LINK 24 The Chemical Structure of Melanin
INTRODUCTION
One
year ago a letter to the Editor entitled ‘’ The Chemical Structure of Melanin
‘’ by Dr. W.L. Cheun and the reply of
Drs J. D. Simon and S. Ito, appeared on Pigment Cell Research ( 2004 ) 17; 422-424 .
Some new aspects concerning the chemical structure of melanin and many fundamental papers ( G.Swan, M.S.Blois, H.Mason, J.Harley-Mason,
J.Bu’Lock, M.G.Peter , H.Wyler,
M.Piattelli, E.Fattorusso V.Hearing,
J.Duchon, H.Rorsman, M.R.Chedekel, M.G.Bridelli, R.A.Nicolaus, G.Prota,
M.d’Ischia, A.Pezzella, A.Bolognese ) have not been adequately treated. Several
important references, especially for
those turning to the study of melanin structure are neglected..The contribute
from Italian Research to melanin chemistry starting from Angelo Angeli is
ignored.
The
main purpose of this paper is to try to
limit the bad scientific information and extend our real knowlrdge of melanin
A new classification and recent advances on
melanin chemistry and structure ( radical-polarone system of acetylene-black )
are presented . Our experiment will not end the debate about a final melanin
structure but it may help to push the research
in a specific and right
direction.
A list of papers which don’t
appear frequently in literature, but
useful for research on melanin, is reported. References for
determination of eumelanin pheomelanin
and allomelanin methods are cited. Some points worth of being recalled to
the melanin expert are the
followings :
1 . Melanoma was found to be constituted by two different melanins ( M. Bakunin 1904 ) 2 . Simple or complex pyrrole acids were
isolated among the oxidative degradation
mixture of Sepia melanin ( L.Panizzi, R.A.Nicolaus
1952 ). DHI and DHICA were obtained for the first time as degradation products
( R: A: Nicolaus, M.Piattelli 1962 ). 3 . The precursor of pheomelanins and pheochromes is the new aminoacid 5-S-Cysteinyldopa and related isomers .( R.A.Nicolaus 1968 ). 4 . The chromophores ( dibenzothiazine
and dibenzothiazinone ) of pheochromes have been synthetised. ( B.Kaul
1974 ). 5
. Melanins are able
to bind organic molecules, ions, liquids, gases ( M.S.Blois 1965), ( H.
Rorsman, 1972 ) ( N.G.Lindquist, B.Larsson ,C.Hanson,
G.Agrup, E.Rosengren and the Swedish
School since 1972 ). 6 . Melanins exhibit two separate
current - voltage characteristics, the on and off. ( J.McGinness, J.P.Proctor
1974 ) . 7 . The neuromelanin of the human Substantia nigra was isolated ( H.Rorsman 1991 ). 8 . Melanins
are particles (M.R.Chedekel 1992 ) . 9 . Eumelanin particles (granules covered by a membrane)
are called melanosomes. Melanosomes may
be obtained in pure form. ( V.J.Hearing
1973 ). 10 . The
particles are formed by oligomers ( melanochromes ) of low molecular weight (M.G.Peter
1996) . 11 . All
melanins show the radical polarone system of acetylene black ( R.A. Nicolaus
2001 ). 12 . All melanins have about one oxygen atom more than the
precursors ( R.A.Nicolaus 2001 ). 13 . The
particle may show a certain level of organization ( J.D.Simon 2001 ) . 14 . All black particles, from carbon to sepiomelanin, have
similar physical properties.The melanin particle gave X-ray examination results which may suggest
not only graphite but also fullerene or helicoidal cages. The helicoidal
system may produce a magnetic field. (
A.Bolognese 2001 ). 15 . The
organic black matter in the interstellar clouds is supposed to protect organic
material from dangerous rays and to regulate the ion/radical/ molecule balance
. ( B.J.R.Nicolaus,R.A.Nicolaus 1999
). All these data and properties suggest
important functions of eumelanins in Biology.( 30 )
CLASSIFICATION
The current
classification of melanins is not
satisfactory.
The black matter may be
organised as followings :
The
black cell matter ( BCM )
The black
synthetic matter ( BSM )
The BCM may be
classified as :
Eumelanin Mammalian colouring is mainly dependent on the secretory activity of a
unique pigmentary system,the melanocyte, which is capable of producing three
chemically distinct types of pigments.These are, the dark insoluble,
nitrogenous eumelanins, the sulphur-containing alkali-souble pheomelanins
which provide the lighter colours, the amphoteric pheochromes ( red and
red-orange colours ), closely related to pheomelanins but found only in certain types of reddish
hair as well in melanoma urines.
eumelanin
Eumelanins are particles generally derived from
DOPA, and widespread in the animal kingdom in
skin, hair, furs, eyes, brain, feathers ( 1-6 ).
The particles covered with a membrane are called melanosomes.
