On the Mechanism of Metabolic Reactions of Amino Acids Catalyzed
by Vitamin B6 and Related Aldehydes
J. Sivý, V. K ettm ann, J. K rätsm ár-Šm ogrovič
D epartm ent of Analytical Chemistry, Faculty of Pharmacy, Comenius University,
Odbojärov 10, 832 32 Bratislava, Slovak Republic
M. B reza
Faculty of Chemical Technology, Slovak Technical University, Radlinskeho 9,
812 37 Bratislava, Slovak Republic
Z. Naturforsch. 49c, 571-578 (1994); received April 25, 1994
[(N-salicylidene-D,L-glutamato)(pyridine)]copper(II), Crystal Structure, INDO/2 Charges,
Metabolic Reactions of Amino Acids, Vitamin B6 Catalysis, Reaction Mechanism
The crystal structure of [(N-salicylidene-D,L-glutamato)(pyridine)]copper(II), a model for
vitamin B6-amino acid-related metal complexes, has been determ ined by an X-ray analysis.
A close examination of the structural data on this and other related complexes combined
with quantum-chemical (INDO/2) calculations enabled us to make a clear distinction be­
tween two mechanisms proposed earlier for metabolic reactions of amino acids catalyzed by
the vitamin BA (or salicylaldehyde)-metal system. The results are consistent with a transient
formation of a carbinolamine species resulting from the addition of a solvent water or alcohol
molecule to the Schiff base double bond, thus supporting the mechanism of the catalysis as
proposed by Gillard and Wootton.
In tro d u ctio n
M etabolic reactions of am ino acids are cata­
lyzed by m etaloenzym es which require pyridoxal
(vitam in B6) (form ula 1, Fig. 1) or its phosphate as
a cofactor (G u ira rd and Snell, 1964). The com m on
featu re of these reactions is a heterolytic cleavage
of one of the th re e bonds to the a-carb o n atom of
the am ino acid. O f p articular biochem ical im p o rt­
ance are tran sam in atio n , racem ization and a,ßelim ination reactions which are d ep en d en t on
cleavage of th e C a - H bond.
T he first in term ed iate of the catalytic reaction is
a Schiff base b etw een pyridoxal and an am ino acid
which subseq u en tly coordinates (as a trid en tate
ligand) to th e m etal ion of the enzym e to form
chelate 2 (these steps may proceed in a concerted
m a n n e r or even be reversed). In the next step a
pro to n is released from the a-carb o n of the am ino
acid m oiety to form a planar, highly reactive carbanion. T hen th e fate of the carbanion depends on
its electronic stru ctu re which can be described by
canonical form ulas 3 a - c . S tructure 3 a predom i-
R eprint requests to J. Sivy.
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nates at pH higher than pK a of the pyridine n itro ­
gen w hen the carbanion is u n p ro to n ated so that
subsequent rep ro tonization on the a-carb o n leads
to racem ization of the am ino acid. O n the other
hand, transam ination, which requires protonation
on the azom ethine carbon, is the m ajor reaction
in the system in an acidic environm ent; structure
3 b, a pred o m in an t form of the p ro to n ated pyrid­
oxal carbanion, is th erefo re an interm ediate of the
transam ination reaction.
M ost of these enzym atic reactions have been
duplicated by non-enzym atic m odel reactions
(L ongenecker et al., 1957; H olm , 1973) in which
pyridoxal (or an o th er ap p ro p riate aldehyde) and
a suitable m etal ion serve as catalysts. A s the p h e­
nolic and form yl groups are sufficient structural
req u irem en t for catalytic activity of the cofactor
(the presence of the heterocyclic nitrogen en ­
hances the rate of the catalytic reaction and the
hydroxym ethyl group functions to link the cofac­
to r to the enzym e), pyridoxal m ay be replaced by
salicylaldehyde so th a t the system salicylaldeh y d e -a m in o a c id -m e ta l (4, Fig. 2) represents a
relatively sim ple m odel to study enzym atic reac­
tions of am ino acids. C atalytic reactions in the
m odel system 4 also proceed through interm ediate
© 1994 Verlag der Zeitschrift für Naturforschung. All rights reserved.
