A small molecule that mimics the metabolic activity of copper-containing amine oxidases (CuAOs) toward physiological mono- and polyamines

Article abstract of DOI:10.1039/c004501b

Primary aliphatic biogenic amines have been successfully oxidized using a quinonoid species that mimics the metabolic activity of copper-containing amine oxidase (CuAO) enzymes. Especially, high catalytic performances were observed with aminoacetone, a threonine catabolite, and methylamine, a metabolite of adrenaline, and with the primary amino groups of putrescine and spermidine which are both decarboxylation products of ornithine and S-adenosyl-methionine. Furthermore, contrary to flavine adenine dinucleotide (FAD)-dependent amine oxidase enzymes, no activity was found toward secondary and tertiary amines.

Full text of DOI:10.1039/c004501b

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A small molecule that mimics the metabolic activity of copper-containing
amine oxidases (CuAOs) toward physiological mono- and polyamines†
a
a
b
Martine Largeron,* Maurice-Bernard Fleury and Margherita Strolin Benedetti
Received 19th March 2010, Accepted 1st June 2010
First published as an Advance Article on the web 24th June 2010
DOI: 10.1039/c004501b
Primary aliphatic biogenic amines have been successfully oxidized using a quinonoid species that
mimics the metabolic activity of copper-containing amine oxidase (CuAO) enzymes. Especially, high
catalytic performances were observed with aminoacetone, a threonine catabolite, and methylamine, a
metabolite of adrenaline, and with the primary amino groups of putrescine and spermidine which are
both decarboxylation products of ornithine and S-adenosyl-methionine. Furthermore, contrary to
flavine adenine dinucleotide (FAD)-dependent amine oxidase enzymes, no activity was found toward
secondary and tertiary amines.
Introduction
Amine oxidases (AOs) are ubiquitous enzymes which metabolize
various monoamines, diamines and polyamines of endogenous,
1
dietary or xenobiotic origin. AOs have been divided into two
main categories depending on the cofactor involved and on the
catalytic mechanism. One class, which encompasses monoamine
oxidases (MAO-A and MAO-B) and polyamine oxidases (PAOs),
is characterized by the presence of flavine adenine dinucleotide
2
(
FAD) as the redox cofactor (Fig. 1). The second class, named
copper amine oxidases (CuAOs), is represented by enzymes which
II
possess tightly bound Cu and a quinone residue as the redox
3
cofactor. Except for lysyl oxidases, whose active site has been
4
identified as lysine tyrosylquinone (LTQ), CuAOs use as re-
dox cofactor, the tyrosine-derived 2,4,5-trihydroxyphenylalanine
5
quinone, also named topaquinone (TPQ). Most CuAOs are
sensitive to inhibition by semicarbazide so that, in the literature,
they are generally referred to as semicarbazide-sensitive amine
oxidases (SSAOs) (EC 1.4.3.6). Recently, it has been suggested
to reclassify them as primary amine oxidases (PrAOs), enzymes
oxidizing primary monoamines with little or no activity toward
diamines (EC 1.4.3.21), and as diamine oxidases (DAOs), enzymes
oxidizing diamines such as histamine and also some primary
monoamines (EC 1.4.3.22). Both enzymes are inactive toward
Fig. 1 Chemical structures of flavine adenine dinucleotide (FAD),
topaquinone (TPQ), lysine tyrosylquinone (LTQ) redox cofactors, together
with the CuAO mimic 1ox
.
levels of endogenous and xenobiotic mono- and polyamines,
by catalyzing their oxidative deamination with the concomitant
production of hydrogen peroxide, ammonia and aldehyde. Each of
these products is potentially harmful, since hydrogen peroxide can
act as a source of reactive oxygen species (ROS), while ammonia
and aldehyde products are known to be toxic in a number of
6
secondary and tertiary amines.
Interest in human enzymes of the CuAO class has increased in
recent years driven by the recent discovery that the human vascular
adhesion protein-1 (VAP-1), which regulates leucocyte trafficking,
7
belongs to the CuAO family. Although DAOs are mainly located
intracellularly, PrAO enzymes are located in plasma membranes
of various tissues and in blood plasma, and their role is to regulate
8
systems.