Melanosomes may be purified with the method of
V.Hearing (7-8) . The
particles are formed by olygomers which are derived from precursors of
different type like DHI, DHICA,DOPA, Cyclodopa, Decarbossicyclodopa The melanin
prepared in vitro by Swan are different from those of cell origin. ( 4 ), ( 5a ), ( 6 ) Melanins
show a typical EPR signal.
Melanins are sensitive to oxidants.Oxidative
degradation products are pyrrole acids. Methods are available for melanin ,
pheomelanin and allomekanin quantitative determination .
. Neuromelanin particles generally derived from dopamine and
cysteinyldopamine. Neuromelanin
from pigmented neurons.. Substantia nigra was isolated by H.Rorsman in 1991. Structural
studies by Zecca in 2001
( 51-52 )Studies on neuromelanin primates ( 50 ),.Adrenalin-black was
studied by J.Bu’Lock in 1960 ( 36d ).
Substantia nigra
As reported by M.G.Bridelli the IR of neuromelanin has features similar to
those of synthetic dopamine-melanin but different with other
catecholamine-black .All that we know about dopamine-black is due to G.Swan
works ( 6 ) Dopamine-melanin have one oxygen more than the precursor
------------------------:
Dopamine-melanin found : 57.9 C% 5.7 H% 8.0
N%
Calculated for ( C8 H5 O3 N )x : 57.2
C% 4.7 H%
8.3 N%
Calculated for ( C8 H3 O2
N )x
: 66.2 C%
2.0 H% 9.6 N%
----------------------
The pigment was found to be soluble in dilute
alkali,to give a lightbrown derivative with benzoyl chloride having one benzoyl
group per 8-carbon unit in the polymer.
IR indicate that benzoylation had occurred chiefly at the phenolic hydroxyl
groups.Analysis led Swan to suggest that the ‘’ polymer ‘’ contain uncyclised dopamine units,
carboxylated pyrrole units 5,6-dihydroxyindole units.The presence of one oxygen
atom more in the polymer was not discussed.As showed by solid state NMR
dopamine melanin contains larger proportions of uncyclised units compared with DOPAmelanin . Black / brown pigmented granules are present in the human
central nervous system The most
pigmented regions are two areas: substantia nigra and the locus coeruleus.
Histological studies displayed pigmentation in the substantia nigra of other mammals phylogenetically close to humans,
including the shimpanzee, and more distant ones, such as horses and sheep.
Histochemical studies on human substantia
nigra and locus coeruleus found
that the pigment had similar properties to the melanins, including insolubility , bleaching by hydrogen peroxide, labelling by
silver stains. The pigment was therefore named neuromelanin. Histological
studies showed that neuromelanin granules were located in the neuronal
perikaryon and were surrounded by a double membrane. In humans and horses,
histochemical analyses indicated an association of neuromelanin granules with
lipofuscin. In the substantia nigra,
neuromelanin accumulates during aging
and is found after the first 2 to 3 years of life. The substantia
nigra neurones are more vulnerable than the non-pigmented ones. However,
important questions remain regarding the possible role of neuromelanin in the substantia nigra, both under
physiological conditions and in the pathogenesis of Parkinson’s disease.
Neuromelanins like others melanins (BCM) show electrical activity.The presence in the brain of electrical material may be interesting.
Dopamine may be a precursor of neuromelanin but like other melanins the polymer has more
oxygen than the precursor.
Dopamine ( C8H11NO2
, mol.weight 153,18 ; 62.7 C% ,
7.2 H%., 9.1 N% ) forms in alkaline medium, by oxidation, black / brown material..Dopamine is present
in bananas being responsible for the blackning of the fruit.Dopamine
partecipate to the biogenesis of
some alkaloids .
Initially, the name neuromelanin
was chosen because of its similarity in appearance to skin melanin. However,
the electron paramagnetic resonance (EPR) and metal analysis studies indicate
that chemically neuromelanin has a
stable free radical structure.
Furthermore neuromelanin and synthetic melanin are amorphous semiconductors.
The
ability of neuromelanin to bind several inorganic and organic compounds, to
chelate metal ions , to store liquids and gases, to show sound and electrical
conductivity, are difficult to understand
from a chemical point of view but not from the bionanoscientists.
Degradation analyses using
potassium permanganate and hydriodic acid hydrolysis showed that neuromelanin
has properties of both pheomelanin and eumelanin. Elemental analyses of
neuromelanin revealed a high sulphur content (2.5–2.8%), with a molar C/H ratio
lower than that of synthetic melanins, thus indicating the presence of
aliphatic groups and benzothiazine rings.
Infrared spectroscopy of
neuromelanin ( and other melanins BCM ) revealed the presence of aliphatic groups
and a low intensity aromatic component, whereas in synthetic melanins the
aliphatic groups were absent. Chemical degradation studies showed that
neuromelanin is a mixture of melanin
(BCM) and pheomelanin .