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J. Sivy et al. • Mechanism of Vitamin Bft-Catalyzed Reactions
3a
3c
Fig. 1. General structures of
the compounds derived from
pyridoxal.
form ation of the carbanion 5 with th e only excep­
tion th at the transam ination reactions are not o b ­
served. This is m ost likely caused by the fact that
the carbanion 5 cannot exist, due to the lack of the
ring nitrogen, in the form analogous to 3 b (or 3c).
The key question is: W hat is the m echanism of
the rate determ ining step of the catalytic reaction,
i.e. form ation of the carbanion from chelate 2 or
4. T here have been a nu m b er of rep o rts dealing
with this question. The first attem p t to rationalize
the literatu re data on these system s was m ade by
M etzler et al. (1954), w ho p roposed a m echanism
(h ereafter m echanism A ) according to which the
labilization of the C ct- H bond was a ttrib u ted to
the direct displacem ent of an electron pair from
the Ca - H bond to the a -C atom , a displacem ent
which is facilitated by the presence of the planar
conjugated system and fu rth er intensified by the
electron-accepting capability of the m etal ion. This
idea was then m odified by P erault et al. (1961) in
the sense that the driving force for the release of
the a-p ro to n was an increase in the delocalization
energy of the system, since after form ation of the
carbanion the a-C atom becam e a p art of the con­
jugated system.
Several years later, G illard and W ootton (1970)
have found that: a) in nucleophilic solvents the
rate of the racem ization reaction of am ino acid
esters 6 is by several orders of m agnitude higher
relative to the corresponding free acids, b) by
using deuterioethanol exchange of hydrogen for
deuterium takes place at position Ca, and c) the
rate of the reaction can be enhanced by addition
of a base. Based on these facts the authors
concluded that in nucleophilic solvents (w ater,
alcohols) the nucleophile can add accross the azo-
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J. Sivy et al. ■Mechanism of Vitamin B6-Catalyzed Reactions
573
RPH
Fig. 2. General structures of the compounds
derived from salicylaldehyde. :B represents
any base present in solution.
m ethine d ouble bond to form a reactive carbinolam ine 7 and su b sequent base-catalyzed elim ina­
tion led to form atio n of the carbanion. G illard and
W ootton advanced a hypothesis th at in system 4 a
sim ilar addition-elim ination m echanism (m echa­
nism B) m ay also be involved in form ation of the
carbanions, the higher rate of racem ization in ch e­
late 6 (com pared to th at in 4) being explainable
in the follow ing way: in the carbinolam ine 7 free
ro tatio n aro u n d the N - C “ bond can bring the
a -p ro to n into a position which favours its rem oval
by the leaving alkoxy group during the elim ination
step; on the o th e r hand, in the carbinolam ine
which w ould result from 4 coordination of the carboxy group fixes th e conform ation of the groups
on the chelate ring so that the a-p ro to n is in a
less favourable position for rem oval by the leaving
O R 3 group.
A lthou g h the experim ental d ata available in the
literatu re seem to be consistent with m echanism
B, th ere are still tw o groups of w orkers which in­
cline to eith e r of th e above m echanism s (see, e.g.,
B kouche-W aksm an et al., 1988). Consequently, the
aim of this w ork was to test which of the tw o
m echanism s fits reality. To achieve this, we have
ad o p ted a sim ple strategy based on the fact th at
upon chelation of the Schiff base the rate of race­
m ization is enhanced by several orders of m agni­
tude; for divalent cations the reaction rate in
system 4 (or 6) increases in the follow ing order:
Z n 2+ < C o2+ < P d2+ < N i2+ < C u2+ (O ’C onnor
et al., 1968; N unez and E ichhorn, 1962). It is also
well docum ented th at the catalytic effect of the
m etal ion is observed just after (and n ot before)
the form ation of the Schiff base (N unez and E ich­
horn, 1962; M artell, 1982).
It is obvious th at in the case of m echanism A the
system (Schiff base) shifts, due to m etal activation,
along the reaction coordinate tow ards the final
state 5, i.e. the com plex should be closer to the
species 5 th an the free, u n coordinated Schiff base.
