606
Chirality in Biology
is a specifc constraint (Fourth condition)
involved in the interaction.
In enzyme–substrate or drug–receptor
interaction, there must be a diastereoiso-
meric relationship at some point in the
p
a
t
h
w
a
yo
ri
na
ni
n
t
e
rm
e
d
i
a
t
ec
om
-
pound/complex. IF a chiral enzyme is
denoted as (
E) and two substrate enan-
t
i
om
e
r
sa
s(
+
S)
and
(
S),
the
com-
plexes (
E)(
+
S) and (
E)(
S) will be
diastereoisomeric. Since diastereoisomers
(unlike enantiomers) have diFFerent chem-
ical properties,
diFFerentiation
between
(
+
S) and (
S) will, in principle, be pos-
sible. The occurrence oF diastereoisomeric
geometries is a necessary but not suFfcient
condition For chiral recognition.
In the reaction oF phenylalanine ammo-
nia lyase, both phenylalanine and substrate
analog enantiomers bound to the enzyme;
it was proposed that they occupied the
same site with ‘‘mirror-image packing.’’
This possibility has been confrmed For
isocitrate enantiomers in reaction with
isocitrate dehydrogenase. These appear to
be special situations deriving From the spe-
cifc structures oF the enzyme substrates
(see ±ig. 17). IF three contact points are
involved in mirror-image packing, clearly
a Fourth condition or site must be involved
For chiral recognition as noted previously.
5
Enzyme Specifcity with Chiral Substrates
Enzymes are polymers oF many chiral
amino acids. Thus, the relatively small
enzyme, ribonuclease (
M
r
=
13 700), has
109 amino acid residues with a single
chiral center, 12 with 2 chiral centers
and 3 residues oF achiral glycine. Put in
simple terms, this and other enzymes are
highly chiral catalysts. Many texts contain
statements such as the Following actual
example: ‘‘It has long been known that
natural enzymes act only on one chiral
Form (enantiomer) oF a chiral substrate.’’
While in general enzymes are oFten highly
specifc For one enantiomer, there are also
many documented cases where specifcity
is not observed or is not absolute. An
extensive listing oF various situations and
reaction types was given previously and
only a Few examples will be noted here.
One highly specifc case is
D-amino
acid oxidase (EC 1.4.3.3). Although
L-
amino acids are not substrates, several
inhibit the oxidation oF D-alanine (but not
L-alanine). Presumably,
these inhibitors
bind at the normal active site. The amino
acyl-tRNA ligases (synthetases, EC 6.1.1.X)
apparently show absolute specifcity For
L-amino acids during ribosomal protein
synthesis. These enzymes are oF interest
since they ligate two chiral substrates.
When examined
in vitro
, there is some
relaxation oF the specifcity as noted earlier
For tyrosine-tRNA
tyr
ligase (EC 6.1.1.1).
±or
arginine
and
proline
ligases
(EC
6.1.1.19 and EC 6.1.1.15 respectively), the
D-enantiomers are inhibitory.
Examples oF enzymes with lack oF enan-
tiospecifcity are alcohol dehydrogenase
(EC 1.1.1.1), where the liver enzyme re-
acts with both enantiomeric Forms oF
butan-2-ol and octan-2-ol (although there
are
rate
diFFerences),
and
with
nico-
tine dehydrogenase (EC 1.5.99.4), con-
verting both nicotine enantiomers to the
(
R
)- and (
S
)-6-hydroxynicotines. ±urther
metabolism oF the 6-hydroxynicotine enan-
tiomers requires separate (
R
)- and (
S
)-6-
hydroxynicotine oxidases (EC 1.1.3.6 and
EC 1.5.3.5 respectively).
A remarkable achievement was the 1992
chemical synthesis oF both enantiomeric
Forms
oF
the
dimeric
enzyme
HIV-1
protease; aminobutyrate was an isosteric
replacement For
cysteine
at
monomer
previous page 1280 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 1282 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off