Neuromelanin shows a peptide component of about 15%. The
amino acids could be derived from a direct reaction between the melanic polymer
and proteins, or dopamine molecules bound to cysteinic residues of polypeptidic
chains. Indeed, the precursor of neuromelanin synthesis has been suggested to be
cysteinyl-dopamine, although a study using hydriodic acid hydrolysis failed to
identify the corresponding degradation products. Moreover, nuclear magnetic
resonance spectroscopy indicates that the presence of both aliphatic and
aromatic hydrogens, and the ratio of aliphatic to aromatic hydrogens is again
higher in neuromelanin than in synthetic melanins, suggesting that dopamine
cannot be the only precursor in neuromelanin synthesis.
x Ray difraction studies have shown
that neuromelanin has a multilayer (graphite-like) three dimensional structure
similar to synthetic and naturally occurring melanins. The three dimensional
structure is derived from planar overlapped sheets consisting of cyclic
molecules of indolebenzothiazine rings. However,these sheets are stacked much
higher in neuromelanin than in any other synthetic and naturally occurring
melanins.
The process of neuromelanin
formation is difficult to understand. It
has long been debated whether the synthesis of neuromelanin is enzymatically
mediated or whether it is a pure autooxidation process of dopamine derivatives.
For eumelanin synthesis, the enzyme tyrosinase
catalyses the conversion of tyrosine to L-dopa and then to dopa-quinone.
Some authors proposed that tyrosinase could also be involved in neuromelanin
biosynthesis because tyrosinase mRNA and promoter activity have been detected
in the substantia nigra.
Moreover, albinos who lack
tyrosinase display normally pigmented substantia nigra. Alternative enzymatic
actions have been suggested, including tyrosine hydroxylase mediated oxidation
of dopamine. In another study, peroxidase catalysed the oxidation of tyrosine
to dopa and then dopamine, and further oxidisation to the respective quinones
that are possible precursors of neuromelanin.
Alternatively, neuromelanin could
derive from non-enzymatic oxidation. The autooxidation of catechols to quinones with the addition of
a thiol has been demonstrated in the brain.
A dopamine-melanin can be
synthesised by the autooxidation of dopamine, although there are several
structural differences between synthetic melanins and the natural one isolated
from the substantia nigra. Recently,
neuromelanin synthesis was induced in rat substantia
nigra neurones and PC cell cultures by exposure to L-dopa. The pigment produced
in this model contains a stable free radical; in addition, both light and
electron microscopy have shown that the pigment synthesised in these cells
appears to be identical to human neuromelanin, and the granules are
surroundedby a double membrane, similar to the naturally occurring neuromelanin
of the substantia nigra. In those experiments, treatment with the iron chelator
desferrioxamine inhibited neuromelanin synthesis stimulated by L-dopa;
therefore, it seems that iron ( or an iron catalyst ) is involved in
neuromelanin formation. In this model, neuromelanin synthesis was shown to be
driven by an excess of cytosolic catecholamines not accumulated in synaptic
vesicles.
The herbicide paraquat has a
molecular structure similar to that of MPTP, and has been proposed as a
Parkinson’s disease inducing agent. The pesticide is accumulated in
neuromelanin containing nerve cells, where it appeared that the neuromelanin
adsorbed intraneuronal paraquat, protecting the neurones from consequent
damage.
Neuromelanin like others BCM can
also accumulate chlorpromazine, haloperidol, and imipramine, thereby
contributing to the control of the intraneuronal concentration of these
molecules.
Because higher intraneuronal concentrations of
dopaminergic drugs might be toxic to substantia nigra neurones, neuromelanin
can influence this toxicity. The association of neuromelanin with lipids has
been described in several studies.
Although previous studies proposed
that lipids were part of the neuromelanin molecule, recent work has shown that
neuromelanin contains about 20% adsorbed lipids. Cholesterol is a minor
component in this lipid mixture, with the major component being a new class of
polyunsaturated lipid with a high molecular weight, low volatility, and low
oxygen content.
High concentrations of iron and
other metals are present in several
brain nuclei. Neuromelanin from the substantia
nigra can interact with many heavy metal ions such as zinc, copper,
manganese, chromium, cobalt, mercury, lead, and cadmium; in addition, it binds
iron particularly EPR studies showed that in the substantia nigra the ferric iron is bound to neuromelanin as a high spin complex with
an octahedral configuration. Mössbauer spectroscopy demonstrates that ferric
iron is chelated by the neuromelanin
polymer and that the iron sites are arranged in a ferritin-like
iron-oxy-hydroxide cluster form. The
cluster conductivity is unknown.
X rays absorption fine structure
spectroscopy and infrared spectroscopy studies confirmed thatiron in
neuromelanin was bound by oxygen derived phenolic groups in an octahedral
configuration. In substantia nigra
tissue, neuromelanin is only about 50% saturated withFe(III), therefore
maintaining an important residual chelating capability, which can protect
against iron toxicity.Values of iron
complex conductivity are unknown.
Neuromelanin can sequester redox
active iron ions, reducing the formation of free hydroxyl radicals. Thus, in
normal subject s, neuromelanin may play a protective role b inactivating the iron ions that induce
oxidative stress. The ability of
neuromelanin to chelate other redox active metals such as copper, manganese,
chromium, and toxic metals including cadmium, mercury, and lead strengthens the hypothesis that neuromelanin
may have a high capacity storage trapping system for metal ions which may prevent neuronal damage.