This should be reflected in redistribution of the
charge density (enhanced electron density on the
a-carb o n accom panied by an ad eq u ate lowering of
this density on the a-h ydrogen) and in the geom e­
try around the a -C atom (change of the bond
angles due to rehybridization from sp3 to sp2, a
tendency of the Ca - H bond to becom e p erp en ­
dicular to the salicylaldim ine plane coupled with a
planarization of the Ca -C ß bond).
O n the o th e r hand, according to m echanism B
the Schiff base is in the first (rate determ ining)
step activated by the m etal ion tow ards nucleophilic attack by R 3O H so that, in agreem ent with
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574
J. Sivy et al. ■Mechanism of Vitamin B6-Catalyzed Reactions
the theory of charge controlled A d N2 reactions
(Flem ing, 1976), one would expect an en h an ce­
m ent of the positive charge on the azom ethine
carbon upon introduction of the m etal ion.
From the above it is clear th a t in o rd er to study
the m echanism of the catalytic (e.g. racem ization)
reaction it is necessary to m o n ito r changes in
geom etry and distribution of the electron density
associated with the transfer of th e Schiff base into
the chelate. In this w ork, single-crystal X -ray dif­
fraction and quantum -chem ical calculations w ere
chosen for this purpose. The crystal structure of
one derivative belonging to class 4 was investi­
gated in this p a p e r and the rem aining w ere re ­
trieved from the C am bridge Structural D atabase
(A llen et al., 1979). The salicylaldehyde chelates
w ere chosen over pyridoxal chelates since the for­
m er m ore readily provide good crystals, and C u ”
was chosen over o th e r m etals because of the high
reaction rate for copper-catalyzed reactions
(N unez and E ichhorn, 1962; M artell, 1982).
Experimental
Selection o f the com pounds
All com pounds selected for this study are listed
in Table II. They differ in the n atu re of the am ino
acid and of the additional ligand L. The glycinato
chelates w ere not included in th e analysis because
of uncertainty which of the tw o C “ - H bonds is
actually cleaved in the catalytic reaction. Since, to
our know ledge, no Schiff base of salicylaldehyde
and an am ino acid has been studied crystallographically, we have chosen for this purpose the
know n structure of ch lo ro -trip h en y l-(0 -ethyl-N salicylideneglycinato) Sn,v (L ee et al., 1990) in
which the O -ethyl-N -salicylideneglycinato ligand
is m onodentately coord in ated via the ph enolate
oxygen to the tin atom , i.e. it contains an un coordi­
nated azom ethine nitrogen and hence may be re ­
garded, to a good approxim ation, as the m etal-free
Schiff base.
X-ray structure o f 4 e
The com plex [C u (sal-g lu )(p y rid in e)] (4e)
(s a l-g lu = N -salicylideneglutam ate) was p repared
by allowing of [C u (sa l-L -g lu )(H 20 ) 2]. H 20 to
react with an equim olar am o u n t of pyridine in a
stirring ethanolic solution at 6 0 -6 5 °C for 0.5 h.
A fter cooling to room tem p eratu re the precipitate
was collected by filtration and recrystallized from
ethanol to give w ell-developed dark-green crystals.
Analysis for C i7H 16N 20 5Cu (394.89)
Calcd
C 51.71 H 4.08 N 7.09,
Found C 51.52 H 4.12 N 6.99.
A crystal of size 0.3 x 0.2 x 0.2 mm was selected
for the structure analysis. The unit cell param eters
were refined by a least-squares fit of positional
angles of 15 reflections with 5 < 2 0 < 26°. The
intensities were m easured on a Syntex P2] dif­
fractom eter
using
graphite-m onochrom atized
C u K a radiation and the 0 - 2 0 scanning technique
in the range 0 < 20 < 100°. The scan speed in the
interval 4.88-29.3° m in -1 was controlled a u to ­
matically, with each reflection scanned 1° (in 2 0 )
above and below the K a doublet. The background
was m easured at each end of the scan for one half
of the scan time. Two standard reflections m oni­
tored after every 98 scans showed th at no correc­
tion for instrum ent instability or crystal decay was
required. O f the 1696 unique reflections recorded,
1410 with I > 1.96o(I) w ere classified as observed
and used for the structure analysis.
