588
Chirality in Biology
prevent or correct for racemization during
isolation.
Posttranslational modiFcation also oc-
curs in the synthesis of the heptapeptide,
dermorphin, obtained from skin secre-
tions of certain frogs. An all-L peptide is
formed initially by the ribosomal mecha-
nism but an L-alanine residue is converted
to D-alanine, probably by dehydrogenation
and rehydrogenation, to yield L-Tyr-D-Ala-
L-Phe-Gly-L-Tyr-L-Pro-L-Ser
(NH
2
).
The
opioid activity of this peptide is greater
than that of morphine. Similarly, riboso-
mally produced lantibiotics (from gram-
positive bacteria) contain
D-alanine and
D-aminobutyric acid units. The material
nisin, approved for use as a food preserva-
tive, contains 10 of 34 amino acid residues
as one lanthionine unit and four
β
-methyl-
lanthionine units. These units have the fol-
lowing structures; if R
=
H, the material
is lanthionine and if R
=
CH
3
,i
ti
s
β
-
methyllanthione. The starred chiral center
(
)hasthe D-conFguration: HOOC
C
H
(NH
2
)
CH(R)
S
CH
2
CH(NH
2
)
COOH.
These
D-residues
may
de-
rive from
L-serine
(lanthionine) and
L-
threonine (
β
-methyl-lanthione) by dehy-
drogenation to dehydroalanine and de-
hydrobutyrine residues respectively, fol-
lowed
by
addition
of
L-cysteine.
The
L-conFguration is lost in the dehydrogena-
tion and L-cysteine addition results in the
formation of a D-conFguration.
Serine has unusual roles. Several mem-
brane proteins are ‘‘glutamate receptors’’
and mediate the effects of this amino acid
in neurotransmission. One group termed
N
-methyl-D-aspartate (NMDA – see later)
receptors plays a role in memory acquisi-
tion, learning, and neurological disorders.
Both glycine and
D-serine
bind to the
NMDA receptor. In brain,
D-serine
is
formed by the action of a serine racemase,
a pyridoxal phosphate-dependent protein.
This brain racemase has been cloned
from astrocytes and it is now clear that
D-serine has an important role as a neuro-
transmitter. The incubation of D-serine-
containing neurons with
D-amino
acid
oxidase to destroy D-serine greatly reduces
the activation of the NMDA receptor. The
racemase activity requires divalent cations
(e.g. Ca
2
+
,Mg
2
+
), and Ca
2
+
may regulate
serine racemase activity. In mutant mice
lacking D-amino acid oxidase activity, high
levels of D-serine were observed in the fore-
brain (100–400 nmol g wet tissue
1
)w
ith
only low levels in the pituitary and pineal
glands. The D-serine levels in the cere-
bellum and the medulla oblongata were
10-fold greater in mutants than in con-
trols. ±or D-alanine, the levels in mutant
mice were higher than those in controls
for all brain regions.
Important roles are becoming appar-
ent for D-aspartate. It had been used as
a probe for high-afFnity
L-glutamate/L-
aspartate
uptake
sites
and
in
studies
of
L-glutamate
transport. Its
N
-methyl
derivative,
N
-methyl-D-aspartate (NMDA),
was known to activate the NMDA recep-
tors. These phenomena were treated as
‘‘unphysiological’’ since in mammalian
metabolism, D-amino acids were regarded
as ‘‘unnatural’’. However, free D-aspartate
has now been found in the tissues of many
invertebrates and vertebrates. It occurs in
nervous tissues (chicken, rat, human), in
embryo and adult brain and cerebrospinal
fluid (humans), and in the pituitary gland
and gonads (many mammals). One of
the highest observed levels of D-aspartate,
114
±
18 nmol g wet tissue
1
,w
a
sinr
a
t
adenohypophysis gland; high levels are
also present in embryonic tissue.
NMDA itself has now been identiFed
in neuroendocrine tissues. Previously, it
was known to be present in the bivalve,
Scapharca broughtonii
. The NMDA levels in
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