Alan Yanahan CPSC 270, 2009 Malathion An Organophosphate

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

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

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

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

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

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

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

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

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

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

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

What Does This Look Like?

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)

Reaction of Acetylcholine with Acetylcholinesterase

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

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

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

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

What Does This Look Like?

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+

Reaction Mechanism Malathion - - - - Anionic Site Anionic Site Serine

Sources Johnson, G., Moore, S.W. Current Pharmaceutical Design. 2006, vol. 12, number 2, pages 217-225. 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.