1. Alan Yanahan
CPSC 270, 2009
Malathion
An Organophosphate

2. History
1820s: investigations into organophosphate (OP) chemistry began
Early 1900s: several OP compounds synthesized
1930s: toxicity of OPs becoming recognized
1940s: insecticidal action observed by Germany during WWII

3. Organophosphates and Germany
Group led by Gerhard Schrader
searching for substitutes to
nicotine as an insecticide
Nicotine in short supply during WWII
Developed a number of incredibly toxic nerve agents
Sarin
Soman
Tabun

4. Organophosphates and Germany
Schrader’s group also created some of the first commercial OP insecticides
TEPP
Dimefox
Schradan
Parathion

5. After WWII Schrader’s research records were captured by Allied forces
Led to massive increase in interest in OP insecticides
Early OPs
very effective against insects
Much more toxic to vertebrates than organochlorine insecticides
Nonpersistent and chemically unstable

6. Malathion First produced by American Cyanamid in 1950 Very safe
due to its
low vertebrate
toxicity
Used on
most fruits,
vegetables and
forage crops
Works on a wide range of insect pests

7. Malathion and the Mediterranean Fruit Fly
The Mediterranean fruit fly (Medfly) is an invasive pest species from the Mediterranean area
Detrimental to many fruit crops including citrus
Appeared in Los Angeles and parts of Florida and Texas on multiple occasions
Outbreaks eradicated each time

8. Malathion and the Mediterranean Fruit Fly
Malathion used in the eradication programs
Mixed with a bait of molasses and yeast
Sprayed from helicopters over the infested and surrounding areas
Both male and female medflies that are drawn to the bait feed on the insecticide and die

9. How Does Malathion Work?
Have to understand the nervous system first

10. The Nervous System
Nerve cells transmit messages from one another by means of electrical impulses (action potentials)
The axon carries the message away from one nerve cell to the dendrites of another nerve cell

11. The Nervous System
Between the axon and dendrite is a gap referred to as the synapse
In order for the electrical message to cross the synapse, it must be converted into a chemical message

12. The Nervous System
When an electrical impulse reaches the end of an axon, it leads to the release of chemicals called neurotransmitters
These neurotransmitters bind with receptors on the dendrites of neighboring nerve cells to cause the generation of another electrical impulse
Enzymes break down neurotransmitters to prevent nerve cells from repeatedly firing

13. What Does This Look Like?

14. Vesicle releases acetylcholine (neurotransmitter) into nerve synapse
Acetylcholine binds with the enzyme acetylcholinesterase
Axon of pre-synaptic cell receives action potential and voltage gated Ca2+ channel opens
Voltage gated Ca2+ channel closes
Acetylcholine
Vesicle
Na+
Na+
Choline is released
Ca2+
Acetylcholine is released from nicotinic acetylcholine receptor
Calcium ions (Ca2+) enter axon
Nicotinic acetylcholine receptor opens
Na+
Ca2+
Ca2+
Acetate is released
Nicotinic acetylcholine receptor closes
Sodium ions (Na+) enter the dendrite and cause an action potential in post-synaptic cell
Acetylcholine binds with receptor (nicotinic acetylcholine receptor)

15. Reaction of Acetylcholine with Acetylcholinesterase

16. Acetylcholinesterase
The job of acetylcholinesterase is to break down acetylcholine into choline and acetate
This prevents the generation of multiple, unnecessary action potentials in post-synaptic cells
It contains an active site
This is where acetylcholine binds
Consists of two regions

17. The Active Site of Acetylcholinesterase
An esteratic site
The amino acid serine
An anionic site
The amino acids Tyrosine (3 of them), Aspartic Acid, and Tryptophan
Serine
Tyrosine
Aspartic Acid
Tryptophan

18. Reaction Mechanism Acetylcholine - - - Anionic Site Serine - Choline -
Acetate - - - -
Anionic Site
Serine

19. When Malathion is Present in the Synapse
Malathion mimics the molecular shape of acetylcholine
Acetylcholinesterase tries to cleave it, but a portion of the malathion molecule remains bound to the protein
Acetylcholine can no longer be broken down so nerves continue to fire
Leads to tremors, convulsions, paralysis, and death in insects

20. What Does This Look Like?

21. This time, malathion binds with acetylcholinesterase
The rest of the molecule remains bound to acetylcholinesterase making it unable to function properly
Ca2+
Ca2+
Ca2+
Acetylcholine is no longer broken down, so it is free to bind again and again with its receptor to cause multiple action potentials
Malathion
Acetylcholine is released from nicotinic acetylcholine receptor
Only a portion of the malathion molecule is released from acetylcholinesterase
Nicotinic acetylcholine receptor closes
Na+
Na+
Na+

22. Reaction Mechanism Malathion - - - - Anionic Site Anionic Site Serine

23. Sources
Johnson, G., Moore, S.W. Current Pharmaceutical Design. 2006, vol. 12, number 2, pages
Kreiger, Robert I. Handbook of Pesticide Toxicology 2nd Edition: Agents. Chambers, Howard W., Boone, J. Scott, Carr, Russell L., Chambers, Janice E. Chapter 44—Chemistry of Organophosphorous Insecticides. San Diego: Academic Press, 2001.
Silverthorn, Dee Unglaub. Human Physiology An Integrated Approach 4th Edition. San Francisco: Pearson Education Inc., 2007.
Ware W., George. Pesticides Theory and Application. New York: W.H. Freeman and Company, 1978.