1. Metabolism
8.1

2. Essential Idea: Metabolic reactions are regulated in response
to the cell’s need.
8.1
Metabolism
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:
End-product inhibition of the pathway that coverts threonine to isoleucine
Use of databases to identify potential new anti-malarial drugs
Skills:
Calculate and plot rates of reaction from raw experimental results
Distinguish different types of inhibition from graphs at specified substrate concentration

3. Metabolism overview
Metabolism is the sum total of all reactions that occur within an organism in order to maintain life.

4. Metabolic pathways
Building/breaking down large molecules usually requires more than one reaction
Each reaction is catalyzed by an enzyme
Metabolic pathways allow for a greater level of regulation, as the chemical change is controlled by numerous intermediates

5. Metabolic pathways Can be chains or cycles of reactions
Examples of a chain: Glycolysis (in cellular respiration),
Examples of cycles: Krebs cycles (in cellular respiration), Calvin cycle (in photosynthesis)

6. Challenge!!!!
Change ONE letter at a time to get from “TREAD” to “BLINK”
All intermediate words must be REAL English words.
TREAD
_______
________
BLINK
BREAD
BREED
BLEED
BLEND
BLIND

7. Challenge!!!! TREAD BREAD BREED BLEED BLEND BLIND BLINK BREAD BREED

8. Induced fit model – enzyme undergoes change in conformation as it interacts with substrate
Still requires proper shape of enzyme and substrate

9. Remember: Enzymes work by lowering activation energy (AE)
AE is the energy required to destabilize existing bonds

10. Mechanism of enzyme action
Enzyme changes shape to fit substrate and enzyme-substrate complex forms
AE is lowered, atoms are rearranged, product is released
Surface of substrate Contacts active site
E + S  ES  E + P

11. Energy in Reactions
Exergonic reaction – energy is released to the organism because reactants contain more energy than products (usually catabolic)
Endergonic reaction – energy is absorbed from the organism because reactants have less energy than products (usually anabolic)

12. Inhibition
Competitive Inhibitors – a molecule binds into the active site, blocking access to the substrate -Can be reversible or irreversible -If reversible, can be overcome by increasing substrate concentration

13. Example of Competitive Inhibition: Alcoholism
Antabuse (disulfiram) competes with the aldehyde oxidase and prevents the acetaldehyde from being converted to acetic acid.
A build of acetaldehyde follows, resulting in a strong feeling a nausea and other strong hangover symptoms – a general deterrent to drinking.
Antabuse is administered as a daily pill, so its efficacy relies on the patients own motivation – if they stop taking it, they can drink again.

14. Non-competitive Inhibitors – bind elsewhere on enzyme and forces change in shape of active site -Also called allosteric inhibition -Can be reversible or irreversible

15. Examples of Non-competitive Inhibition: Cyanide
Cyanide is a poison which prevents ATP production via aerobic respiration, leading to eventual death.
It binds to an allosteric site of cytochrome oxidase – a carrier molecule that forms parts 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.

17. Think Time!!! Discuss with a partner.
What is the difference between competitive and non- competitive inhibition.
Person A – competitive
Person B – non-competitive

18. End-Product Inhibition -Used to regulate metabolic pathways -Final product acts as an allosteric (non- competitive) inhibitor to the first enzyme in the series

19. Example of End-Product inhibition: Threonine  Isoleucine Pathway
Isoleucine is an essential amino acid, meaning it is not synthesized by the body in humans (and hence must be ingested)
Food sources rich in isoleucine include eggs, seaweed, fish, cheese, chicken and lamb.
In plants and bacteria, isoleucine may be synthesized from threonine in a five-step reaction pathway.
In the first step of this process, threonine is converted into an intermediate compound by an enzyme (threonine deaminase).
Isoleucine can bind to an allosteric site on this enzyme and function as a non-competitive inhibitor.

20. As excess production of isoleucine inhibits further synthesis, it functions as an example of end-product inhibition.
This feedback inhibition ensures that isoleucine production does not cannibalize available stocks of threonine.

21. Rate of reactions
The rate of an enzyme-catalyzed reaction can be calculated and plotted according to the time taken for the reaction to proceed.
The time can be measured according to either the amount of product formed or the amount of substrate consumed.
Reaction rate is the inverse of time, meaning that the reaction rate is higher when less time is taken (and vice versa)
The rate of reaction can be calculated according to the following formula:
Rate of reaction (s-1) = 1/time taken (s)

23. Anti-Malarial Drugs
Malaria is a disease caused by parasitic protozoans of the genus; Plasmodium

24. Scientists have sequenced the genome of infectious species of Plasmodium and used it to determine the parasite’s proteome.
From the proteome, enzymes involved in parasitic metabolism have been identified as potential targets for inhibition.
These enzymes may be screened against a bioinformatics 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.
In one particular study, over 300,000 chemicals were screened to identify 19 new chemicals that might function as inhibitors.

25. An alternative method by which potential new anti-malarial medications can be synthesized is via rational drug design.
Involves using computer modelling techniques to invent a compound that will function as an inhibitor.
Using combinatorial chemistry, a compound is synthesized that is complementary to the active site of the target enzyme.

27. Brainstorm
As a group, brainstorm at least one question you would like answered or clarified.