The activity of CuAOs are mostly increased in various human
disorders, including type 1 and type 2 diabetes, congestive heart
failure, atherosclerosis, liver cirrhosis, Alzheimer’s disease and
a
UMR 8638 CNRS-Universit e´ Paris Descartes, Synth e` se et Structure de
9
many inflammation-associated diseases. For example, PrAOs
Mol e´ cules d’Int e´ r eˆ t Pharmacologique, Facult e´ des Sciences Pharmaceu-
tiques et Biologiques, 4 avenue de l’Observatoire, 75270 Paris cedex 06,
France. E-mail: martine.largeron@parisdescartes.fr; Fax: +33144073588;
Tel: +33153739646
catalyze the oxidative deamination of methylamine (produced
from the metabolism of adrenaline by MAO) and of aminoacetone,
a threonine and glycine catabolite. These endogenous monoamines
generate formaldehyde and methylglyoxal respectively, as highly
reactive side products which contribute to the formation of
advanced-glycation end products (AGE) associated with vascular
b
UCB Pharma SA, 420 rue d’Estienne d’Orves, 92705 Colombes, France
†
Electronic supplementary information (ESI) available: Full experi-
mental procedures and NMR spectra of isolated products. See DOI:
0.1039/c004501b
1
3
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10
complications of diabetes. These aldehydes are capable of
inducing protein cross-linking. They are able to enhance the
formation of b-amyloid misfolding oligomers and protofibrils, but
also to increase the size of the aggregates, two phenomena closely
11
associated with Alzheimer’s disease. Consequently, it has been
recognized that PrAO inhibitors might have potential therapeutic
8c
value. In this respect, a potent orally active and selective inhibitor
of PrAO activity (LJP 1586) is currently under investigation as a
12
potential anti-inflammatory agent.
The natural polyamines such as putrescine, spermidine and
spermine, which are formed from the decarboxylation products of
ornithine and S-adenosyl-methionine, are also endogenous sub-
13
strates for CuAO enzymes. In cancerous cells, these polyamines
are present at elevated levels as compared to normal tissues,
because of enhanced putrescine synthesis from ornithine by
ornithine decarboxylase, but also due to increased uptake of
polyamines. Consequently, by delivering CuAOs into cancerous
cells, the cytotoxic products of polyamine oxidation, hydrogen
peroxide and aldehydes, could be produced in situ for selective
killing of the same cells. The utilization of CuAOs in anticancer
therapy has been recently suggested as a promising strategy to
14
overcome multi drug resistance of cancer.
Through the utilization of synthetic models of TPQ and
15
Scheme 1 1ox-mediated catalytic oxidation of primary aliphatic amines
into imines.
LTQ cofactors and using benzylamine as the substrate, it
has been established that TPQ catalyzes the conversion of a
primary amine substrate into an aldehyde through a classical ping
16
17c
pong mechanism. However, these models of cofactors failed to
oxidize nonactivated primary amines under the same experimental
conditions, that are in the absence of a metal ion. In contrast, a
few years ago, we found that electrogenerated o-iminoquinone
of the o-iminoquinone catalyst 1ox, is ideal for the reaction.
When the controlled potential of the Pt anode was fixed at +
0.6 V vs. SCE, which is a potential at which 1red could be oxidized
to the o-iminoquinone species 1ox, the anodic current remained
constant for a long time, and the current efficiency obtained by the
electrolysis for 7 h was 100%, indicating that no side reaction took
place under the experimental conditions used (Table 1, entry 1).
These results indicated that the 1red/1ox system behaved as a redox
mediator for the indirect electrochemical oxidation of benzylamine
to the corresponding N-benzylidenebenzylamine, according to re-
action Scheme 1. After exhaustive controlled potential electrolysis
(c.p.e.), N-benzylidenebenzylamine was isolated by conversion to
the 2,4-dinitrophenylhydrazone (DNPH), obtained upon workup
of the oxidized solution with 2,4-dinitrophenylhydrazine under
aqueous acidic conditions (See Experimental). Note the yield
could not exceed 50%, because 5 mmol of benzylamine only
1ox (Fig. 1) behaved as an effective biomimetic catalyst for the
oxidation of primary aliphatic monoamines, under metal free
17
conditions. The catalytic cycle produced the reduced catalyst
red and N-alkylidenealkylamine as the product of amine oxidation
Scheme 1). This process is analogous to the above mentioned ping
1
(
16
pong mechanism, but N-alkylidenealkylamine was generated
instead of aldehyde, because methanol was used as the solvent,
in place of aqueous solution. Consequently, no hydrolysis to
generate the aldehyde took place during the catalytic process.
