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Metabolism summary lectures
Summary of the lectures and part of the book of the course metabolism given in the first year of biology.
[Meer zien]Voorbeeld 4 van de 48 pagina's
Voorbeeld 4 van de 48 pagina's
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Door: philiplinderberg • 2 jaar geleden
Door: danilmoerman • 3 jaar geleden
Voorbeeld van de inhoud
Lecture 1 – ATP, Gibbs energy, Glycolysis, Fermentation:Metabolism is constrained by the laws of chemistry and physics (energy is the law of
thermodynamics). In healthy metabolic network supply and demand of nutrients are balanced to
support growth or other vital functions.
ATP = adenosine triphosphate, has three phosphate bonds, and two of them contain high energy
(first two). When the first and second phosphate bond are broken, you release Gibbs energy= the
driving force. The second law of thermodynamics; In all spontaneous processes Gibbs energy is
dissipated (in a certain direction, does not require all the time, sometimes enzymes are necessary,
but it cannot invert its directions) at constant environmental temperature and pressure.
Entropy= probability creates a net flow from left to right (where there is the
highest/lowest concentration).
Energy= electrical force creates a flow from right to left.
This is a problem, because now we have two forces that push the
molecules into different directions. This is where the second law
comes in: If an event occurs in which the Gibbs energy is negative, so a decrease of Gibbs
energy, then the process can occur in that specific reaction.
The Gibbs energy of ATP hydrolysis to ADP + inorganic phosphate. There are different driving forces
of ATP hydrolysis:
- Negative charges on phosphate repel each other
- Resonance stabilization (different structure molecules) of inorganic phosphate (entropy)
- Two molecules are formed from one (entropy)
- ADP and Pi are stabilized by bound water molecules.
It still is difficult to calculate Gibbs energy from this. So, there is another formula:
The inorganic phosphates are stable, the phosphates in the ATP is not that stable,
because of low Gibbs energy.
What makes ATP a good carrier of Gibbs energy?
- ATP hydrolysis has strong driving force, hence ATP is capable of driving uphill reactions.
- There are reactions with even more negative deltaG, which are required to recharge the
carrier (i.e. drive synthesis of ATP from ADP).
- ATP is stable in the absence of enzymes.
Other carriers of Gibbs-energy are GTP, a proton gradient and creatine phosphate (is only present in
the muscle, serves as a large buffer when you have a burst-out exercise, provides energy
immediately, but only for a few seconds).
Gibbs energies are additive (you can add them).
Thus, a thermodynamically unfavourable reaction
can be driven by a thermodynamically favourable
reaction to which it is coupled . In this example, the reactions are coupled by the shared chemical
intermediate B. Metabolic pathways are formed by the coupling of enzyme-catalysed reactions such
that the overall free energy of the pathway is negative.
More generally, the hydrolysis of n ATP molecules changes the equilibrium ratio of a coupled
reaction (or sequence of reactions) by a factor of 10 8n . For example, the hydrolysis of three ATP
molecules in a coupled reaction changes the equilibrium ratio by a factor of 10 24 . Thus, a
thermodynamically unfavourable reaction sequence can be converted into a favourable one by
coupling it to the hydrolysis of a sufficient number of ATP molecules in a new reaction.
,NADPH is used almost exclusively for reductive biosynthesis, whereas NADH is used primarily for the
generation of ATP . The extra phosphoryl group on NADPH is a tag that enables enzymes to
distinguish between high-potential electrons to be used in anabolism and those to be used in
catabolism.
Glycolysis
Conversion of glucose to pyruvate under anaerobic/aerobic conditions. Glucose is a favourite fuel for
many organisms, so it is an old pathway; can see it throughout evolution. Glycolytic
enzymes were the first enzymes ever discovered. And started in 1860 with Pasteur proves
that fermentation requires living cells. in 1897 Eduard Buchner proves that fermentation
takes place in yeast extracts without living cells. In the period from 1909-1942 there was
identification and purification of glycolytic enzymes.
During short and intense exercise glycolysis can be upregulated 400-fold (e.g. in a 100 m
sprint).
Glycolysis is the first phase of glucose catabolism. First, glucose is split into two 3-carbon
molecules DHAP and GAP. In order to start with glycolysis you need to invest 2 ATP
molecules, so cells have to have a minimal amount of ATP. In the second and last part you
get per molecule 2 ATP molecules, so net yield is 2 ATP.
Microorganisms have many variants of the canonical Emden-Meyerhof-Parnas pathway
(=glycolysis).
*Have to know all the names of the molecules in the glycolysis pathway by heart*
There is only a limited number of reaction types:
o Oxidation-reduction, electron transfer
o Ligation requiring ATP cleavage, formation of covalent bonds (carbon-carbon)
o Isomerization, rearrangements of atoms to form isomers
o Group transfer, transfer of functional group from one molecule to another
o Hydrolytic, cleavage of bonds by the addition of water
o Carbon bond cleavage (other than hydrolysis/oxidation), two substrates yielding one product
Enzyme names often reveal the reaction type:
• Kinase, a transferase that transfers phosphate from ATP to an acceptor molecule (like
hexokinase).
Enzymes often have an induced fit, this is in contrast to the thought that the
enzyme and the substrate fit perfectly in each other. When a molecule binds,
the enzyme folds nicely around it, so that it is ‘locked’, until then it could
move in or out. It is, however, specific because the enzyme only recognizes
and binds around glucose. This is for protecting the ATP from reacting with
the wrong substrate.
