Chemistry Reference
In-Depth Information
aminoacyl-AMP mixed anhydride, which is then
transferred to the PCP domain to form an aminoacyl
thioester. The thioester linkage is not to a cys-
teine residue in the protein, as we described in
Section 13.4.3. Instead, it involves pantothenic acid
(vitamin B
5
) bound to the enzyme as pantetheine, and
this is used to carry the growing peptide chain via its
thiol group. The important significance of this is that
the long '
pantetheinyl arm
' allows different active
sites on the multi-functional enzyme to be reached in
the chain assembly process (compare biosynthesis of
fatty acids, see Box 15.2).
'pantetheinyl arm'
O
O
attached to growing
peptide chain
bound to enzyme
through phosphate
HS
OH
H
H
OH
cysteamine
pantetheine
pantothenic acid
Nucleophilic attack by the amino group of the
neighbouring aminoacyl thioester is catalysed by
the C domain, and this results in amide (peptide)
bond formation. Enzyme-controlled biosynthesis in
this manner is a feature of many microbial peptides,
especially those containing unusual amino acids
not encoded by DNA and where post-translational
modification (see Section 13.1) is unlikely.
As well as activating the amino acids and
catalysing formation of the peptide linkages, the
enzyme may possess other domains that are respon-
sible for epimerizing
L
-amino acids to
D
-amino acids,
probably through enol-like tautomers in the peptide
(see Box 10.10). A terminal
thioesterase
domain is
also required. This is responsible for terminating the
chain extension process by hydrolysing the thioester
and releasing the peptide from the enzyme.
Many medicinally useful peptides have cyclic
structures. Cyclization may result if the amino acids
at the two termini of a linear peptide link up to form
another peptide bond. Alternatively, ring formation
can very often be the result of ester or amide linkages
that utilize side-chain functionalities (CO
2
H, NH
2
,
OH) in the constituent amino acids.
Box 13.10
Ciclosporin, a cyclic peptide composed mainly of unusual amino acids
The
cyclosporins
are a group of cyclic peptides produced by fungi such as
Cylindrocarpon lucidum
and
Tolypocladium inflatum
. These agents show a rather narrow range of antifungal activity, but high levels
of immunosuppressive and anti-inflammatory activities. The main component from the culture extracts is
cyclosporin A, but some 25 naturally occurring cyclosporins have been characterized.
(Me)Bmt
Abu
(Me)Leu
(Me)Val
Me
O
Me
O
Me
(Me)Bmt = 4-(2-butenyl)-
4,
N
-dimethyl-L-threonine
O
N
N
N
N
N
Sar
Abu = L-α-aminobutyric acid
(Me)Leu
Me
O
O
H
HO
O
Sar = sarcosine (
N
-methylglycine)
N
Me
H
N
Me
H
O
O
O
amide linkages (peptide bonds)
N
N
N
H
D-Ala
(Me)Leu
O
Me
O
Ala
(Me)Leu
Val
ciclosporin (cyclosporin A)
