Enzymes: How can antibodies be used to treat cocaine overdoses?
What cocaine?
Proteins are chains of aminoisacids
• An alkaloid metabolite found in the leaves of Erythroxylon coca
• Blocks removal of dopamine from synapses in the reward pathway of the central nervous system
BiolSci 210‐B | 1/28/13 | 2
Cocaine is of amino our bodies by hydrolysis
Proteins are chains degraded inacids
Hydrolysis of cocaine yields two biologically inactive products
+H2O
BiolSci 210‐B | 1/28/13 | 3
(Bio)chemical reactions progress through transition states (TS)
Proteins are chains of amino acids
BiolSci 210‐B | 1/28/13 | 4
Transition chains of amino acids
Proteins are states are often different from reactant and products
How is cocaine different from its transition state in hydrolysis?
Transition state analog (TSA)
BiolSci 210‐B | 1/28/13 | 5
Proteins are chains ofWhat are acids amino antibodies?
• Antibody (Ab) is a large Y‐shaped protein produced by B‐cells that is used by the immune system to identify and neutralize foreign objects
• Antibody recognizes a unique part of the foreign target, called an antigen
Is this a tertiary or quaternary structure?
BiolSci 210‐B | 1/28/13 | 6
Production of chains of amino acids
Proteins areantibodies can be induced by injection of specific antigens
immunize with antigen
obtain antibody specific for antigen
BiolSci 210‐B | 1/28/13 | 7
Discussion: How do antibodies help
Proteins are chains of amino acidsprevent cocaine overdose?
immunize with cocaine
challenge with excess cocaine
dies from overdose
immunize with cocaine
TSA
challenge with excess cocaine
survives
5 min
BiolSci 210‐B | 1/28/13 | 8
Stabilization of transition state leads
Proteins are chains of amino acids to lower activation energy
BiolSci 210‐B | 1/28/13 | 9
Enzymes catalyzes reactions by binding to and stabilizing TS
Proteins are chains of amino acids
BiolSci 210‐B | 1/28/13 | 10
Enzymes are highly specific
Proteins are chains of amino acids catalysts
Enzyme = a protein (or RNA) that catalyzes a specific chemical reaction
Catalyst = enhances reaction rate without being consumed in the reaction
BiolSci 210‐B | 1/28/13 | 11
Proteins are chainsMost drugs inhibit enzymes of amino acids
FDA orange book
• 1278 chemical entities approved for therapeutic use in the US
317 drugs act as enzyme inhibitors
78 target enzymes human 48 bacterial 13 viral 5 fungal 4 protozoal 1
http://www.fda.gov/cder/orange/obreadme.htm
When the first print edition of Approved Drug Products with
Therapeutic Equivalence
Evaluations was being prepared
October 1980, staff members had to choose a color for the cover. The project manager suggested, “It's almost
Halloween. How about orange?”
BiolSci 210‐B | 1/28/13 | 12
Enzyme inhibitors are among
Proteins are chains of amino acids the top 20 drugs
Prescribed
1. Lipitor
2. Zocor
6. Nexium
11. Celebrex
17. Pravachol
20. Prevacid
~30% of approved drugs are enzyme inhibitors
Understanding principles of enzyme inhibition has practical consequences
BiolSci 210‐B | 1/28/13 | 13
HIV of amino acids
Proteins are chains maturation requires proteases
HIV proteins are made as polyproteins, which are then processed by HIV protease to form individual, functional proteins
BiolSci 210‐B | 1/28/13 | 14
ProteinsDiscussion: How do HIV protease inhibitors function? are chains of amino acids
5 min
Indinavir
