Give an example of a metabolic reaction of a drug or endogenous substance for each of the following reaction types and determine the electrophile and nucleophile (10 points): S N 1 reaction Radical...

SN1 REACTION:
You probably know that ca
ohydrates, (also called oligosaccharides), are sugar polymers.
Cellulose, the tough, fi
ous material in plants, is one of the most abundant organic
compounds found in nature. It is basically a long chain of glucose molecules linked together:
The bonds connecting individual sugar units in ca
ohydrate chains are called glycosidic
onds, and enzymes that
eak them are called glycosidases. Humans do not have
glycosidases capable of
eaking the glycosidic bonds in cellulose - and thus we cannot use
cellulose a source of energy - but cellulose is nonetheless necessary to us as dietary fiber.
Cows and other ruminants are able to derive energy from cellulose because they maintain
acteria in their digestive tract which possess the proper glycosidase enzymes.
Starch, the ca
ohydrate that we eat in
ead and pasta, is also a long chain of glucose
molecules. However, the glycosidic bonds linking the individual glucose units in starch have
a different stereochemical configuration from those in cellulose, and humans do have the
proper glycosidase enzymes to digest starch. We will discuss ca
ohydrates again in chapter
11, and you will learn many more details if you take a course in biochemistry.
We focus now on the chemistry by which glycosidic bonds are
oken and formed. Enzymes
called glycosidases catalyze these reactions. Consider for example the following reaction,
catalyzed by a bacterial enzyme, in which the glycosidic bond between two glucose
molecules in cellulose is cleaved.
This is a hydrolysis reaction – recall that this term is used to describe any reaction where a
ond is being
oken by water. If you look carefully, you will recognize that this reaction is
simply a nucleophilic substitution at the ca
on indicated by the a
ow: water is the
nucleophile, and the leaving group is an alcohol, specifically the glucose molecule on the
ight side. In the next few figures, the leaving group will be refe
ed to as 'HO-R' for
simplicity.
(A quick note on hydrolysis reactions: we will see many more examples of hydrolysis
eactions throughout our study of organic chemistry. In eukaryotic cells, many hydrolysis
eactions occur in the acidic (pH ~4.5) environment of the lysosome, an organelle that
specializes in
eaking large molecules down into small ones.)
Evidence suggests that glycosidase reactions probably occur through an SN1 mechanism,
implying the formation of a short-lived cationic intermediate. Here is the first, rate-
determining step:
Notice that the positively charged ca
on on the intermediate is adjacent to an
oxygen. Recall from previous discussions (section 8.4B) that oxygen can act as a powerful
electron donating group because of the resonance effect of its lone pairs. This is best
illustrated by drawing a second resonance contributor, in which the positive charge is placed
on the oxygen. This intermediate is generally refe
ed to as an oxonium ion.
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ocation_stability
The active site of the enzyme has two aspartate residues, one positioned above the substrate
(Asp1) and one below (Asp2). The leaving group is protonated by Asp1: protonation, as you
ecall, creates a better leaving group.
Here is the second step of the glycosidase mechanism:
Notice that this substitution occurs with inversion of configuration:
This is because the leaving group remains bound in the active site after the formation of the
oxonium ion intermediate, and blocks the bottom side of the electrophilic ca
on from
attack. The water nucleophile, as it attacks from the bottom side, is deprotonated by Asp2.
Because the reaction results in inversion of configuration, the enzyme is called an inverting
glycosidase.
Researchers have also identified retaining glycosidases, which catalyze similar hydrolysis
eactions except with retention of configuration:
The active site architectures of the inverting and retaining glycosidases are actually very
similar: both have two aspartate residues positioned above and below the electrophilic
ca
on. The first step in the retaining mechanism is the same as in the inverting mechanism:
formation of the...