Electrical
conductivity of the different chelates has not determined until now. Neuromelanin
accumulates normally with age in human substantia
nigra neurones. A neuronal pigment has also been observed in the ubstantia
nigra of adult rats and dogs, and its concentration seems to depend upon age.
In very old (23 months) rats, but not in younger animals, neuromelanin granules
were detected by electron microscopy; similar results were observed in aged
dogs. Neuromelanin granules were also detected in catecholaminergic cerebellar
cells of monkeys and their presence
correlated with age. In human substantia
nigra, the first small, brown neuromelanin granules were clearly
discernable at approxim tely 3 to 5 years of age. The neuromelanin content of
neurones is highest in individuals in th ir 60s, after which it decreases; this
phenomenon may reflect the neuronal loss observed in these anatomical
structures during aging. However, there is no significant loss of
catecholaminergic neurones in the substantia
nigra of normal subjects until very old ages.
In patients with Parkinson’s
disease, neuromelanin values were 1.2–1.5 mg/g of substantia nigra , which is less than 50% of that seen in age matched
controls . The absolute number of pigmented neurones in the substantia nigra of normal subjects may
be dependent upon ethnicity—an Indian population was found to have fewer
pigmented neurones than an agematched Western population.. Because the neuromelanin
concentration in substantia nigra
neurones increases, and the number of pigmented neurones appears to be constant
over the life span, it seems that neuromelanin accumulates only in a
subpopulation of nigral neurones, whereas other dopaminergic neurones remain
nonpigmented. The observed decrease in the neuromelanin concentration occurring
in the substantia nigra of patients with Parkinson’s disease confirms the loss
of pigmented neurones occurring in the substantia
nigra of these patients, as has been reported in neuropathological studies.
Other studies indicate that neuromelanin values decrease in the surviving
neurones of the substantia nigra during Parkinson’s disease. This could be the
result of reduced neuromelanin synthesis, neuromelanin degradation, or higher
vulnerability of the pigmented neurones.
Although in idiopathic Parkinson’s
disease the neurones are depleted in both the substantia nigra and locus
coeruleus, in MPTP intoxicated subjects, locus coeruleus neurones are
spared. Such a different neuronal vulnerability might eventually be explained
by structural differences in the neuromelanin of the substantia nigra and locus
coeruleus.
Although neuromelanin may play a
cytoprotective role by sequestering redox active metals, toxic metals, and
organic toxic compounds, neuromelanin might also become a source of free
radicals by reaction with hydrogen peroxide. When free neuronal iron increases
to the point where neuromelanin becomes saturated and it starts to catalyse the
production of free radicals, neuromelanin would become cytotoxic with an
increasing of the conductivity.
Moreover, because hydrogen peroxide can
degrade neuromelanin, the pigmented neurones could loose this putatively
protective agent. The consequence may be a release of iron and other cytotoxic
metals or compounds from neuromelanin that could accelerate neuronal death.
The pigmented neurones of the
substantia nigra are typically lost in Parkinson’s disease; however, the
possible relation between neuronal vulnerability and thepresence of
neuromelanin has not been elucidated. Early histological studies revealedthe
presence of increasing amounts of neuromelanin in the substantia nigra
with aging in higher mammals, showed that the neuromelanin granules are
surrounded by a membrane, and comparatively evaluated the pigmentation of the substantia
nigra in different animal species. Histochemical studies showed the
association of neuromelanin with lipofuscins. However, systematic
investigations of the structure, synthesis, and molecular interactions of
neuromelanin have been undertaken only during the past decade. In these later
studies, neuromelanin was identified as a genuine melanin with a strong
chelating ability for iron and an affinity for compounds such as lipids,
pesticides, MPP+ (methylphenylpyridine ion ). The affinity of
neuromelaninfor a variety of inorganic and organic toxins is consistent with a
postulated protective function for neuromelanin. Moreover, the neuronal
accumulation of neuromelanin during aging and the link between its synthesis
and a high cytosolic concentration of catechols suggest a protective role.
However, its putative neuroprotective effects could be quenched in conditions
of toxin overload.
Black / brown pigmented granules in
the human central nervous system has been observed since the half past
century (1) The most pigmented regions are two mesencephalic areas:
Sömmering’s substantia nigra and the locus coeruleus. Histological studies
displayed pigmentation in the substantia nigra of other mammals phylogenetically
close to humans, including the shimpanzee, gibbon, and baboon, and more distant
ones, such as horses and sheep. Histochemical studies on human substantia nigra
and locus coeruleus found that the pigment had similar properties to the
melanins, including being insoluble in organic solvents, being bleached by
hydrogen peroxide, and being labelled by silver stains. The pigment was
therefore named neuromelanin.Histological studies showed that neuromelanin
granules were located in the neuronal perikaryon and were surrounded by a
double membrane. In humans and horses, histochemical analyses indicated an
association of neuromelanin granules with lipofuscin.In the substantia nigra,
neuromelanin accumulates during aging and is found after thefirst 2 to 3 years
of life.
