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Summary Metabolism
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MetabolismLECTURE 1 CHAPTER 15/16.1; GIBBS ENERGY AND GLYCOLYSIS
Living organisms require a continual input of free energy for three major purposes:
1. The performance of mechanical work in muscle contraction and cellular movement.
2. The active transport of molecules and ions.
3. The synthesis of macromolecules and other biomolecules from simple precursors.
Metabolism is a tightly integrated network of reactions figure 15.1. reactions that transform fuels
into cellular energy are called catabolic reactions. Reactions that need energy are called anabolism.
A thermodynamically unfavorable reaction can be driven by a thermodynamically favorable reaction
to which it is coupled, page 426 so minus delta reaction occurs spontaneously.
Basic principles:
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 & Regulation
We take a quantitative approach, but physical and chemical principles should always serve to
understand biological function.
ATP and Gibbs energy
ATP is the carrier of Gibbs energy, Gibbs energy is the driving force.
The first two phosphate groups of ATP are energy rich. A large amount of free
energy is liberated when ATP is hydrolyzed to ADP or AMP. The oxidation of
carbon fuels powers the formation of ATP.
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.
Energy: Electrical force creates a flow from right to left.
Gibbs energy balances energy and entropy to look which is stronger: - is
favorable than the reaction is spontaneous.
Driving force of ATP hydrolysis
1. Negative charges on phosphate repel each other .
2. Resonance stabilization of inorganic phosphate (Pi) figure 15-4.
3. Two molecules are formed from one .
4. ADP and Pi are stabilized by bound water molecules.
However, it is difficult to calculate G from first principles.
The entropy of the products of ATP hydrolysis is greater, in that there are now two molecules instead
of a single ATP and water binds to ADP and Pi, stabilizing these molecules and rendering the revere
reaction more unfavorable. So this makes ATP an efficient phosphoryl-group donor.
1
,Why is ATP a good carrier of Gibbs energy?
ATP hydrolysis: G0’ = -30.5 kJ mol-1 IMPORTANT FORMULA -> PAGE 425
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.
Other carriers of Gibbs-energy:
ATP
GTP
proton gradient
creatine phosphate
Creatine-P + ADP -> creatine + ATP Creatine-P is a short-term storage form of Gibbs energy in
skeletal muscle (for the initial 5-6 sec of a sprint).
Low oxygen; last seconds of a sprint, producing of lactate.
Normal oxygen; long slow run, production of CO2 of H2O.
Figure 15-11; the electrochemical potential of ion gradients across membranes, produced by the
oxidation of fuel molecules or by photosynthesis, ultimately powers the synthesis of most of the ATP
in cells. In animals proton gradients generated by the oxidation of carbon fuels account for more
than 90% of ATP generation.
The production of glucose-6-P would be thermodynamically infeasible
without an enzyme to couple it to ATP hydrolysis.
Glycolysis figure 16.1
Glycose is a favorite fuel. Glycolysis is the sequence of reactions that
metabolizes one molecule of glucose to two molecules of pyruvate with
the concomitant net production of two molecules of ATP, this is
anaerobic. Pyruvate can be further processed anaerobically and
aerobically.
Glycolysis in cancer research PET scan: highly glycolytic
tumor lesions. Growing tumor cells metabolize glucose to
lactate even in the presence of oxygen, a process called
aerobic glycolysis or Warburg effect.
Glycolysis in top sport: Short and intense exercise
depends primarily on glycolysis. Glycolysis can be
upregulated 400-fold during a 100 m sprint.
Glycolysis, detailed overview figure 16.2 (you need
to know this pathway and the names, but not the
structures very hard!)
Enzyme names often reveal the reaction type, table 15-5.
Kinase (hexokinase): a transferase that transfers phosphate from ATP to an acceptor molecule, page
451.
Induced fit; the active site closes around glucose and ATP.
First the environment around the glucose becomes more nonpolar, which favors rection between
the hydrophilic hydroxyl group of glucose and the terminal phosphoryl group of ATP.
2
,Second the conformational changes enable the kinase to discriminate against water as a substrate.
The closing of the cleft keeps water molecules away from the active sites. Figure 16.3.
Isomerase: identical atomic composition of product and substrate, Glucose 6-phosphate
isomerase page 454. Enzyme that confer one isomer to another (same (number) atoms).
Kinase: phosphate transfer from ATP, page 454 under.
Aldolase: splits hexose (C6) into two C3 compounds (GAP and DHAP) is reversable, page 455.
Aldolase is a lyase: Carbon bond cleavage, forming a double bond elsewhere.
Triose-phosphate isomerase: Rapid and reversible close to chemical equilibrium
At equilibrium 96% is dihydroxyacetone, page 455.
Dehydrogenase: catalyze electron transfer to NAD+ with concomitant extraction of hydrogen.
Page 457 reaction above.