Importantly, the presence of the active 2-hydroxyl group, which
was engaged in an intramolecular hydrogen bond with the imine
nitrogen to form a highly reactive Schiff base cyclic transition state
1
¢
ox, constituted a prerequisite to the development of the catalytic
gave 2.5 mmol of N-benzylidenebenzylamine. Finally, the 1ox-
17c
process (Scheme 1).
mediated oxidation of benzylamine reference compound afforded
the corresponding N-benzylidenebenzylamine, in quantitative
yield since the current efficiency and the yield of DNPH reached
100% and 50%, respectively. In contrast to other existing amine
In this paper, we further investigate the catalytic efficiency of the
quinonoid electrocatalyst 1ox using different endogenous mono-
and polyamines, which are substrates for CuAO enzymes, and we
demonstrate that 1ox exhibits the same substrate specificity as the
CuAO enzymes but markedly differs from FAD-dependent amine
oxidase enzymes.
15
oxidase mimics, nonactivated aliphatic primary monoamines
also proved good substrates for the catalyst 1ox (Table 1, entries
2–4). In the specific case of methylamine (entry 2), the current
efficiency (50%) was roughly halved, whereas no DNPH could
be detected as a result of conversion of methylamine into volatile
reaction products on the time scale of anodic electrolysis. As a
proof, when propylamine (entry 3) was used as the amine substrate,
30% of DNPH could be isolated, as roughly expected on the
basis of the current efficiency (70%). Interestingly, o-iminoquinone
Results and discussion
First, we examined the catalytic efficiency of 1ox toward different
primary monoamines which are substrates for PrAO enzymes.
Benzylamine, which is a good exogenous substrate, was used as
the reference compound. Upon optimization, we have previously
shown that a combination of 5 mmol of benzylamine with
1ox was effective in oxidizing aminoacetone (entry 4), a specific
endogenous substrate for PrAOs, as the current efficiency and the
yield of DNPH reached 94% and 44%, respectively. Because of
0
.1 mmol of the reduced catalyst 1red, which corresponds to 2 mol%
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a
Table 1
1ox-mediated oxidation of CuAOs mono- and polyamine substrates
Yield of DNPH (%)
Entry
1
Amine substrate
Aldehyde produced
PhCHO
Current efficiency
100
vs Amine
vs 1ox
50
2500
b
b
2
3
MeNH
2
HCHO
50
70
—
—
MeCH
2
CHO
30
1500
4
5
MeCOCHO
MeCOCHO
94
30
44
2200
14
0
700
0
6
7
CHOCHO
—
c
d
d
20
—
—
c
8
9
88
41
2100
c
e
e
84
—
—
a
b
Reagents and c.p.e. conditions: [1red] = 0.4 mM, [amine substrate] = 20 mM, MeOH, rt, Pt anode (E = + 0.6 V vs. SCE). Volatile reaction products
c
were lost during the anodic electrolysis. The Pt anode was replaced by a Hg anode (E = 0.0 V vs. SCE) because polyamines spontaneously attached to
21
d
e
the Pt electrode surface. No DNPH could be isolated. Putrescine was isolated as an insoluble ammonium disulfate, the sole reaction product.
the instability of the free form, aminoacetone was prepared as its
masked acetal according to reaction Scheme 2.
primary amino termini of polyamines such as spermidine and
20
21
spermine. Unfortunately, as previously reported, diamines and
polyamines spontaneously attached to the platinum anode which,
consequently, had to be replaced by a mercury pool whose
potential was fixed at 0.0 V vs. SCE. Under these experimental
conditions, high current efficiencies were obtained for the 1ox
mediated oxidation of putrescine (entry 8) and spermidine (entry
). However, with spermidine, no DNPH could be detected
-
9
because the catalytic process produced an alkylimine which, under
aqueous acidic conditions, afforded an unstable aldehyde. As
previously reported, the latter spontaneously decomposed through
20
a retro-Michael reaction into volatile acrolein and putrescine,
which could be isolated as an insoluble ammonium disulfate. On
the basis of the current efficiency which laboriously reached 20%,
histamine seemed to be an inferior substrate for the biomimetic
electrocatalyst 1ox (entry 7). Actually, no conclusion could be
drawn because of the partial adsorption of histamine on the
mercury pool resulting in a rapid decrease of the current intensity.
1
8
Scheme 2 Synthesis of aminoacetone as its masked acetal form.
As shown in Table 1, the electrocatalyst 1ox exhibited the same
substrate specificity as the PrAO enzymes, that is poor reactivity
with a-branched primary amines (Table 1, entry 5) and no
reactivity toward secondary (Table 1, entry 6) and tertiary amines
(
1ox was found to be inactive toward trimethylamine).