Parkinson’s disease is a
neurodegenerative disorder
caused by the selective death of pigmented substantia nigra neurones,
giving rise to dopamine depletion in the neostriatum, and
resulting in clinical syndrome characterised by tremor, rigidity, and severely
impaired motility. The pigmented substantia nigra neurones are more vulnerable
than the non-pigmented ones. However, important questions remain regarding the
possible role of neuromelanin in the substantia nigra, both under physiological
conditions and in the pathogenesis of Parkinson’s disease. Here, we review
those studies undertaken during the past 10 years on the molecular aspects of
neuromelanin, and attempt to integrate these structural aspects with
morphological findings.
Initially, the name neuromelanin was
chosen because of its similarity in appearance to cutaneous melanin. However,
recent electron paramagnetic resonance (EPR) and metal analysis studies
indicate that chemically neuromelanin is indeed a genuine melanin because it
has a stable free radical structure and avidly chelates metals. The ability of
neuromelanin to interact with several inorganic and organic compounds,
including metal ions and lipids, complicates studies of the structure of this
pigment. Degradation analyses using potassium permanganate and hydriodic acid
hydrolysis showed that neuromelanin has properties of both pheomelanins and
eumelanins. Elemental analyses of neuromelanin revealed a high sulphur content
(2.5–2.8%), with a molar C/H ratio lower than that of synthetic melanins, thus
indicating the presence of aliphatic groups and benzothiazine rings. Infrared
spectroscopy of neuromelanin revealed the presence of aliphatic groups and a
low intensity aromatic component, whereas in synthetic melanins the aliphatic groups
were absent. Chemical degradation studies showed that neuromelanin contains
equal amounts of indole and benzothiazine molecules. Neuromelanin consistently
shows a peptide component of about 15%. The amino acids could be derived from a
direct reaction between the melanic polymer and proteins, or dopamine molecules
bound to cysteinic residues of polypeptidic chains. Indeed, the precursor of
neuromelanin synthesis has been suggested to be cysteinyl-dopamine, although a
study using hydriodic acid hydrolysis failed to identify the corresponding
degradation products. Moreover, nuclear magnetic resonance spectroscopy
indicates that the presence of both aliphatic and aromatic hydrogens, and the
ratio of aliphatic to aromatic hydrogens is again higher in neuromelanin than
in synthetic melanins, suggesting that dopamine cannot be the only precursor in
neuromelanin synthesis. x Ray difraction studies have shown that neuromelanin
has a multilayer (graphite-like) three dimensional structure similar to
synthetic and naturally occurring melanins. The three dimensional structure is
derived from planar overlapped sheets consisting of cyclic molecules of
indolebenzothiazine rings. However,these sheets are stacked much higher in
neuromelanin than in any other synthetic and naturally occurring melanins. The
process of neuromelanin formation is obscure, although a recent in vitro study
has clearly established some steps of this complex process. It has long been
debated whether the synthesis of neuromelanin is enzymatically mediated or
whether it is a pure autooxidation process of dopamine derivatives. For
eumelanin synthesis, the enzyme tyrosinase (also known as monophenol
monoxygenase) catalyses the conversion of tyrosine to L-dopa and then to
dopa-quinone. Some authors proposed that tyrosinase could also be involved in
neuromelanin biosynthesis because tyrosinase mRNA and promoter activity have
been detected in the substantia nigra. However, tyrosinase has not been
detected in the substantia nigra by immunohistochemistry. Moreover, albinos who
lack tyrosinase display normally pigmented substantia nigra. Alternative
enzymatic actions have been suggested, including tyrosine hydroxylase mediated
oxidation of dopamine. In another study, peroxidase catalysed the oxidation of
tyrosine to dopa and then dopamine, and further oxidisation to the respective
quinones that are possible precursors of neuromelanin. It was proposed that
prostaglandin H synthase, which has peroxidase activity and is located on the
mitochondrial membrane, could mediate the oxidation of dopamine to
dopaminequinone, which can internally cyclise to form a pseudo indole
derivative called dopachrome. In addition, enzymatic activity of macrophage
migration inhibitory factor was suggested for neuromelanin synthesis, because
it converts catecholamines intodihydroxyindole derivatives, which are potential
precursors of neuromelanin. Alternatively, neuromelanin could derive from
non-enzymatic oxidation. The autooxidation of catechols to quinones with H2O2
formation and addition of a thiol has been demonstrated in the brain. A
dopamine-melanin can be synthesised by the autooxidation of dopamine, although
there are several structural differences between synthetic melanins and the
natural one isolated from the substantia nigra. Recently, neuromelanin
synthesis was induced in rat substantia nigra neurones and PC cell cultures by
