ECDA
October 2009

METABOLISM
Metabolism is essentially a linked series of chemical reactions that begins with a particular molecule and converts it into some other molecule or molecules in a carefully defined fashion

METABOLISM
 There are many such defined pathways in the cell
 The pathways are interdependent, and their activity is coordinated by exquisitely sensitive means of communication in which allosteric enzymes are predominant

METABOLISM
 Metabolic pathways can be divided into two broad classes:
(1) those that convert energy into biologically useful forms
(CATABOLISM)
(2) those that require inputs of energy to proceed (ANABOLISM)

METABOLISM
 Those reactions that transform fuels into cellular energy are called
catabolic reactions or, more generally,
catabolism.
Fuels (CHO, Fats) CO2 + H2O + useful energy

METABOLISM
 Those reactions that require energy—such as the synthesis of glucose, fats, or DNA— are called
anabolic reactions or anabolism.
Energy + small molecules complex molecules
 The useful forms of energy that are produced in catabolism are employed in anabolism to generate complex structures from simple ones, or energy-rich states from energy-poor ones.

METABOLISM
 A metabolic pathway is constructed from individual reactions and it satisfies two criteria at the least:
1. The individual reactions must be specific.
- that is, it will yield only one particular product or set of products from its reactants
2. The entire set of reactions that constitute the pathway must be thermodynamically favored.
A reaction can occur spontaneously only if ΔG, the change in free energy, is negative.

Gibb’s Free Energy
 In thermodynamics, the Gibbs free energy measures the "useful" or process-initiating work obtainable from an isothermal, isobaric thermodynamic system.
 ΔG < O means favored reaction (Spontaneous)
 ΔG = O means neither the forward nor the reverse reaction prevails (equilibrium)
 ΔG > O means disfavored reaction
(Nonspontaneous)

Gibb’s Free Energy
 An important thermodynamic fact is that the overall free-energy change for a chemically coupled series of reactions is equal to the sum of the free energy changes of the individual
steps. Consider the following reactions:
A B + C
B D
A C + D
ΔG = +5 kcal/mol
ΔG = - 8 kcal/mol
ΔG = - 3 kcal/mol

Gibb’s Free Energy
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Under standard conditions, A cannot be spontaneously converted into B and C, because
ΔG is positive.
However, the conversion of B into D under standard conditions is thermodynamically feasible. (ΔG is negative)
Because free- energy changes are additive, the conversion of A into C and D has a ΔG° ′ of -3 kcal/ mol, which means that it can occur spontaneously under standard conditions.
Thus, a thermodynamically unfavorable reaction can be driven by a thermodynamically favorable
reaction to which it is coupled.

METABOLISM
 Just as commerce is facilitated by the use of a common currency, the commerce of the cell—metabolism—is facilitated by the use of a common energy currency, adenosine
triphosphate (ATP) .
 ATP, a highly accessible molecule, acts as the free-energy donor in most energy-requiring processes such as motion, active transport, or biosynthesis.

ATP



ATP is a nucleotide consisting of an adenine, a ribose, and a triphosphate unit
The active form of ATP is usually a complex of ATP with Mg 2+ or Mn 2+
In considering the role of
ATP as an energy carrier, focus on its triphosphate moiety.

ATP
 ATP is an energy-rich molecule because its triphosphate unit contains two phosphoanhydride
bonds, which are referred to as highenergy bonds.


ATP
A large amount of free energy is liberated when ATP is hydrolyzed to adenosine diphosphate (ADP) and orthophosphate (P i
) or when ATP is hydrolyzed to adenosine monophosphate (AMP) and pyrophosphate
(PP i
).
 ATP + H2O AMP + PPi
 ΔG = -10 kcal/mol
 ATP + H2O ADP + Pi
 ΔG = -7.3 kcal/mol

ATP
 The free energy liberated in the hydrolysis of
ATP is harnessed to drive reactions that require an input of free energy, such as muscle contraction

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In turn, ATP is formed from ADP and P i when fuel molecules are oxidized in chemotrophs or when light is trapped by phototrophs.
This ATP—ADP cycle is the fundamental mode of energy exchange in biological systems.

