Effect of aluminum (III) on the conversion of dopachrome in the melanin synthesis pathway

Article abstract of DOI:10.1016/S1386-1425(02)00403-1

The effect of aluminum ions on the kinetics and mode of the conversion of dopachrome (DC) in acidic environment has been studied using UV-Vis spectrophotometric and cyclic voltammetric methods. The DC conversion step is an important reaction in melanogenesis. Aluminum ions catalyze greatly the decarboxylative transformation of DC to give 5,6-dihydroxyindole (DHI) rather than 5,6-dihydroxyindole-2-carboxylic acid (DHICA) at pH 5.5, which enhance the ratio of formation DHI/DHICA in melanin synthesis pathway. The kinetics of DC conversion catalyzed by aluminum ions is dependent on the concentration of DC and aluminum ions. These results provide evidence that aluminum ions could play a role in the synthesis of melanin pathway in acidic condition through catalyzing the DC decarboxylative transformation to yield DHI and influence the melanin structure and properties.

Full text of DOI:10.1016/S1386-1425(02)00403-1

Spectrochimica Acta Part A 59 (2003) 1689ꢀ1696
/
www.elsevier.com/locate/saa
Effect of aluminum (III) on the conversion of dopachrome in
the melanin synthesis pathway
a,b
Junwei Di , Shuping Bi *
a,
a
State Key Laboratory of Coordination Chemistry of China, Department of Chemistry, Nanjing University, Nanjing 210093, People’s
Republic of China
b
Department of Chemistry, Suzhou University, Suzhou 215006, People’s Republic of China
Received 10 September 2002; accepted 21 September 2002
Abstract
The effect of aluminum ions on the kinetics and mode of the conversion of dopachrome (DC) in acidic environment
has been studied using UV-Vis spectrophotometric and cyclic voltammetric methods. The DC conversion step is an
important reaction in melanogenesis. Aluminum ions catalyze greatly the decarboxylative transformation of DC to give
5
,6-dihydroxyindole (DHI) rather than 5,6-dihydroxyindole-2-carboxylic acid (DHICA) at pH 5.5, which enhance the
ratio of formation DHI/DHICA in melanin synthesis pathway. The kinetics of DC conversion catalyzed by aluminum
ions is dependent on the concentration of DC and aluminum ions. These results provide evidence that aluminum ions
could play a role in the synthesis of melanin pathway in acidic condition through catalyzing the DC decarboxylative
transformation to yield DHI and influence the melanin structure and properties.
#
2002 Elsevier Science B.V. All rights reserved.
Keywords: Dopachrome conversion; Melanin; 5,6-Dihydroxyindole; Aluminum ion
1
. Introduction
Melanin has many biological functions. It may
function as a chemoprotective pigment by acting
as a sink for reactive oxygen species and free
radicals or as a means of binding potentially toxic
cations such as transition meals. If the detoxifying
capacity is exceeded, then the melanin is known to
Melanin is an amorphous, irregular, ubiquitous
pigment largely distributed in the living organisms.
In humans, it is found in the hair and epidermis, as
well as in areas of high nerve activity such as the
middle ear, retina, substantia nigra of the brain,
and some tissues either as a result of inflammation
or as an important of malignant tumors [1].
mediate oxidative stress by yielding free radicals
+
and reactive oxygen species, including HO [1ꢀ
/4].
The melanin is synthesized in vivo from tyrosine
through a complex series of enzymatic and chemi-
cal reactions. According to RaperꢀMason’s con-
/
cept of melanin formation, melanogenesis can be
divided into two phases. The first one, which is
fairly well understood, involves two tyrosinase-
*
Corresponding author. Tel.: ꢁ
5-331-7761.
E-mail address: bisp@nju.edu.cn (S. Bi).
/
86-25-620-5840; fax: ꢁ86-
/
2
1
386-1425/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved.
doi:10.1016/S1386-1425(02)00403-1