Crystal data: Form ula weight M x = 394.9, m o n o ­
clinic, space group P 2 x!n, a = 8.128(2), b 10.649(3), c = 19.113(5) A , ß = 95.47(2)°, V =
1646.7(7) Ä 3, Z = 4, [i = 2.19 m m “ 1, qx =
1.59 g- cm “3, F(000) = 804, M oK a, X = 0.71069 Ä ,
room tem perature.
The structure was solved by P atterson and F ou­
rier m ethods and refined on F by block-diagonal
least-squares with anisotropic therm al param eters
assigned to all non-hydrogen atoms. Positions of
the H atom s H 1 - H 9 , which w ere found on a
difference Fourier map, were refined while
the rem aining (H 1 0 -H 1 6 ) were fixed at calcu­
lated positions; therm al param eters of all the
H atom s were set to 0.5 A 2 higher than Beq
of the associated C or O atoms. The function
Z w (IF0 l - IFc I)2 was minim ized by using unit
weights (w = 1) for all the observed reflections.
Final residuals were R = 0.062, wR = 0.059, S =
1.22. In the final cycle (A /o)max = 0.043, (AQ)max =
0.30, (A0 )min = -0.45 e • A -3. The scattering factors
for the neutral atom s w ere taken from In te r­
national Tables, 1974. All crystallographic calcu­
lations w ere carried out with the X R C 83 program
package (Pavelcik et al., 1985). Prelim inary results
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J. Sivy et al. ■Mechanism of Vitamin B6-Catalyzed Reactions
575
of the crystal stru ctu re of 4 e have been reported
previously (K rätsm är-Sm ogrovic et al., 1985).
Table I. Final atomic coordinates (xlO4) and equivalent
isotropic thermal parameters Beq (A2) with E.S.D.'s in
parentheses*. Beq = 4/3 YZ. BVj c?j, ctj.
'j
M O calculations
Atom
E lectronic stru ctu res in term s of total atom ic
charges, W iberg indices and orbital energies were
o btained from a local version of the IN D O /2 p ro ­
gram (Boca, 1989) by using a fixed geom etry constructed on th e basis of know n X-ray struc­
tures - for all six chelates studied. Initial geo­
m etries of the m etal-free Schiff bases were derived
from the X -ray stru ctu re of the corresponding che­
late p aren ts by rem oval of the copper atom and
com pleting the freed valencies on the phenolate
and carboxylate oxygens by H atoms. Subsequent
optim izations using A M I (D ew ar et a l, 1985)
have revealed only slight torsional rearrangem ent
indicating th at the p lanar conform ation of the
Schiff base ligand observed in the chelate is also a
low -energy conform ation for the ligand itself.
CO(l)
0(1)
0(2)
0(3)
0(4)
0(5)
N(l)
N(2)
C(l)
C(2)
C(3)
C(4)
C(5)
0(6)
C(7)
0(8)
0(9)
0(10)
0(11)
0(12)
0(13)
0(14)
0(15)
0(16)
0(17)
R esults and D iscussion
Final atom ic coordinates for 4 e are given in
Table I. R elevant structural p aram eters and the
total atom ic charges in the catalytically interesting
p art of the chelates studied are com pared in
Tables II and III, respectively. A s the atom ic
charges calculated for the six m etal-free Schiff
bases w ere alm ost identical, only the m ean values
are given in Table III.