exposure to L-dopa. The pigment produced in this model contains a stable free
radical; in addition, both light and electron microscopy have shown that the
pigment synthesised in these cells appears to be identical to
humanneuromelanin, and the granules are surrounded by a double membrane,
similar to the naturally occurring neuromelanin of the substantia nigra. In
those experiments, treatment with the iron chelator desferrioxamine inhibited
neuromelanin synthesis stimulated by L-dopa; therefore, it seems that iron is
involved in neuromelanin formation. In this model, neuromelanin synthesis was
shown to be driven by an excess of cytosolic catecholamines not accumulated in
synaptic vesicles. Neuromelanin interacts with numerous organic molecules
including lipids, pesticides, and toxic compounds. MPTP (1-methyl-4-
phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin that after systemic
administration selectively kills substantia nigra neurones by conversion
through monoamino-oxidase type B activity to methylphenylpyridine (MPP+), which
in turn stops the respiratory chain at the NADH-CoQ1 reductase stage, leading
in humans and several other animal species to an irreversible parkinsonian
syndrome. Neuromelanin might reduce the toxicity of MPTP by accumulating its
toxic metabolite MPP+ in vivo. The herbicide paraquat has a molecular structure
similar to that of MPTP, and has been proposed as a Parkinson’s disease inducing
agent. The pesticide is accumulated in neuromelanin containing nerve cells,
where it appeared that the neuromelanin adsorbed intraneuronal paraquat,
protecting the neurones from consequent damage. Neuromelanin can also
accumulate chlorpromazine, haloperidol, and imipramine, thereby contributing to
the control of the intraneuronal concentration of these molecules. Because
higher intraneuronal concentrations of dopaminergic drugs might be toxic to
substantia nigra neurones, neuromelanin can influence this toxicity. The
association of neuromelanin with lipids has been described in several studies.
Although previous studies proposed that lipids were part of the neuromelanin
molecule, recent work has shown that neuromelanin contains about 20% adsorbed
lipids. Cholesterol is a minor component in this lipid mixture, with the major
component being a new class of polyunsaturated lipid with a high molecular
mass, low volatility, and low oxygen content.31 It may be that neuromelanin
itself catalyses the synthesis of this type of lipid. Alternatively,
neuromelanin could originate from lipofuscin by an enzymatic reaction occurring
in lysosomes, although this hypothesis is not supported by recent observations.
In this case, high molecular mass lipids could be derived from a lysosomal
metabolic pathway and might interact with neuromelanin within these organelles.
High concentrations of iron and other nonalkaline metals are present in several
brain nuclei. Neuromelanin from the substantia nigra can interact with many
heavy metal ions such as zinc, copper, manganese, chromium, cobalt, mercury,
lead, and cadmium; in addition, it binds iron particularly strongly. In the
course of Parkinson’s disease and related syndromes, the concentration of iron
in the substantia nigra increases by 30–35%. This accumulation of nigral iron
seems to occur within the neuromelanin granules: the concentration of iron in
these granules is higher in patients with Parkinson’s disease than in normal
subjects. Although a neuromelanin–glycolipid complex was proposed as a good
chelating and insolubilising system to bind iron ions, it now appears that iron
is bound to catecholic groups and not to lipids. EPR studies showed that in the
substantia nigra the ferric iron is bound to neuromelanin as a high spin complex
with an octahedral configuration. Mössbauer spectroscopy demonstrates that
ferric iron is chelated by the neuromelanin polymer and that the iron sites are
arranged in a ferritin-like ironoxyhydroxide cluster form. x Ray absorption
fine structure spectroscopy and infrared spectroscopy studies confirmed that
iron in neuromelanin was bound by oxygen derived phenolic groups in an
octahedral con-figuration. In substantia nigra tissue, neuromelanin is only
about 50% saturated with Fe(III), therefore maintaining an important residual
chelating capability, which can protect against iron toxicity. Neuromelanin can
sequester redox active iron ions, reducing the formation of free hydroxyl
radicals. Thus, in normal subjects, neuromelanin may play a protective role by
inactivating the iron ions that induce oxidative stress. The ability of
neuromelanin to chelate other redox active metals such as copper, manganese,
chromium, and toxic metals including cadmium, mercury, and lead
strengthens the hypothesis that neuromelanin may be a high capacity storage
trapping system for metal ions and, as such, may prevent neuronal damage.
Neuromelanin accumulates normally with age in human substantia nigra neurones.
A neuronal pigment has also been observed in the substantia nigra of adult rats
and dogs, and its concentration seems to depend upon age. In very old (23
months) rats, but not in younger animals, neuromelanin granules were detected
by electron microscopy; similar results were observed in aged dogs.