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/
catalyzed oxidations from tyrosine to dopaqui-
none and very fast chemical steps leading to
dopachrome (DC). The second phase, from DC
to melanin, can proceed by a series of enzymatic
and chemical processes, which remains to be
elucidated and the structure is partially known
such as enhancement of iron-mediate lipid perox-
idation and reactive oxygen species formation [22ꢀ
/
28], and has been implicated in neuropathalogical
disorders, the mechanism has not been established
[29,30]. This prompted us to study the effect of
aluminum ion on the conversion of DC, which
represents a key step in the biosynthesis of
melanins.
[
5ꢀ
/
9].
DC is a fairly stable compound in vitro envir-
onment. The DC conversion step is an important
reaction in melanogenesis and has been shown to
be under the control of DC conversion factor
2. Materials and methods
[
10,11]. DC tautomerase (DCT), tyrosinase-related
protein-2 (TRP2), catalyzes the tautomerization of
DC to 5,6-dihydroxyindole-2-carboxylic acid
2.1. Reagents
(
DHICA) and from insect cuticle a similar enzyme
generates 5,6-dihydroxyindole (DHI). Several en-
zymes, such as tyrosinase, tyrosinse-related pto-
tein-1 (TRP1), peroxygenase and lipoxygenase,
have been shown to catalyze the oxidation of
L-DOPA was obtained from Acros Organics,
Swiss. All other chemicals were of analytical grade
and twice-distilled water was used throughout.
NaAc and HAc buffer solution (pH 5.5) was used.
ꢂ1
DHI or DHICA [12ꢀ/16]. Recently, it is reported
Aluminum stock solution (0.02 mol l ) was
12H O and added HCl
to pH 3.
that peroxidase and lipoxygenase can catalyze the
oxidation of DHI and DHICA more easily than
tyrosinase and hypothesized a role for these
enzymes in the synthesis of melanin [15,17]. It is
now well accepted that natural melanins are
produced by copolymerization of DHI and
DHICA. Moreover, the ratio of DHI and DHICA
in natural melanins influences their chelating and
cytoprotective properties [16,18]. The presence of
DCT in mammalian melanocytes can result in the
high content of carboxylic groups in natural
melanins as opposed to synthetic melanins ob-
tained by the autooxidation of 3,4-dihydroxyphe-
nylalanine (DOPA) or by the enzymatic action of
tyrosinase alone [7,18].
Another important factor which has been no-
ticed is some metal ions, in particular copper and
zinc. A number of transition metal ions are
particularly effective in inducing the non-decar-
boxylative conversion of DC at physiological pH
value, leading mainly to DHICA rather than DHI.
The effect depends on the nature and concentra-
tion of metal ion [6,8,11,19]. On the other hand, it
is reported that in some patients with PD there is
an accumulation of aluminum with neuromelanin
granules of substantia nigra [20], but the work of
aluminum in synthetic melanins is little [11,21].
Although aluminum may increase oxidative stress,
prepared by KAl(SO ) ×
/
4
2 2
2.2. DC preparation
DC was prepared by mixing 5 mmol lꢂ1
DOPA in HacꢀNaAc buffer or deionized water
L-
/
with sufficient solid MnO . The mixture was
2
vigorously shaken for about 10 min and then
stood. The DC solution was obtained by means of
decantation. This procedure resulted in a more
than 85% conversion of
L-DOPA to DC as
determined spectrophotometriclly. DC formation
ꢂ1
ꢂ1
was followed at 475 nm (oꢃ/3600 l mol
cm
)
[31,32]. DC was stable for about 2 h (at 15 8C),
which is consistent with Ref. [33].
2.3. Spectrophotometric experiments
Spectrophotometric experiments were carried
out by means of a 7530G UV-spectrophotometer
(HP-Shanghai Analytical Instrument, China). The
conversion of DC was followed spectrophotome-
trically by monitoring the absorbance from 250 to
800 nm. The data for each run were collected and
stored in software. The experiments were carried
out at about 15 8C.

J. Di, S. Bi / Spectrochimica Acta Part A 59 (2003) 1689ꢀ
/1696
1691
2
.4. Voltammetric experiments
or other chemical methods and was not affected by
ꢁ
2
Mn
[33]. Wavelengths for maxima absorption
A three-electrode voltammetric system consists
of DC were 305 and 475 nm, which did not vary in
the whole process. The major product is colorless
DHI [9,11,34], which can be oxidated by oxygen
and then polymerized to melanin (black).
of a glassy carbon working electrode (4 mm in
diameter), a platinum counter electrode, and a
saturated Ag/AgCl reference electrode. The glassy
carbon electrode was polished on abrasive paper
Since in many cases the effect of aluminum on
iron-induced lipid peroxidation and stabilization
of ferrous iron is favored by decreasing the pH of
the medium to pH 5.5 [22,23,28], the effect of
aluminum ions on the DC conversion was tested at
(
2000 mesh) with water, then sonicated in twice-
distilled water for 3 min. The solution in the
electrolytic cell was bubbled by nitrogen gas before
starting record. CHI 660a electrochemical work-
station (Shanghai Chenhua Instrument, China)
3
ꢁ
acidic pH values because it was reported that Al
was used for cyclic voltammetry with scan rate
ꢂ1
had a only a slight influence on the DC conversion
at pH 6.8 using phosphate buffer [11]. It was
observed that, at pH 5.5, aluminum ions greatly
increased the conversion of DC (Fig. 2). Inspec-
tion of the spectral changes accompanying the
conversion reaction both in the presence and in the
absence of metal ions showed the progressive
disappearance of the absorption maxima of DC
at 475 and 305 nm and the concomitant formation
of 5,6-dihydroxyindole (DHI) at 274 and 298 nm
[17,31], which can be slowly oxidated by oxygen in
the solution to indole-5,6-quinone (IQ) at 360 nm
and then quickly polymerize to melanin. Melanins
1
00 mV s
.
3
. Results
Fig. 1 showed the bleaching of DC sponta-
neously in pH 5.5 HacꢀNaAc buffer solution. The
color of DC was stable for about 2 h, then it turn
to blueꢀblack (Fig. 1, curve c) and finally to black
/
/
precipitation (Fig. 1, curve d and e). The sponta-
neous decrease of DC, obtained chemically using
solid MnO , was similar to that from enzymatical
2
Fig. 1. Spectrum of DC bleaching spontaneously in pH 5.5 Hacꢀ/NaAc buffer solution at about 15 8C. The spectral changes
associated with the reaction were monitored at a, 0; b, 2; c, 3; d, 6; e, 18 h.

