TOPIC 8.

1 METABOLISM, CELL RESPIRATION & PHOTOSYNTHESIS (AHL)

UNDERSTANDINGS
⦿ Metabolic pathways consist of chains and cycles of enzyme-catalyzed reactions
⦿ Enzymes lower the activation energy of the chemical reactions that they catalyze
⦿ Enzyme inhibitors can be competitive or non-competitive
⦿ Metabolic pathways can be controlled by end-product inhibition

APPLICATIONS & SKILLS

⦿ End-product inhibition of the pathway that converts threonine to isoleucine
⦿ Use of databases to identify potential new anti-malarial drugs
⦿ Calculating and plotting rates of reaction from raw experimental results
⦿ Distinguishing different types of inhibition from graphs at specified substrate
concentration

METABOLISM
The sum of the total reaction that occurs with an organism in order to maintain
life.
* Most chemical changes in cell = are a result from a series of reactions
(pathways)
* Each step is controlled by a specific enzyme.
* Metabolic pathways allow for a greater level of regulation as chemical change
is controlled by numerous intermediaries.
* Each step controlled by a specific enzyme
Typically organized into chains or cycles of enzyme catalyzed reactions.
metabolic pathways
* Chains: Glycolysis (in cell respiration), coagulation cascade (in blood
clotting)
* Cycles: Krebs cycle (in cell respiration), Calvin cycle (in photosynthesis)

ACTIVATION ENERGY: The energy all chemical reactions require a certain amount of
energy to proceed
* Enzymes lower the activation energy which speeds up the rate of biochemical
reactions.
* When an enzyme binds to a substrate = it stresses and destabilizes the bonds in
the substrate.
* This reduces the overall energy level of the substrate's transition state =
less energy is needed to convert it into a product and the reaction proceeds at a
faster rate.

TYPES OF ENZYMATIC REACTIONS

* If the reactants contain more energy than the products, the free energy is
released into the system (exergonic)
* These reactions are usually catabolic (breaking down), as energy is released
from broken bonds within a molecule= Degenerative
* If the reactants contain less energy than the products, free energy is lost to
the system (endergonic)
* These reactions are usually anabolic (building up), as energy is required to
synthesize bonds between molecules = Biosynthetic

END-PRODUCT INHIBITION
* End-product inhibition (or feedback inhibition) is a form of negative feedback by
which metabolic pathways can be controlled
* The final product in a series of reactions inhibits an enzyme from an earlier
step in the sequence and binds to an allosteric site and temporarily inactivates
the enzyme (via non-competitive inhibition)
* As the enzyme can no longer function, the reaction sequence is halted and
the rate of product formation is decreased
* End-product inhibition functions to ensure levels of an essential product are
always tightly regulated
* If product levels build up, the product inhibits the reaction pathway and
hence decreases the rate of further product formation
* If product levels drop, the reaction pathway will proceed unhindered and the
rate of product formation will increase

ENZYME KINETICS
* The rate of an enzyme-catalyzed reaction can be calculated and plotted
according to the time taken for the reaction to proceed (RATE OF REACTION)
* The time taken can be measured according to either the amount of product
formed or the amount of substrate consumed
* Reaction rate is the inverse of time taken, meaning that the reaction rate is
higher when less time is taken (and vice versa)
* Calculated: Rate of reaction (s–1) = 1 / time taken (s)

FACTORS AFFECTING ENZYME KINETICS

* Factors which can influence the rate of an enzyme-catalyzed reaction include
temperature, pH and substrate concentration

INHIBITION EFFECT ON ENZYME KINETICS

* Both inhibitors reduce the rate of reaction by limiting the amount of
uninhibited enzyme available for reaction
 * Enzyme inhibitors prevent the formation of an enzyme-substrate complex and
hence prevent the formation of product
* Can be reversible or irreversible depending on specific effect of the
inhibitor being used
* Competitive inhibitors bind directly to the active site and hence exist in
direct competition with the substrate. Maximum rate can be achieved if substrate
levels are high enough
* Non-competitive inhibitors bind to an allosteric site and hence do not exist
in direct competition with the substrate. Maximum rate cannot be achieved if
substrate levels are high enough

Competitive inhibition: binds to enzyme’s active site competitive inhibition

* Inhibitor is structurally and chemically similar to the substrate (hence
able to bind to the active site)
* The competitive inhibitor blocks the active site and thus prevents
substrate binding
* As the inhibitor is in competition with the substrate, its effects can be
reduced by increasing substrate concentration

Non-Competitive Inhibition:involves a molecule binding to a site other than the

active site (an allosteric site)
* Causes conformational changes to the enzyme's active site noncompetitive
inhibition
* the active site and substrate no longer share specificity, meaning the
substrate cannot bind
* As the inhibitor is not in direct competition with the substrate,
increasing substrate levels cannot mitigate the inhibitor’s effect

Examples of Inhibitors:
* Competitive: Treatment of Influenza via the neuraminidase inhibitor,
Relenza
* Virions are released from infected cells when the viral enzyme
neuraminidase cleaves a docking protein (haemagglutinin)
* Relenza competitively binds to the neuraminidase active site and
prevents the cleavage of the docking protein
* Consequently, virions are not released from infected cells, preventing
the spread of the influenza virus
* Non-Competitive: use of Cyanide as poison (prevents aerobic respiration)
* Cyanide is a poison which prevents ATP production via aerobic
respiration, leading to eventual death
* It binds to an allosteric site on cytochrome oxidase – a carrier
molecule that forms part of the electron transport chain
* By changing the shape of the active site, cytochrome oxidase can no
longer pass electrons to the final acceptor (oxygen)
* Consequently, the electron transport chain cannot continue to function
and ATP is not produced via aerobic respiration
INHIBITORS USED IN THERAPY AND DRUG DESIGN
* The maturation and development of the malaria parasite in both human and
mosquito host is coordinated by specific enzymes.
* By targeting these enzymes for inhibition, new anti-malarial drugs and
medications can be produced
* These enzymes may be screened against a bioinformatic database of
chemicals to identify potential enzyme inhibitors
* Once a promising compound is identified, it may be chemically modified
to improve its binding affinity and lower its toxicity
* An alternative method by which potential new antimalarial medications
can be synthesized is via rational drug design
* This involves using computer modeling techniques to invent a compound
that will function as an inhibi

End Product Inhibition:

•When the end-product is present in a sufficient quantity, the chain of reactions
is shut down
•Usually done by inhibiting the first enzyme of the chain
•As the existing end-product is used by the cell, the first enzyme is reactivated
•This first enzyme is usually an allosteric enzyme

Example:
E.coli produces isoleucine from threonine, using a metabolic pathway → 5-step
process → the culture of E.coli is given isoleucine → the first enzyme is
inactivated → the bacteria shut down the metabolic pathway
More on Enzyme Inhibition

* Sometimes genes are induced (“turn on” to be transcribed) only when

an enzyme product is required to catalyze reactions that may occur infrequently,
e.g. use of a particular substrate that is not always available.
* Other genes are being transcribed all the time because their enzyme
products are in constant demand, e.g. the genes coding for respiratory
Benefits of Feedback Inhibition
Preventing overproduction of the product being made. Feedback inhibition balances
production of product with the energy of the metabolic pathway.

Once enough of the product is made in high enough concentration, it inhibits the
pathway of its formation so that the cell doesn’t waste energy on creating a
product it already has enough of
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