BCH2022

METABOLIC
BASIS OF
HUMAN
DISEASE
Lecture 1: Introduction to metabolism and
disease

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At the end of this lecture, students should
be able to:
• Define metabolism
• Predict if a reaction is an energy requiring or energy producing
one
• Discuss the concept of ATP as a currency of energy

References
Lehninger, Principles of Biochemistry by Nelson & Cox
• Physical Foundations: p 20 (6th edn) or p 21 (7th edn)
• Introduction to Bioenergetics and Metabolism: p 501 (6th edn) or p 491 (7th
edn)
• Bioenergetics and Biochemical Reaction Types: p 505 (6th edn) or p 495
(7th edn)
What is metabolism?
 What is metabolism?
• Highly coordinated, enzyme catalyzed chemical reactions that
occur sequentially.
• Metabolic pathways are;
– Anabolic; uses energy to synthesise larger molecules
– Catabolic; breaks down larger molecules via oxidative
pathways to produce energy (energy rich molecules)
– Amphibolic; links anabolic and catabolic pathways
Understanding of metabolism is essential because……

• Knowledge of normal metabolism is

essential for us to understand
abnormalities that underlie disease.
• Normal metabolism includes adaptation to
fasting, starvation, exercise, pregnancy
and lactation
• Abnormal metabolism can result from
nutritional deficiency, enzyme
defect/deficiency, abnormal secretion of
hormones, action of drugs and toxins
Energy production is central to metabolism
 Why do nerve and muscle cells need
energy?
• Synthetic work = building macromolecules
• (e.g., Making protein)

• Mechanical work = moving molecules past each other

• (e.g., Muscle shortening)

• Concentration work = creating chemical gradients

• (e.g., Storing glucose)

• Electrical work = creating ion gradients

• (e.g., Unequal distribution of sodium and potassium ions)

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 What is energy?

• Energy is the capacity to do work.

• Potential energy is the energy of state or position (energy stored in

chemical bonds, concentration gradients and electrical potentials).

• Kinetic energy is the energy of motion (heat, mechanical, electrical).

 Potential versus kinetic energy
Potential energy can be converted to kinetic energy, which does work.

The potential energy of a chemical system is called “Gibbs-free energy” (G)

or the amount of energy capable of doing work during a reaction (constant
temperature and pressure)

G
 The Gibb’s free energy change (ΔG)
∆G is a measure of the energy change in a biological reaction

For living systems at constant temperature & pressure

∆G = ∆H - T∆S
where ∆G = change in free energy of a reacting system
(Gibb’s free energy)
∆H = change in heat content of reacting system (enthalpy)
T = absolute temperature
∆S = change in entropy of reacting system (randomness)

• For breakdown reactions: ∆G -ve

• For biosynthetic reactions: ∆G +ve
Free Energy Changes

∆G = -ve
Stored energy is released
Catabolic

∆G = +ve
Utilises energy
Anabolic
Free Energy Determines the Spontaneity of
Processes

TABLE 13-3 Relationships among K'eq, ∆G'˚, and the Direction of Chemical
Reactions
Starting with all components at 1 M, the
When K'eq is . . . ∆G'˚ is . . . reaction . . .
>1.0 negative proceeds forward
1.0 zero is at equilibrium
<1.0 positive proceeds in reverse
Energy Coupling
• Chemical coupling of exergonic and endergonic reactions
allows otherwise unfavorable reactions.
• The “high-energy” molecule (ATP) reacts directly with
the metabolite that needs “activation.”
 Exergonic reactions can be used to
drive endergonic reactions
A strongly exergonic reaction will readily proceed forward.
An endergonic reaction can proceed only if coupled with an
exergonic reaction.

Example of a coupled reaction:

Glucose + Pi Glucose-6-phosphate ∆G +ve (endergonic).

ATP ADP + Pi ∆G -ve (VERY exergonic).

Overall:

Glucose + ATP Glucose-6-phosphate + ADP ∆G -ve (exergonic).