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Fig. 2. Spectrum analysis of DC (0.16 mmol lꢂ1) transformation in the presence of Al3ꢁ (0.16 mmol lꢂ1) in pH 5.5 HAcꢀ
buffer solution at 15 8C. The spectra were monitored at a, 0; b, 3; c, 5.5; d, 8; e, 10.5; f, 13; g, 15.5; h, 100 min.
/NaAc
are general absorption in the range of 250ꢀ
/
800
Fig. 3 showed the course of DC conversion in
the presence of a number of aluminum ions
concentration at pH 5.5. When concentration of
aluminum ions were far less than that of DC, the
nm, which is utilized in photoreceptor shielding
and may play a role as a photoprotective pigment
in humans.
Fig. 3. Effect of aluminum ions on the conversion of DC (0.16 mmol lꢂ1) in pH 5.5 HAcꢀ
concentration of aluminum ions [Al] was a, 0.40; b, 0.16; c, 0.08; d, 0.04; e, 0.016; d, 0.008 mmol l
/
NaAc buffer solution at 15 8C. The
ꢂ1
.

J. Di, S. Bi / Spectrochimica Acta Part A 59 (2003) 1689ꢀ
/1696
1693
decrease of DC was linear with time (Fig. 3, line e
ꢂ5
and f). The apparent rate constant is 5.0ꢄ
/
10
ꢂ1
ꢂ1
3ꢁ
s
in the presence of 8 mmol l
Al . On the
other hand, the conversion of DC followed first-
order kinetics with respect to the DC concentra-
tion for at least 60% of the reaction (Fig. 4) when
the concentration of aluminum ions was higher.
The apparent first-order rate constant is 2.5ꢄ
/
ꢂ3 ꢂ1
ꢂ1
3ꢁ
1
0
s
It is known that cyclic voltammetric analysis is
in the presence of 0.4 mmol l
Al
.
also useful and convenient in determining the
redox behavior of catecholamine. Fig. 5 showed
the cyclic voltammograms of L-DOPA, DC and
the colorless production of DC conversion by
aluminum ions. Voltammetric measurements
ꢂ1
were performed at 100 mV s in pH 5.5 medium
removed oxygen by bubbling nitrogen starting the
record. The DOPA oxidation peak and the corre-
sponding dopaquinone reduction peak appeared
at about 0.30 and 0.25 V, respectively. They were
followed by another set of peaks at most negative
Fig. 5. Cyclic voltammograms of DOPA (a), DC (b) and the
3ꢁ
colorless solution of DC after added Al
ꢂ1
(c) in pH 5.5 HAcꢀ
/
NaAc buffer solution at 100 mV s
scan rate. Nitrogen gas
was bubbled through the solution before starting the record.
Work electrode: glassy carbon electrode; reference electrode:
saturated Ag/AgCl electrode; counter electrode: Pt electrode.
potentials: the DC reduction at about ꢂ
and the leucodopachrome oxidation at about ꢂ
.10 V. In the middle, there was an irreversible
/0.15 V
/
oxidation peak at 0.20 V, which corresponded to
DHI oxidation peak.
0
Fig. 4. Plot of ln[DC] /[DC]
o
t
against time in the presence of 0.16 mmol lꢂ1 DC and 0.4 mmol lꢂ1 Al3ꢁ in pH 5.5 HAcꢀ
NaAc buffer
/
solution at 15 8C.

