case if
the product concentrations are low compared to the substrate concentrations. Note that also
inorganic phosphate (Pi) is a substrate. Hence, the phosphate concentration in the cell contributes
strongly to the driving force of lower glycolysis. The same holds for the pH. The proton is not
depicted here, but you see it in the full reaction equation on p. 457. A
low pH (acid environment, high proton concentration) will decrease the
driving force for GAPDH.
The net ATP formation by pyruvate kinase: it transfers
phosphoenolpyruvate into pyruvate by forming ATP from APD and H+.
Pyruvate is the last product of the glycolysis pathway. Phosphoglycerate
mutase needs a catalytic amount of 2,3-bisphosphoglycerate (i.e. a
small amount that will be recycled in the reaction). This 2,3-
bisphosphoglycerate donates a phosphate to the enzyme, such that a
histidine in the active site can be kept in the phosphorylated state. See Berg p. 460 for the
mechanism. The phosphate bond in phosphoenolpyruvate has a higher Gibbs energy than that of 2-
phosphoglycerate. This is the function of the enolase reaction. Also, pyruvate has multiple resonance
structures that stabilize the molecule. This makes the pyruvate kinase reaction strongly exergonic (=
negative delta G). The kinases have a highly negative deltaG (except PGK) → they drive glycolysis in
the forward direction.
The kinase has a highly negative delta G (except PGK) → they drive glycolysis in the forward
direction. Note that some of the G values are denoted as small and positive. Of course, they should
be small and negative to run in the forward direction. But the experimental analysis of the
metabolites has not been accurate enough to detect the difference. Phosphoglycerate kinase has a
large negative G0’, but the G is close to zero. This is because the concentration of the substrate
1,3-bisphosphoglycerate is so low. This enables the GAPDH reaction to run in the forward direction.
The tandem GAPDH-PGK is typically close to equilibrium.
Glycolysis can only occur when the glucose can be taken up. You have
glucose transporters: GLUT4 recruitment to the plasma membrane is
insulin-sensitive → insulin promotes the uptake of glucose by muscle
and fat cells at a high blood glucose level. The glucose concentration in
blood is approximately 5 mM. GLUT1 and GLUT3 are always saturated
and do not respond to a changing glucose concentration in blood.
Michaelis-Menten kinetics: the model takes the form of an equation
describing the rate of enzymatic reactions, by relating reaction rate
(rate of formation of product) to, the concentration of a substrate S.
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