 Energy Coupling via ATP Hydrolysis
Consider the synthesis of Glucose-6-phosphate (also the first step in glucose utilization):
glucose + Pi ⇒ glucose-6-phosphate + H2O (∆G0 = 13.8kJ/mol)

The hydrolysis of ATP:

ATP + H2O ⇒ ADP + Pi + H+ (∆G0 = -30.5kJ/mol)

These two reactions share the common intermediates: Pi & H20 and can be written
sequentially:
(1) glucose + Pi ⇒ glucose-6-phosphate + H2O
(2) ATP + H2O ⇒ ADP + Pi + H+ YOU ARE NOT
__________________________________________ EXPECTED TO
REMEMBER THESE
glucose + ATP ⇒ glucose-6-phosphate + ADP
REACTIONS!
∆G0SUM = 13.8 + (-30.5) = -16.7kJ/mol

Overall an EXERGONIC reaction, because energy in the bonds of ATP is used to drive G-6-P
synthesis whose formation from Pi is ENDERGONIC
 TABLE 13-4 Standard Free-Energy Changes of Some Chemical Reactions
YOU ARE NOT ∆G'˚
EXPECTED TO Reaction type (kJ/mol) (kcal/mol)
REMEMBER Hydrolysis reactions
THESE VALUES! Acid anhydrides
Acetic anhydride + H2O 2 acetate –91.1 –21.8
ATP + H2O ADP + Pi –30.5 –7.3
ATP + H2O AMP + PPi –45.6 –10.9
PPi + H2O 2Pi –19.2 –4.6
UDP-glucose + H2O UMP + glucose 1-phosphate –43.0 –10.3
Esters
Ethyl acetate + H2O ethanol + acetate –19.6 –4.7
Glucose 6-phosphate + H2O glucose + Pi –13.8 –3.3
Amides and peptides
Glutamine + H2O glutamate 1 NH4+ –14.2 –3.4
Glycylglycine + H2O 2 glycine –9.2 –2.2
Glycosides
Maltose + H2O 2 glucose –15.5 –3.7
Lactose + H2O glucose + galactose –15.9 –3.8
Rearrangements
Glucose 1-phosphate glucose 6-phosphate –7.3 –1.7
Fructose 6-phosphate glucose 6-phosphate –1.7 –0.4
Elimination of water
Malate fumarate + H2O 3.1 0.8
Oxidations with molecular oxygen
Glucose + 6O2 6CO2 + 6H2O –2,840 –686
Palmitate + 23O2 16CO2 + 16H2O –9,770 –2,338
 ATP plays a central role in energy cycling

+
Stored ATP is used
chemical in energy
energy is requiring
released in reactions
catabolic like muscle
reactions to movement
make ATP

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 The Biochemistry of ATP
YOU ARE NOT
EXPECTED TO
REMEMBER THESE
STRUCTURES!

Fig 13.11
 The Biochemistry of ATP

Main reason for high -ve ΔG0

At pH 7, molecule has 4 negative

charges which are closely spaced
electro-repulsive strain relieved
by hydrolysis to ADP + Pi
How is ATP generated?

• ATP is formed through metabolic pathways.

• In metabolic pathways, the product of one
reaction is a reactant for the next.
• Each reaction is catalyzed by an enzyme.

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Energy Coupling; Catabolism and Anabolism
Functional organisation of metabolic pathways :

1. Catabolism – break down of organic nutrients into simple end

products in order to extract useful energy

2. Anabolism – energy dependent conversion of small precursor

molecules into more complex molecules.

ATP is the intermediate coupling the catabolism and

anabolism

Require: enzymes
 BCH2011
What are enzymes?

• Enzymes (usually proteins) are biological catalysts,

highly specific for their substrates (reactants).
• Enzymes change reactants into products through
transition state intermediates.
• Enzymes are not consumed in the reaction.

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 BCH2011
Enzymes as Catalysts

• Enzymes “speed up”

reactions by lowering the
“activation energy” of a
reaction.
• Enzymes DO NOT
change the overall
energy released in a
reaction.

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