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biochem lec 05-05 proteins enzymes part 1

ds
von dawn S.

C. The Active Site

- cleft or crevice in the enzyme formed by one or more regions of the polypeptide chain

- cofactors and functional groups from the polypeptide chain participate in transforming the bound

substrate molecules into products


- substrate molecules bind to their substrate binding sites (substrate recognition sites)

- the three-dimensional arrangement of binding sites in a crevice of the enzyme allows the reacting

portions of the substrates to approach each other from the appropriate angles

- proximity of the bound substrate molecules and their precise orientation toward each other contribute to

the catalytic power of the enzyme


- active site also contains functional groups that directly participate in the reaction

- functional groups are donated by the polypeptide chain or by bound cofactors (metals or complex

organic molecules called coenzymes)

- as the substrate binds, it induces conformational changes in the enzyme that promote further interactions

between the substrate molecules and the enzyme functional groups

- ex: coenzyme might form a covalent intermediate with the substrate, or an amino acid side

chain might abstract a proton from the reacting substrate

- activated substrates and the enzyme form a transition state complex, an unstable high-energy complex

with a strained electronic configuration that is intermediate between substrate and product

- additional bonds with the enzyme stabilize the transition state complex and decrease the energy required for its formation


- free enzyme then binds another set of substrates and repeats the process



The Transition State Complex

1. Energy Changes Occurring During the Reaction

a. Free Energy of Activation

- energy barrier separating the reactants and the products

- energy difference between that of the reactants and a high-energy intermediate that

occurs during the formation of a product

- difference in energy between the substrate and the transition state complex

b. Transition State

- condition in which bonds in the substrate are maximally strained in some enzyme-

catalyzed reactions

- electronic configuration of the substrate becomes very strained and unstable as it

enters the transition state in other enzyme-catalyzed reactions

c. Transition State Theory

- the reactants of a reaction pass through a short-lived high-energy state that is

structurally intermediate to the reactants and products

- overall rate of the reaction is determined by the number of molecules acquiring the

activation energy (energized molecules) necessary to form the transition state

complex

- for molecules to react, they must contain sufficient energy to overcome the energy

barrier of the transition state (large activation energy  slow rates of

uncatalyzed chemical reactions)

- the lower the free energy of activation  more molecules have sufficient energy to pass

over the transition state  faster rate of reaction

d. Alternate Reaction Pathway

i. Enzymes

- increase the rate of the reaction by decreasing the activation energy (provides

a pathway with a lower free energy of activation)

- does not change the free energies of the reactants or products

- does not change the equilibrium of the reaction

In humans, most of ingested ethanol is oxidized to acetaldehyde

in the liver by alcohol dehydrogenase (ADH):

Ethanol + NAD+

 Acetaldehyde + NADH + H+

ADH - active as a dimer

- active site containing zinc present in each subunit

Humans have at least seven genes that encode isozymes of

ADH, each with a slightly different range of

specificities for the alcohols it oxidizes

Acetaldehyde

- highly reactive, toxic, and immunogenic

- responsible for much of the liver injury associated

with chronic alcoholism


A patient was admitted to the hospital after intravenous

thiamine was initiated at a dose of 100 mg/day

(compared with an RDA of 1.4 mg/day). His congestive

heart failure was believed to be the result, in part, of the

cardiomyopathy (heart muscle dysfunction) of acute

thiamine deficiency known as beriberi heart disease.

This nutritional cardiac disorder and the peripheral

nerve dysfunction usually respond to thiamine

replacement. However, an alcoholic cardiomyopathy

can also occur in well-nourished patients with adequate

thiamine levels. Exactly how ethanol, or its toxic

metabolite acetaldehyde, causes alcoholic

cardiomyopathy in the absence of thiamine deficiency is

unknown.

At low concentrations of ethanol, liver alcohol

dehydrogenase is the major route of ethanol

oxidation to acetaldehyde, a highly toxic

chemical. Acetaldehyde not only damages the

liver, it can enter the blood and potentially

damage the heart and other tissues. At low

ethanol intakes, much of the acetaldehyde

produced is safely oxidized to acetate in the

liver by acetaldehyde dehydrogenases.

Author

dawn S.

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