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ENZYME INHIBITION

2008 Paul Billiet ODWS

Inhibitors

Inhibitors are chemicals that reduce the rate of enzymic reactions The are usually specific and they work at low concentrations They block the enzyme but they do not usually destroy it Many drugs and poisons are inhibitors of enzymes in the nervous system

2008 Paul Billiet ODWS

The effect of enzyme inhibition


Irreversible inhibitors: Combine with the functional groups of the amino acids in the active site, irreversibly Examples: nerve gases and pesticides, containing organophosphorus, combine with serine residues in the enzyme acetylcholine esterase

2008 Paul Billiet ODWS

The effect of enzyme inhibition


Reversible inhibitors: These can be washed out of the solution of enzyme by dialysis. There are two categories

2008 Paul Billiet ODWS

The effect of enzyme inhibition


1. Competitive: These compete with the substrate molecules for the active site The inhibitors action is proportional to its concentration Resembles the substrates structure closely
2008 Paul Billiet ODWS

E+I Reversible reaction

EI Enzyme inhibitor complex

The effect of enzyme inhibition


Succinate Fumarate + 2H++ 2e-

Succinate dehydrogenase
CH2COOH CH2 CH2COOH COOH Malonate
2008 Paul Billiet ODWS

COOH

CHCOOH

CHCOOH

The effect of enzyme inhibition


2. Non-competitive: These are not influenced by the concentration of the substrate. It inhibits by binding irreversibly to the enzyme but not at the active site Examples Cyanide combines with the Iron in the enzymes cytochrome oxidase Heavy metals, Ag or Hg, combine with SH groups. These can be removed by using a chelating agent such as EDTA
2008 Paul Billiet ODWS

Applications of inhibitors

Negative feedback: end point or end product inhibition Poisons snake bite, plant alkaloids and nerve gases Medicine antibiotics, sulphonamides, sedatives and stimulants

2008 Paul Billiet ODWS

Enzyme pathways
Cell processes (e.g. respiration or photosynthesis) consist of series of pathways controlled by enzymes eA
eB eC eD eF

Each step is controlled by a different enzyme (eA, eB, eC etc) This is possible because of enzyme specificity

2008 Paul Billiet ODWS

End point inhibition


The first step (controlled by eA) is often controlled by the end product (F) Therefore negative feedback is possible A
eA

eB

eC

eD

eF

Inhibition

The end products are controlling their own rate of production There is no build up of intermediates (B, C, D and E)

2008 Paul Billiet ODWS

Example: Phosphofructokinase and ATP


Substrate: Fructose-6-phosphate Reaction
phosphofructokinase

fructose-6-phosphate + ATP fructose-1,6-bisphosphate + ADP

2008 Paul Billiet ODWS

ATP is the end point

This reaction lies near the beginning of the respiration pathway in cells The end product of respiration is ATP If there is a lot of ATP in the cell this enzyme is inhibited Respiration slows down and less ATP is produced As ATP is used up the inhibition stops and the reaction speeds up again

2008 Paul Billiet ODWS

The switch: Allosteric inhibition


Allosteric means other site
Active site E Allosteric site

2008 Paul Billiet ODWS

Switching off

These enzymes have two receptor sites One site fits the substrate like other enzymes The other site fits an inhibitor molecule

Substrate cannot fit into the active site

Inhibitor molecule

Inhibitor fits into allosteric site

2008 Paul Billiet ODWS

The allosteric site the enzyme onoff switch


Active site Substrate fits into the active site E Allosteric site empty

Conformational change
Substrate cannot fit into the active site

Inhibitor molecule is present


Inhibitor fits into allosteric site

The inhibitor molecule is absent

2008 Paul Billiet ODWS

A change in shape

When the inhibitor is present it fits into its site and there is a conformational change in the enzyme molecule The enzymes molecular shape changes The active site of the substrate changes The substrate cannot bind with the substrate

2008 Paul Billiet ODWS

Negative feedback is achieved

The reaction slows down This is not competitive inhibition but it is reversible When the inhibitor concentration diminishes the enzymes conformation changes back to its active form

2008 Paul Billiet ODWS

Phosphofructokinase

This enzyme an active site for fructose-6-phosphate molecules to bind with another phosphate group It has an allosteric site for ATP molecules, the inhibitor When the cell consumes a lot of ATP the level of ATP in the cell falls No ATP binds to the allosteric site of phosphofructokinase The enzymes conformation (shape) changes and the active site accepts substrate molecules

2008 Paul Billiet ODWS

Phosphofructokinase

The respiration pathway accelerates and ATP (the final product) builds up in the cell As the ATP increases, more and more ATP fits into the allosteric site of the phosphofructokinase molecules The enzymes conformation changes again and stops accepting substrate molecules in the active site Respiration slows down

2008 Paul Billiet ODWS

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