Patrick, An Introduction to Medicinal Chemistry 4e
Chapter 2 – Proteins: structure and function
Answers to end-of-chapter questions
1)
Ph
O
H2N
Me
N
H
O
H
N
OH
O
2) Glycine is the only amino acid with no side chain and is the only naturally
occurring amino acid that is not asymmetric.
3) Possible interactions are shown below for the side chains of serine, phenylalanine,
glycine, lysine and aspartic acid (HBA= hydrogen bond acceptor; HBD = hydrogen
bond donor; vdw = van der Waals interactions)
Serine
H2N
H
Glycine
Phenylalanine
CO2H
R
R=
Amino acid
structure
H
O HBA
H
HBD
vdw
Lysine
No side
chain
Aspartate
Aspartic acid
HBA
O
R=
HBA
H
HBD
N
ionic
H
HBD
N
HBDH H H
HBD
HBD
O
HBA
H
HBD
HBA
O
ionic
4) If a sequence of amino acids with hydrophobic side chains can be identified in the
primary structure, it is possible that this is a transmembrane (TM) region of the
protein (i.e it is located within the cell membrane as shown below) This is because
hydrophobic side chains would interact more favourably with the fatty cell membane
than with the aqueous environments on either side of the cell membane. Regions of the
protein that are made up predominantly of polar side chains are almost certainly
located intracellularly or extracellularly.
However, it would be wrong to conclude that all amino acids with hydrophobic side
chains are located in transmembrane regions and all amino acids with polar side chains
are located intracellularly or extracellularly.
OXFORD H i g h e r E d u c a t i o n
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O
HBA
Patrick, An Introduction to Medicinal Chemistry 4e
Chapter 2 – Proteins: structure and function
H2N
Extracellular
loop
CO2H
TM1 TM2
TM3
Cell
membrane
TM4
Intracellular
loop
Intracellular
loop
5)
The structure of L-alanyl-L-valine is shown below.
H2N
H
O
N
CH3
H
H
CO2H
An attempt to couple alanine directly to valine may well produce the desired product
but a whole range of other structures will also be formed.
H2N
H
CO2H
CH3
H2N
H
CO2H
+
H3C
CH3
H2N
H
O
N
CH3
H
H
CO2H
+ many other peptides
For example, L-valyl-L-alanine is an equally likely product. There is also nothing to
stop alanine coupling with itself, or valine coupling with itself to form L-alanyl-Lalanine and L-valyl-L-valine respectively.
Furthermore, there is no reason why any of the above dipetides that are formed could
not undergo a further coupling reaction to form tripeptides, tetrapeptides etc.
The reaction is also likely to need forcing conditions since one is attempting to form
an amide between an amine and a carboxylic acid which are more likely to form a salt
at room temperature. Forcing conditions are likely to result in racemisation of
asymmetric centres.
Due to these problems, it is necessary to protect the amino group of one amino acid
and the carboxylic acid of the other before a coupling reaction is attempted. It is also
important to have coupling reagents (e.g. dicyclohexylcarbodiimide) in order to achieve
milder, non-racemising conditions.
6) The functional groups involved are alcohols and phenols. Both of these functional
groups can form hydrogen bonds. When the groups are phosphorylated, the
phosphate groups are ionised and will interact with ionic groups rather than hydrogen
bonding groups.
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© Oxford University Press, 2009. All rights reserved.
Patrick, An Introduction to Medicinal Chemistry 4e
Chapter 2 – Proteins: structure and function
H2N
H
R
Tyrosine
Threonine
Serine
CO2H
R=
HBA O
H
HBD H
alcohol
O
H HBD
HBD
H
O
HBA
CH3 HBA
alcohol
Phosphorylation
phenol
Phosphorylation
Phosphorylation
O
O
O
P
O
H
O
CH3
P
O
Ionic
O
O
O
Ionic
O
O
P
O
Ionic
The tertiary structure will alter as a result (see section 5.2.6).
7) Glu-Leu-Pro-Asp-Val-Val-Ala-Phe-Lys-Ser-Gly-Gly-Thr
The one letter coding is ELPDVVAFKSGGT
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© Oxford University Press, 2009. All rights reserved.