Chemistry Reference
In-Depth Information
an ingenious interplay between cofactor and active site organization, the required re-
action is optimized while all possible others are nearly completely prevented. Vitamin
B6-dependent enzymes have thus evolved to be highly efficient in terms of speed, as
well as in terms of reaction and substrate specificity.
The pioneering work of Snell and Braunstein helped to clarify the mechanisms of all
the PLP and PMP-dependent reactions [4]. In simple model systems, pyridoxal and
pyridoxamine (with or without their phosphate group) could perform essentially all
of the reactions in which they are involved metabolically. However, these non-enzy-
matic reactions were very slow, and the characteristic selectivities of the enzymatic
processes were not present. This motivated us and several other groups to construct
more sophisticated model systems to imitate vitamin B6-dependent enzymes, with
several goals. The first goal is to improve the reaction rate. The second is to attain
substrate selectivity, chemical reaction selectivity, regioselectivity, and stereoselectiv-
ity. A further goal is to achieve turnovers in the catalysis. Herein we review the pro-
gress made in this field [5].
2.2
Transamination
Almost all amino acids are synthesized by the biochemical reaction of PMP with
-keto
acids, in one of the steps of an overall process referred to as transamination (Scheme
2.2). PMP is converted into PLP, and PLP can react with a second amino acid to re-
generate PMP and convert the amino acid into its corresponding keto acid. As a result,
a keto acid and an unrelated amino acid interchange functionality.
a
2.2.1
Pyridoxamines with Small Auxiliary Groups
A basic group of the enzyme catalyzes the proton transfer characteristics of transami-
nations. Bruice found that imidazole buffer can catalyze transamination reactions in
model systems [6]. We conjectured that transamination rates should be improved by
attaching a basic side arm to pyridoxamine. Thus we synthesized a series of simple
pyridoxamine derivatives carrying basic groups at the end of flexible chains of various
lengths [7-9]. We measured the transamination rates of these pyridoxamine deriva-
tives in the presence of Zn(OAc)
2
at pH 4.00 in methanol.
The results (summarized in Table 2.1) showed that all the pyridoxamines with basic
side chains led to significant accelerations relative to pyridoxamine itself (
2
) and to
1
.
For the N,N-diaminoalkyl series, catalyst
4
with two methylene groups carries the di-
methylamino function so far out that it would form a nine-membered ring on remov-
ing the proton from the C4
0
carbon of the ketimine. From the work of Hine [10], this
was more than long enough to permit such a process, but interestingly this was not the
optimum chain. Compound
5
, with one additional methylene, showed an improved
rate. This makes no sense if the dimethylamino group is functioning only as a base -
but this increased chain length would be needed if, after removing the proton from the