Neuromelanin granules were also detected in catecholaminergic cerebellar cells
of monkeys (Macaca mulatta and Macaca
nemertina) and their presence correlated with age. In human substantia
nigra, the first small, brown neuromelanin granules were clearly discernable at
approximately 3 to 5 years of age. The neuromelanin content of neurones is
highest in individuals in their 60s, after which it decreases; this phenomenon
may reflect the neuronal loss observed in these anatomical structures during
aging. However, there is no significant loss of catecholaminergic neurones in
the substantia nigra of normal subjects until very old ages. A new
spectrophotometric method indicates that neuromelanin is not detectable during
the 1st year of life, but starts to accumulate thereafter, with a continuous
linear trend, and reaches a concentration of 2.3–3.7 mg/g of substantia nigra
pars compacta in 50–90 year old individuals. Male and female subjects showed
the same age trend of neuromelanin concentration. In patients with Parkinson’s
disease, neuromelanin values were 1.2–1.5 mg/g of substantia nigra pars
compacta, which is less than 50% of that seen in age matched controls . The
absolute number of pigmented neurones in the substantia nigra of normal
subjects may be dependent upon ethnicityan Indian population was found to have
fewer pigmented neurones than an age matched Western population. These
observations suggest that neurodegenerative disorders characterised by nigral
neurone loss, best typified by Parkinson’s disease and other parkinsonian
syndromes, are not the result of early aging, as hypothesised in the past.
Because the neuromelanin concentration in substantia nigra neurones increases,
and the number of pigmented neurones appears to be constant over the life span,
it seems that neuromelanin accumulates only in a subpopulation of nigral
neurones, whereas other dopaminergic neurones remain nonpigmented. The observed
decrease in the neuromelanin concentration occurring in the substantia nigra of
patients with Parkinson’s disease confirms the loss of pigmented neurones
occurring in the substantia nigra of these patients, as has been reported in
neuropathological studies. Other studies indicate that neuromelanin values
decrease in the surviving neurones of the substantia nigra during Parkinson’s
disease. This could be the result of reduced neuromelanin synthesis,
neuromelanin degradation, or higher vulnerability of the pigmented neurones.
Neuropathological investigations have examined the presence of extraneuronal
neuromelanin in subjects with idiopathic Parkinson’s disease and MPTP
intoxication. Most of this extraneuronal neuromelanin is phagocytosed by
microglia and is associated with astrocytic and microglial activation. It may
be that neuromelanin could be the eVector of a chronic inflammation process in
the substantia nigra. Although in idiopathic Parkinson’s disease the neurones
are depleted in both the substantia nigra and locus coeruleus, in MPTP
intoxicated subjects, locus coeruleus neurones are spared. Such a different
neuronal vulnerability might eventually be explained by structural differences
in the neuromelanin of the substantia nigra and locus coeruleus. Although
neuromelanin may play a cytoprotective role by sequestering redox active
metals, toxic metals, and organic toxic compounds,81 neuromelanin might also
become a source of free radicals by reaction with hydrogen peroxide. When free
neuronal iron increases to the point where neuromelanin becomes saturated and
it starts to catalyse the production of free radicals, neuromelanin would
become cytotoxic. Moreover, because hydrogen peroxide can degrade neuromelanin,
the pigmented neurones could loose this putatively protective agent. The
consequence may be a release of iron and other cytotoxic metals or compounds
from neuromelanin that could accelerate neuronal death. A critical review of the function of neuromelanin and an attempt to
provide a unified theory was recently reported ( Bruno J.R. Nicolaus Medical Hypotheses 2005 65, 791-796 ). This
paper provides a critical review of the numerous and various biological
functions so far attributed to neuromelanin and an attempt to provide a unified
theory based on the peculiar physical and chemical properties of the black
particle (the neuromelanin cage).It is stressed that neuromelanin is not
homogeneous, as is commonlyaccepted, but is made up of different substrate
specific black pigments formed by the oxidation of o.diphenols or other oxygenated
precursors (substantia nigra melanin, locus coeruleus melanin, retinal
pigmented epithelium or ocular melanin, inner ear melanin, and so on). Ocular
melanin is believed to protect the eye by trapping metals and free radicals.
The paper shows that this unconfirmed mechanism is a rather fortuitous
irreversible molecular accident, which a times may prove itself
deleterious.Albinism often leads to deafness in animals, indicating a
geneticcorrelation. These two conditions appear to be correlated at a molecular
level to eye/ ear pigmentation and suggest verifying this hypothesis in normal
and albino human individuals.Skin and ocular melanin are chemically different. However,
they are both involved in lightabsorption/dissipation. The black particle
structure (melanin cage) is believed to be fundamental to this process because
there is a common bioelectric mechanism. The latter isworth of further investigation.
It is also proposed checking how ocular melanin dissipates the excessive
absorbed light (as heat or as current?). It has been claimed that inner ear
melanin mutes acoustic waves.This paper suggests investigating the underlying
mechanism and also studying whether this pigment is bio-electrically involved
in audio logy. According to numerous authors, Substantia nigra melanin is only
biological garbage. This view is rejected, and it is stressed that intracellular
melanogenesis is a fundamental and genetically controlled physiological
process. It has been repeatedly claimed that the binding of iron, heavy metals,
free radicals and harmful chemicals by substantia nigra melanin is fundamental
to body detoxification/protection. Presumably, such irreversible and generic
binding mechanisms have no physiological foundation; it is suggested the
alternative that, substantia nigra melanin acts as semiconductor, transmitting
and modulating nervous impulses, in a reversible way. In fact, substantia nigra
melanin is absent or significantly scarce in two conditions of life in which
the coordination of movement is either inefficient (newborn babies) or strongly
compromised (Parkinson). To check this assumption, further investigation of nucleus caudatus, putamen, globus pallidus,substantia
nigra pars compacta and reticulata, nucleus hypothalamicus is recommended .