y
X
1450(2)
2117(7)
986(7)
1122(7)
-3793(7)
-1977(8)
512(8)
2223(8)
-617(11)
-1231(11)
-745(13)
399(13)
1001(11)
1299(10)
1930(11)
668(11)
-1079(11)
-2300(12)
3102(10)
3604(10)
4672(11)
5227(11)
4732(11)
3694(11)
3108(11)
1301(1)
61(5)
2585(5)
2983(6)
-412(6)
-1393(8)
2430(6)
358(6)
3315(8)
4117(8)
4017(9)
3106(9)
2333(8)
2303(8)
949(8)
233(8)
346(9)
-581(9)
-876(8)
-1263(8)
-2305(8)
-2968(9)
-2611(9)
-1600(8)
-630(8)
z
Beq [A2]
4547(1)
5238(3)
3813(3)
2683(3)
2671(3)
2100(4)
5251(3)
3781(3)
5036(5)
5523(6)
6219(5)
6435(5)
5941(5)
3201(4)
3082(4)
2591(4)
2843(5)
2477(5)
5146(4)
4496(4)
4456(5)
5049(6)
5692(5)
5756(4)
3847(4)
6.52(4)
5.57(18)
5.85(17)
6.51(19)
7.18(21)
9.82(28)
5.07(20)
5.41(21)
5.92(31)
6.77(35)
7.38(33)
7.13(35)
5.97(29)
5.63(27)
5.82(28)
5.66(27)
6.31(30)
6.50(30)
5.23(25)
5.15(25)
6.06(26)
6.70(32)
6.55(31)
5.81(28)
5.58(26)
* Anisotropic thermal parameters, H-atom coordinates,
F0/Fc tables, and complete lists of geometrical param­
eters are available at the authors.
The overall geom etry of 4 e (Fig. 3) shows the
usual features of this type of com plex, perhaps
with the exception th at the coordination around
the Cu atom is exactly square-planar. This is sub-
Table II. List of compounds3 studied here and their relevant geometric parametersb.
Compound
N -C a -C
N -C a -CP
C -C a-CP
C=N
C = N -C a-CP
C = N -C a-H
Ref.
4a
4b
4c
4d
4e
4f
usbd
107.4
108.5
107.3
107.5
109.6
105.3
111.8
109.5
112.3
112.7
111.7
112.6
108.3
109.1
110.2
108.3
109.1
110.0
114.8
1.270
1.275
1.286
1.285
1.267
1.288
1.303
83.3
70.6
73.7
72.8
75.9
74.0
-39.8C
-46.6C
-48.8
-47.7C
-50.3
-41.8
18
19
20
21
this work
22
13
a The compounds are designated as follows (see also Fig. 2): 4a: R i = CH3, L = pyrazole; 4b: R, = CH3, L = NCO;
4c: R, = CH2Ph, L = NCO; 4d: R, - (CH2)2COOH, L = H20 ; 4e: Rj = (CFb)2COOH, L = pyridine; 4f: R, =
CH(CH3)2, L = h 2o.
b E.S.D.’s for the bond angles range from 0.2 to 0.6°, for the C=N bond length from 0.003 to 0.011 Ä, and for the
torsion angles from 0.3 to 0.7° (C =N -C “- C P) and from 0.6 to 1.0° (C = N -C “-H ).
c Position of the hydrogen calculated, i.e. not actually found in the difference Fourier synthesis.
d Uncoordinated Schiff base (see text).
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J. Sivy et al. ■Mechanism of Vitamin B6-Catalyzed Reactions
576
Table III. INDO/2 net atomic charges.
Compound3
Qc
Qn
Ra-C
qa-H
4a
4b
4c
4d
4e
4f
usbb
0.26
0.25
0.25
0.26
0.26
0.26
0.20
-0.02
-0.01
-0.03
-0.05
-0.05
-0.02
-0.22
0.05
0.06
0.07
0.05
0.03
0.06
0.11
-0.01
-0.02
-0.02
-0.01
-0.02
-0.01
-0.02
a For designation of the compounds see the footnote of
Table II.
b Atomic charges for the uncoordinated Schiff base
(usb) are means of six values (see text).
stantiated by the fact th at no atom occurs at a dis­
tance sho rter than 3.3 A in the axial direction and
by the coplanarity of Cu w ith the four donor
atoms. The p ro to n a te d side chain carboxyl group
is not involved in the coordin atio n to th e copper
atom , but it form s a strong hydrogen b ond with
the carbonyl oxygen 0 3 [ 0 —0 = 2.593(5) A] of
a n o th er m olecule at ( - 0 .5 - jc, -0 .5 + y, 0.5 - z),
thus form ing chains going along the diagonal of
the unit cell.