ATP

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Some biosynthetic reactions are driven by hydrolysis of nucleoside triphosphates that are analogous to ATP—namely, guanosine triphosphate (GTP), uridine triphosphate
(UTP), and cytidine triphosphate (CTP).
Although all of the nucleotide triphosphates are energetically equivalent, ATP is nonetheless the primary cellular energy carrier.

ATP


ATP hydrolysis makes possible an otherwise unfavorable reaction
Consider a chemical reaction that is thermodynamically unfavorable without an input of free energy, a situation common to many biosynthetic reactions:
A
ATP
A + ATP
B ΔG = + 4.0 kcal/mol
ADP + PPi ΔG = - 7.3 kcal/mol
B + ADP + Ppi ΔG = -3.3

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
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ATP
ATP acts as an energy-coupling agent.
Thus, 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.
The active transport of Na + and K + across membranes is driven by the phosphorylation of the sodium-potassium pump by ATP and its subsequent dephosphorylation

METABOLISM
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Phosphoryl transfer is a common means of energy coupling. Furthermore, it is also widely used in the intracellular transmission of information.
ATP and many prosphoryl containing molecule can be a phosphoryl donor, and thus, good energy producers upon hydrolysis

METABOLISM
 Consider the hydrolysis of glycerol-3-phosphate:
Glycerol-3-PO4 + H2O glycerol + Pi ΔG = -2.2
 Compare with hydrolysis of ATP:
ATP + H2O ADP + PPi ΔG = -7.3

METABOLISM
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The magnitude of ΔG° ′ for the hydrolysis of glycerol 3-phosphate is much smaller than that of ATP, which means that ATP has a stronger tendency to transfer its terminal phosphoryl group to water than does glycerol
3-phosphate .
In other words, ATP has a higher phosphoryl transfer potential (phosphoryl-group transfer
potential) than does glycerol 3-phosphate.

METABOLISM

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The standard free energies of hydrolysis, ΔG , provide a convenient means of comparing the phosphoryl transfer potential of phosphorylated compounds.
ATP is not the only compound with a high phosphoryl transfer potential. In fact, some compounds in biological systems have a higher phosphoryl transfer potential than that of ATP.

METABOLISM
 Some compounds in biological systems have a higher phosphoryl transfer potential than that of ATP:
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METABOLISM
 With the information given, it can be deduced that:
 PEP can transfer its phosphoryl group to ADP to form ATP
 ATP has a phosphoryl transfer potential that is intermediate among the biologically important phosphorylated molecules
 This intermediate position enables ATP to function efficiently as a carrier of phosphoryl groups

METABOLISM
 Creatine phosphate in vertebrate muscle serves as a reservoir of high-potential phosphoryl groups that can be readily transferred to ATP.
 Creatine phosphate is used to regenerate ATP from ADP every time we exercise strenuously.
This reaction is catalyzed by creatine kinase.
Creatinine-PO4 + ADP + H ATP + creatine

METABOLISM
REMEMBER!
 Creatine phosphate and ATP are abundant in muscle cells, Crea-Po4 > ATP in amount
 Crea-PO4 is the major source of phosphoryl groups for ATP regeneration for a runner during the first 4 seconds of a 100-meter sprint.
 After that, ATP must be generated through metabolism of CHO and fats

SUBSTRATE-LEVEL PHOSPHORYLATION
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The phosphorylation of ADP to form ATP, a good energy storage molecule, is a type of substrate-level phosphorylation
It is the direct transfer of phosphate group to
ADP from a higher energy containing molecule (e.g. Crea-PO4, PEP)
 This type of phosphorylation is present in
Glycolysis and Kreb’s cycle.

SUBSTRATE-LEVEL PHOSPHORYLATION
 Substrate-level phosphorylation is also seen in working skeletal muscles and the brain.
 Phosphocreatine is stored as a readily available high-energy phosphate supply
 The enzyme creatine phosphokinase transfers a phosphate from phosphocreatine to ADP to produce ATP.
 Then the ATP releases giving chemical energy.

 SUBSTRATE-LEVEL PHOSPHORYLATION