In a second series of experiments, we investigated the catalytic
efficiency of the electrocatalyst 1ox toward endogenous diamines
Conclusions
and polyamines. Histamine and putrescine (Table 1, entries 7
and 8) were chosen as they are good substrates for DAOs,
The discovery that vascular adhesion protein 1 (VAP-1) is an amine
oxidase and is probably a source of soluble PrAO activity, has
13,14
22
while spermidine is a substrate of the widely-studied bovine
serum amine oxidase (BSAO) which remains as a member of
the new PrAO group. This enzyme is known to oxidize the
stimulated a great deal of new research on the physiological roles
of CuAO enzymes which may be more diverse than previously
considered. Especially, these enzymes are important in the
19
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Table 2 Substrate specificity for amine oxidase enzymes in comparison with mimic 1ox
FAD-Dependent Enzyme
TPQ Dependent Enzyme
PrAO
Mimic
Substrate
MAO
PAO
DAO
1
ox
Primary amine
Secondary amine
Tertiary amine
Diamine
Polyamine (primary amino group)
Polyamine (secondary amino group)
¥
—
—
—
—
—
¥
¥
¥
¥
¥
—
—
—
¥
—
—
¥
¥
—
—
¥(BSAO)
—
—
—
—
—
—
¥
—
(
¥) catalytic activity; (–) no catalytic activity. BSAO : Bovine serum amine oxidase
3,7
growth, development and metabolism of multiple organisms.
Effective inhibitors of PrAOs are of current interest because of
platinum grid was replaced by a mercury pool because polyamines
21
spontaneously attached to the electrode surface. A platinum
sheet was placed in the concentric cathodic compartment (counter
electrode), which was separated from the main compartment with
a glass frit. The reference electrode was an aqueous saturated
calomel electrode (SCE), which was isolated from the bulk solution
in a glass tube with a fine-porosity frit. The electrolyte solution
12
their desired applications as therapeutic agents. In particular, it
will be highly desirable to obtain inhibitors with notable selectivity
toward CuAOs over mitochondrial flavoproteins MAO-A and
MAO-B. Consequently, the design of small artificial catalysts
that closely approach the activity and specificity of CuAOs,
might provide important guidelines for designing selective CuAO
inhibitors. Using diverse endogenous mono- and polyamines,
we have demonstrated that the electrocatalyst 1ox presents the
chemoselectivity observed for the CuAO enzymes, that is, high
reactivity with unbranched primary amines and with the primary
amino group of diamines and polyamines but poor reactivity with
a-branched amines. Overall, 1ox mimics the metabolic activity
of PrAO enzymes, as high catalytic performances have been
observed with primary monoamines (benzylamine, aminoacetone,
propylamine and methylamine) and the terminal primary amino
group of spermidine. In addition, 1ox has been observed to mimic
DAOs, as shown by the data obtained with putrescine, and to
a lesser extent histamine. In contrast to FAD-dependent amine
oxidases, no activity was observed with secondary and tertiary
amines (Table 2). Finally, a last question emerges whether known
selective CuAOs inhibitors can also prevent the activity of the
electrocatalyst 1ox. This study is currently envisioned in our
laboratory because, in the affirmative, this small molecule might be
used for a preliminary screening of potential inhibitors of CuAO
enzymes.
-
1
(0.1 mol L lithium perchlorate in methanol) was poured into the
anodic and the cathodic compartments, as well as into the glass
tube that contained the SCE electrode. Reduced catalyst 1red (0.1
mmol) and an excess of primary aliphatic amine (5 mmol) were
then added to the solution in the main compartment (250 mL),
and the resulting solution was oxidized, under nitrogen, at room
temperature, at + 0.6 V vs. SCE (initial current 30–40 mA).
After exhaustive electrolysis, that is when a negligible current was
recorded (0.5–1.0mA), the solutionwas worked-up bytheaddition
of 2,4-dinitrophenylhydrazine reagent (2.5 mmol in 5 mL of pure
24
H
2
SO , 15 mL of EtOH, and 5 mL of water), the stoichiometry
4
reflecting the fact that 5 mmol of the primary amine gave only
2.5 mmol of the N-alkylidenealkylamine (Scheme 1). After 1 h,
the resulting solution was concentrated to a volume of 40 mL.
The solid obtained was collected by filtration, washed with water
and dried in a vacuum desiccator. The identity and purity of 2,4-
1
dinitrophenylhydrazone was confirmed by TLC and H NMR
spectroscopy, after comparison with an authentic sample.
Acknowledgements
Experimental Section
We thank Dr Andrew Holt, Associate Professor at the University
of Alberta (Canada) for fruitful discussions.
1
13
H and C NMR spectra were recorded on a Bruker AC-300 spec-
trometer operating at 300 MHz and 75 MHz, respectively. Chem-
icals were commercial products of the highest available purity and
were used as supplied. Reduced catalyst 1red was synthesized in
two steps from commercially available 2-nitroresorcinol, according
to our published procedure (see the supporting information of
reference 23).
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