• Isomerase, identical atomic composition of product and substrate, in
the case of glucose 6-phosphate isomerase= shifting of the double bond of
oxygen, so you just rearrange the groups of a molecule. Thus, the
isomerization of glucose 6-phosphate to fructose 6-phosphate is a conversion
of an aldose into a ketose. The reaction catalyzed by phosphoglucose
isomerase takes several steps because both glucose 6-phosphate and
fructose 6-phosphate are present primarily in the cyclic forms. The enzyme
must first open the six-membered ring of glucose 6-phosphate, catalyze the
isomerization, and then promote the formation of the five-membered ring of
, fructose 6-phosphate. A second phosphorylation reaction follows the isomerization step.
• Phosphofructokinase an allosteric enzyme that sets the pace of glycolysis, the CH2OH binds
to a phosphate (from ATP), so now you get fructose 1,6-biphosphate. This creates a sense of
symmetry, which is important in the next reaction.
• Lyase, carbon bond cleavage, forming a double
bond elsewhere, like aldolase; splits hexose (C6)
into two C3 compounds, this could not happen
without the previous ones.
• Triose phosphate isomerase, because there are
three carbons and a phosphate. Changes the
structure of the dihydroxyacetone phosphate to
glyceraldehyde 3-phosphate. This reaction is rapid and reversible. At equilibrium, 96% of the
triose phosphate is dihydroxyacetone phosphate. However, the reaction
proceeds readily from dihydroxyacetone phosphate to glyceraldehyde 3-
phosphate because the subsequent reactions of glycolysis remove this
product. Triose phosphate isomerase deficiency, a rare condition, is the
only glycolytic enzymopathy that is lethal. This deficiency is characterized
by severe haemolytic anaemia and neurodegeneration. TPI suppresses an
undesired side reaction, the decomposition of the enediol intermediate into methyl glyoxal
and orthophosphate. Hence, TPI must prevent the enediol from leaving the enzyme. This
labile intermediate is trapped in the active site by the movement of a loop of 10 residues.
This loop serves as a lid on the active site, shutting it when the enediol is present and
reopening it when isomerization is completed. We see here a striking example of one means
of preventing an undesirable alternative reaction: the active site is kept closed until the
desirable reaction takes place
After this step, we now have two molecules of GAP (see overview in 1st figure on this page) which will
continue with the following steps.
• Dehydrogenase, redox enzymes, like; glyceraldehyde 3-phosphate dehydrogenase (GADPDH)
which thus catalyses a redox reaction. Because the electrons often move with hydrogen, you
often see them in these reactions. At first you don’t see any electrons, but when you split it
into a donor and
acceptor reaction,
you do see them.
, NADH always gets 2 electrons and a proton! These two processes must be coupled so that
the favourable aldehyde oxidation can be used to drive the formation of the acyl phosphate.
How are these reactions coupled? The key is an intermediate, formed as a result of the
aldehyde oxidation, that is linked to the enzyme by a thioester bond. Thioesters are high-
energy compounds found in many biochemical pathways. This intermediate reacts with
orthophosphate to form the high-energy compound 1,3-bisphosphoglycerate. The thioester
intermediate is higher in free energy than the free carboxylic acid is. The favourable
oxidation and unfavourable phosphorylation reactions are coupled by the thioester
intermediate, which preserves much of the free energy released in the oxidation reaction.
There are also a limited number of electron carriers, like NAD+ (where it is a hydrogen) or NADP+
(where it is in a phosphate), also FAD has three aromatic rings (instead of one in the other two).
These rings are important, because in these rings electrons can move very freely. Cofactors like these
three are derived from vitamins (most often B vitamins).
• Phosphoglycerate kinase (PGK), there is a high energetic phosphate (which you can often
recognize by a double bond next to the phosphate), which reacts with ADP to from ATP. So,
1,3-bisphosphoglycerate loses a phosphate and becomes 3-phosphoglycerate. This is an
example of phosphate phosphorylation= substrate
donates high energy phosphate to ADP to create ATP.
These two enzymes (GAPDH and PGK) are extremely
dependent on each other. GAPDH has a positive Gibbs
energy, which creates a barrier. Luckily, this can be
undone by PGK which keeps the concentration of the instable (also a reason why it needs to
be low) 1,3-biphosphoglycerate low. You can lower the Gibbs free energy, by having low
product concentration and high substrate
concentration.
• Phosphoglycerate mutase, causes an isomerase
reaction from 3-phosphoglycerate to 2-
phosphoglycerate.
• Enolase, subtracts a water molecule and forms a
double bond, the molecules is now phosphoenolpyruvate. This double
bond is interesting, because it is next to a phosphate, which makes
the phosphate energy-rich. This phosphate is then donated to ADP
with the help of pyruvate kinase, now you have the last ATP molecule
and the final product pyruvate. Also pyruvate has multiple resonance
structures that stabilize the molecule. This makes the pyruvate kinase
reaction strongly exergonic (negative Gibbs energy). Why does
phosphoenolpyruvate have such a high phosphoryl-transfer potential? The phosphoryl group
traps the molecule in its unstable enol form. When the phosphoryl group has been donated
to ATP, the enol undergoes a conversion into the more stable ketone—namely, pyruvate.
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