A s the space group (P 2 \/n) is centrosym m etrical, the crystal structure of 4 e is a racem ic
m ixture of [Cu(sal-D ,L-glu)(pyridine)] even
though an optically active p aren t com plex
[C u(sal-L -glu)(H 20 ) 2] was used in the reaction
with pyridine (see above). This again d em o n ­
strates that the racem ization of the Schiff base
ligand readily occurs under mild conditions even
in neutral or weak acidic aqueous or alcoholic
solutions (K rätsm är-Sm ogrovic et al., 1991).
A s can be seen in Table II, bond angles at the
a-C atom for the six chelates studied range from
105.3 to 114.8° with the m ean value of 109.7° cor­
responding exactly to the tetrah ed ral (sp3) value.
M oreover, the N - C a - C angle in all six chelates is
even sm aller than that found in the u n coordinated
Schiff base (111.8°). Similarly, as shown by the to r­
sion angles presented in Table II, it is the C a - C |3
bond rath er than the Ca - H bond which tends to
be oriented perpendicularly to the jt system of the
molecule. Inspection of Table III fu rth e r shows
th at although chelation of the Schiff base causes a
low ering of the positive charge on the a-carb o n ,
the lowering is not at the expense of reduced elec-
Fig. 3. A perspective drawing of the
5-enantiomer of 4e derived from the
X-ray coordinates.
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J. Sivy et al. ■Mechanism of Vitamin B6-Catalyzed Reactions
tron density on th e a-hydrogen. H ow ever, as the
sem iem pirical quantum -chem ical m ethods of
IN D O type are generally know n to underestim ate
the charge polarization, the results of the charge
d istribution should be taken with caution. N ever­
theless, this draw back of the IN D O m ethods is
supposed to affect the C - H polarization in both
the m etal-free Schiff bases and the corresponding
chelates in a sim ilar m anner.
From the above it is clear th a t o u r results are
not consistent with reaction m echanism A, which
predict a direct activation of the am ino acid by the
ji system o f the Schiff base and the m etal ion. In
contrast, according to m echanism B the catalytic
reaction is in itiated by nucleophilic attack of
R 3O H on the azom ethine carbon of the Schiff
base. A s show n in Table III, the characteristic fea­
ture of all the com plexes studied is an 0.05 to 0.06
increase in the positive charge on this atom rela­
tive to the m etal-free Schiff bases. C om parison of
the charges on the azom ethine nitrogen (Table III)
shows th at the enhanced positive charge on the
azom ethine carb o n results from electron w ith­
draw al by the co p p er atom. It is notable th at the
azom ethine b ond shortens from 1.303 to 1.2671.288 A upon co p p er introduction (Table II). This
interval corresp o n d s to the range 1.27-1.29 A
generally accepted for a pure C=N double bond
(B urke-L aing and Laing, 1976). It should be em ­
phasized in this context that IN D O /2 was unable
to rep ro d u ce th e observed increase in the C=N
577
bond o rd er so th at the m etal-induced en hance­
m ent of the positive charge on the azom ethine car­
bon is probably even higher than that indicated by
IN D O /2.
The above electron distribution coupled with
the high double-bond character in the azom ethine
group is in line with enhanced susceptibility of this
carbon tow ard nucleophilic attack by a solvent
w ater or alcohol m olecule (Flem ing, 1976). That
the addition of the nucleophile to the Schiff base
double bond is indeed charge controlled was veri­
fied by com parison of the fro n tier orbital energies:
the L U M O energy for the six chelates studied
here was calculated by IN D O /2 to range from 1.7
to 2.0 eV while the H O M O energy of w ater or al­
cohols is know n to be < - 1 0 e V (Flem ing, 1976);
this indicates that the H O M O /L U M O energy sep­
aration is large enough for the fro n tier orbital
interactions to be neglected.
In conclusion, the results of this study strongly
indicate th at the catalytic effect of the copper ion
resides in electron w ithdraw al from the azo­
m ethine linkage and in increase in the C=N bond
polarization. B oth these electronic effects enhance
the electrophilicity of the im ine carbon. This in
turn im plies th a t activation of the am ino acid by
the it system of the Schiff base, if any at all, is
insufficient and instead it requires an active influ­
ence of the nucleophilic solvent as originally sug­
gested by G illard and W ootton (1970).
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