Malathion

An Organophosphate

Alan YanahanCPSC 270, 2009

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

Schradan

Dimefox

Parathion

TEPP

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 vertebratetoxicity

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?

Ca2+

Ca2+

Ca2+

Na+Na+

Na+

Axon of pre-synaptic cell receives action potential and voltage gated Ca2+ channel opens

Calcium ions (Ca2+) enter axon

Voltage gated Ca2+ channel closes

Vesicle releases acetylcholine (neurotransmitter) into nerve synapse

Acetylcholine

Vesicle

Acetylcholine binds with receptor (nicotinic acetylcholine receptor)

Nicotinic acetylcholine receptor opens

Sodium ions (Na+) enter the dendrite and cause an action potential in post-synaptic cell

Acetylcholine is released from nicotinic acetylcholine receptor

Nicotinic acetylcholine receptor closes

Acetylcholine binds with the enzyme acetylcholinesterase

Choline is released

Acetate is released

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

H3C O

O

N+ CH3

CH3H

3C

Acetylcholine

Serine

Anionic Site-

ONH

O–

R2R1

H3C O

O–

N+ CH3

CH3H

3C

ONH

O

R2R1

-

O

HH

HON+ CH

3

CH3H

3C

Choline

-

-

H3C

O

ONH

O

R2R1

O–

HH3C

O–

ONH

O

R2R1

O HH

H

-

O

HHH3C

O

OH

O

NH

OH

R2R1

Acetate

O–

H- - --

Anionic SiteSerine

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?

Ca2+

Ca2+

Ca2+

Na+Na+

Na+

Acetylcholine is released from nicotinic acetylcholine receptor

Nicotinic acetylcholine receptor closes

This time, malathion binds with acetylcholinesterase

Only a portion of the malathion molecule is released from acetylcholinesterase

The rest of the molecule remains bound to acetylcholinesterase making it unable to function properly

Acetylcholine is no longer broken down, so it is free to bind again and again with its receptor to cause multiple action potentials

Malathion

Reaction Mechanism

Serine

-

ONH

O–

R2R1

-

P

SO

O

H3C

H3C

S

O CH3O

O CH3O

Malathion

-

P

S–

O

O

H3C

H3C

S

O CH3O

O CH3O

NH

R2R1

O

O

Anionic Site-

Anionic Site

S

O CH3O

O CH3O

H

O

H H

P

SO

O

H3C

H3C

NH

R2R1

O

O O–

H--

Anionic Site

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.