Electron carriers: Biochemical redox reactions involve a limited number of
electron carriers, predominantly FAD and NAD +. The nicotinamide ring of
NAD+ accepts a hydrogen ion and two electrons, which are equivalent to a
hydride ion H-. The isoalloxazine ring of FAD takes up two protons and two
electrons. Cofactors are derived from vitamins, table 15-3 and 15-14.
Phosphoglycerate kinase (PGK): The first ATP is harvested from the Gibbs-
energy-rich phosphate bond of 1,3-bisphosphoglycerate
Substrate-level phosphorylation, page 459.
Pyruvate kinase: A recurring principle: also pyruvate has multiple resonance structures that stabilize
the molecule. This makes the pyruvate kinase reaction strongly exergonic (= negative G).
The kinases have a highly negative G (except PGK) -> They drive glycolysis in the forward direction.
Table 16-4: 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.
This equation is called the Michaelis–Menten equation. Here,
Vmax represents the maximum rate achieved by the system
(which happens at saturating substrate concentration). The
value of the Michaelis constant Km is numerically equal to the
substrate concentration at which
the reaction rate is half of Vmax.
S is the concentration of the
substrate and P the concentration
of formation of the product.
Fermentation
Fermentation is a process without oxygen, you get ethanol or lactate!
Alcoholic fermentation: he formation of ethanol deoxidizes NADH without an external electron
acceptor.
Examples: yeast, goldfish, rice root. Yeast also ferments in the presence of O2, when glucose
is abundant.
Fermentation in the presence of O2: PET scan, tumors have an increased rate of glucose uptake.
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, Energy from food is taken in three steps: first the large molecules are broken
down in smaller subunits. Second these small molecules are degraded to a few
simple units that play a central role in metabolism. Third ATP is produced from
the complete oxidation of the acetyl unit of acetyl COA.
The glycolytic pathway has a dual role; it degrades glucose to generate ATP and
it provides building blocks for biosynthetic reactions -> 2 ATP, 2 NADH, and 2
pyruvate molecules.
Hexokinase - Phosphorylates glucose
Phosphoglucose isomerase - Converts glucose 6-phosphate into
fructose 6-phosphate
Phosphofructokinase - Forms fructose 1,6-bisphosphate
Aldolase - Cleaves fructose 1, 6-bisphosphate
Triose phosphate isomerase - Catalyzes the interconversion of three carbon isomers
Glyceraldehyde 3-phosphate dehydrogenase - Generates the first high-phosphoryltransfer
potential compound that is not ATP
Phosphoglycerate kinase - Generates the first molecule of ATP
Phosphoglycerate mutase - Converts 3-phosphoglycerate into 2phosphoglycerate
Enolase - Generates the second high-phosphoryltransfer potential compound that is not ATP
Pyruvate kinase - Generates the second molecule of ATP
What reactions of glycolysis are not readily reversible under intracellular conditions?
The conversion of glucose into glucose 6-phosphate by hexokinase.
The conversion of fructose 6-phosphate into fructose 1,6-bisphosphate by phosphofructokinase.
The formation of pyruvate from phosphoenolpyruvate by pyruvate kinase. Page 452
LECTURE 2 CHAPTER 16.2-16.4 G LUCONEOGENESIS , R EGULATION OF GLYCOLYSIS AND GLUCONEOGENESIS
Metabolic processes are regulated in three principal ways: Controlling the amount of enzymes -
Controlling catalytic activity - Controlling the accessibility of substrates (compartmentation).
Regulation of glycolysis in the skeletal muscle
Glycolysis in skeletal muscle provides ATP primarily to power contraction. At rest glycolysis is
inhibited, high ATP. Glycolysis (glucose -> pyruvate is an anaerobic process) Figure 16.18
Phosphofructokinase (most prominent regulator enzyme in glycolysis) high levels of ATP inhibit the
enzyme. ATP binds to a specific regulatory site, this binding lowers the affinity for fructose 6-
phosphate. Thus, a high concentration of ATP converts the hyperbolic binding curve of
fructose 6-phosphate into a sigmoidal (shape curve) one. Figure 16-16/17. It catalyzes the
phosphorylation of fructose-6-phosphate to fructose 1,6-bisphosphate.
Hexokinase is also a regulator enzyme in glycolysis, it catalyzes the first step of glycolysis.
Hexokinase is inhibited by its own product glucose 6-phosphate (negative feedback). High
concentrations of this molecule signal that the cell no longer requires glucose for energy or
for the synthesis of glycogen.
The inhibition of phosphofructokinase leads to the inhibition of hexokinase.
Pyruvate kinase is the enzyme catalyzing the third irreversible step in glycolysis. This final
step yields ATP and pyruvate. ATP inhibits pyruvate kinase to slow glycolysis when the energy charge is high.
Why does AMP, not ADP, signal a low Gibbs-energy state?
During exercise glycolysis is stimulated, low ATP.
AMP reverses the inhibitory action of ATP, the activity of the enzyme increases when the
ATP/AMP ratio lowered. In other words, glycolysis is stimulated as the energy charge falls. So
AMP activates phosphofructokinase so fructose 1,6-bisphosphate is made that stimulates
pyruvate kinase.
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