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J. Di, S. Bi / Spectrochimica Acta Part A 59 (2003) 1689ꢀ1696
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4
. Discussions
two different pathways [10,38]. The first possible
mechanism is that it undergoes decarboxylation to
form the indolemine derivative and subsequent
transformation to DHI. A possible alternative
pathway involves the formation of unstable qui-
none methide which can decarboxylate to yield
DHI.
The results reported in this paper provide the
evidence that aluminum ions exert a profound
influence on the kinetics and mode of conversion
of DC in acidic conditions. As it is now generally
accepted that dopachrome tautomerase (DCT, EC
5
.3.2.3) might play a central role in the regulation
In a few words, the mechanism proposed for the
DC conversion in the presence of aluminum ions
can be shown in Eq. (1).
of mammalian melanogenesis [14,18]. It catalyzes
the tautomerization of DC into the more stable
intermediate 5,6-dihydroxyoxyindole-2-carboxylic
acid (DHICA), rather than the decarboxylative
conversion to DHI, the spontaneous step that
proceeds in the absence of DCT [14]. Natural
melanins are considered copolymers of DHI and
DHICA in various ratios [7,35]. The presence of
the carboxy group in DHICA-derived monomers
is believed to be a strong effect on the properties of
the melanins. They might have a higher chelating
capacity, and, owing to the limitation of the
number of polymerization positions available in
the indole ring, they are thought to be smaller,
more ordered structure and lighter in color than
DHI-rich pigments [16,34,35]. Therefore, the con-
version of DC to DHI and DHICA is a key
reaction in melanin biosynthetic pathway.
k1
k2
DCꢁAl X DCꢂAl 0 DHIꢁAl
(1)
k
ꢂCO2
ꢂ1
Therefore,
d[DHI]=dtꢃꢂd[DC]=dt
ꢃk [AlꢀDC]
2
ꢃk (k =kꢂ1)[Al][DC]
(2)
2
1
The rate of DC conversion depends on both of
the concentration of aluminum ion and DC.
When [Al] is high enough, the concentration of
aluminum ions is constant in the reaction process.
Therefore,
It has been demonstrated that aluminum ions
form stable complexes with DOPA and related
compounds through a type O,O bonding at the
ortho-phenolic hydroxyl groups [36,37]. The con-
version of DC catalyzed by transition metals, such
d[DHI]=dtꢃꢂd[DC]=dt
ꢃk?[DC]
(3)
1
where k
?
represents the apparent first-order rate
1
2
ꢁ
2ꢁ
as Cu
metalꢀ
the DC conversion process involves a transition
state of aluminumꢀdopachrome (AlꢀDC) com-
and Zn , involves the intermedia of
constant for DHI formation. The conversion of
DC follows first-order kinetics with respect to the
DC concentration (Fig. 4).
/DC complex [11]. Therefore, by analogy
When [Al]ꢀ[DC], the concentration of DC
/
/
/
changes little in the earlier stage of the reaction
process and can be regard as constant.
plex (Fig. 6). The complex with decarboxylation
and deprotonation at carbon may produce DHI by
d[DHI]=dtꢃꢂd[DC]=dt
ꢃk?[Al]
2
ꢃk?[Al]o
(4)
2
where [Al] represents the whole concentration of
o
aluminum added in the system and k represents
?
2
Fig. 6. A possible intermedia of aluminumꢀ
plex (AlꢀDC) involving in the DC conversion catalyzed by
aluminum ions.
/
dopachrome com-
the apparent rate constant of the DC conversion.
Since the aluminum ions are recycled, the concen-
/

J. Di, S. Bi / Spectrochimica Acta Part A 59 (2003) 1689ꢀ
/1696
1695
tration of aluminum ions ([Al] ) is almost constant
t
ions may enhance the melanin formation by means
of catalyzing the DC conversion, which increases
oxidative stress. It also may increase the ratio of
DHI/DHICA and influence the structure of mel-
anins, which could greatly influence the properties
of the melanins.
in the earlier stage of the reaction and approximate
to the whole concentration of aluminum ions
added ([Al] ). The rate of DC bleaching presents
o
linear with the time in the earlier stage of the
reaction (Fig. 3, line e and f).
Data from cyclic voltmmetric measurements
further show that the formation of DHI is
enhanced by the presence of aluminum ions under
these conditions. In contrast to quinone species
derived from o-diphenolic compounds, IQ, once
formed, polymerizes rapidly, as shown by the
darkening of the reaction mixture. This explains
the absence or presence of only a very small
reverse peak (reduction peak) during cyclic vol-
tammogram of DHI.
Acknowledgements
This project is supported by the National
Natural Science Foundation of China (No.
20075011) and research funding from the State
Education Administration of China for young
teachers. The authors would like to thank Profes-
sor Yifen Tu for his support and help.
Aluminum ions catalyze DC conversion to
produce DHI at pH 5.5, but have little effect at
pH 6.8. Moreover, the effect of aluminum ions on
iron-induced lipid peroxidation is favored by
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/
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to be associated with inflammatory response [3].
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