Pheomelanin particles
generally derived from the aminoacid 5-S-cysteinyldopa ( R.A.Nicolaus 1965) . Light brown, or reddish , free or as
protein complex alkali soluble animal pigments found in hair, fur, feather .
The pigments of
pheomelanin
Typical degradation products are thiazole acids,
3-amino-4-hydroxy-benzoic acid , 3-hydroxy-4-aminobenzoic acid, 3-amino-4-hydroxytoluene,
3-hydroxy-4-aminotoluene, 1,6-(4-hydroxybenzothiazolyl)-alanine,
beta-6-(2-methyl-4-hydroxybenzothiazolyl)-alanine, beta-7-(4-hydroxybenzothiazolyl)-alanine,
beta-7-(3-oxo-5-hydroxy-3,4-dihydro-2H-1,4-benzothiazinyl)-alanine,
3-hydroxy-4-aminophenylalanine.After methylation of the pigments the followings
degradation products were obtained :
2,3,4,6,-tetracarbomethoxypyridine,
3,4,6-tricarbomethoxypyridine-2-carboxamide, 2-( 2’-(4’,5’-dicarbomethoxythiazolyl)
)-3,4,6-tricarbomethoxypyridine ,
3-Carbomethoxy-6-methoxy-7-aminoisoquinoline,
1-methyl-3-carbomethoxy-6-methoxy-7-aminoisoquinoline,
1-methyl-3-carbomethoxy-6,7-dimethoxy-isoquinoline. Some of these products are
utilized for pheomelanin identification.
Eumelanins and Pheomelanins may
coexist (copolymerized ? ) in Nature ( 1a ), ( 4 ) ( 9 ).
Some of these degradative compounds have been used for pheomelanin
identification.
Pheochromes
red or yellow crystallisable, low molecular weight,
compounds derived from 5-S-Cysteinyldopa ( Cysdopa ) and isomers . The
only pigment structure elucidated (see
formula below) is that isolated for the
first time from the
The Pigment of red hair
The cromophores
Allomelanin ( 5
) derived from nitrogen-free precursors
like catechol and 1,8-dihydroxynaphtalene have been found in plants, mould, yeast, bacteria, humic acid, fulvic
acid etc. Benzenepolycarboxylic
acid and
catechol derivatives were obtained as oxidative degradation products. A
typical allomelanin is the graphite-like pigment of the Aspergillus
The photo was a gift of Professor A.Quilico (
Some well known and famous BSM are
: Acetylene-black ( 12
),( 13), Pyrrole-black, Aniline-black.
Sepiomelanin chemistry
Melanin chemistry ( 1-4 ), ( 6) has produced poor results so far, due to the use of raw materials in chemical and physical
analyses and to scarce knowledge of solid state science by the researchers
involved. The discovery of the particle ( Chedekel 1992 ) is expected, in our
view, to change the strategy of future structural and functional melanin studies. Mass spectrometry is expected to be the most relevant fragmentation tool, replacing
the old oxidative and reductive degradation techniques used in the chemistry of
organic natural products.
Melanin generally does not dissolve
in water, acids, alkalies or organic solvents. Sonication may produce a fine
dispersion in alkali. IR and NMR spectra show the presence of OH, COOH, NH2, NH, CH2 groups.
Alkali fusion of eumelanin gave
5,6-dihydroxyindole ( DHI ) together with 5,6-dihydroxyindole-2-carboxylic acid
( DHICA ) ( Table I , 14, 15 ) Typical pyrrolic acids ( TABLE
I ) are formed by oxidation of eumelanin ( 16-21,
22-25 ).Pyrrole-tricarboxylic acid is also formed by boiling sepiomelanin
with dilute NaOH 4% . Although degradation products are formed in low yield
they gave interesting information about melanin structure.
--------------------------------------------------------
TABLE I
:Sepiomelanin degradation products : alkali fusion .
DHICA
5,6-dihydroxyindole 5,6-dihydroxyindole-2-carboxylic
acid
Sepiomelanin degradation products : KMnO4 oxidation
Pyrrole
acids ( 1 – 23, 44- 45 )
Complex pyrrole acids obtained as degradation
products of sepiomelanin (
26a, 26b, 42 ) :
----------------------------------------------------------------------
On heating at 200° CO2 is evolved.
Melanin reacts with diazomethane ( Table II ) and CH3OH+HCl giving
an ether and an ester respectively. Melanin is oxidised by H2O2
( a process which occurs also in vivo), KMnO4 , chlorine and bromine water, but is difficult
to be reduced. Oxidation produces not only simple but also complex pyrrole acids ( isolated as Ba salt
) ( 26a ). MALDI spectra (26b)
show degradation products useful in the study
of the chemical structure of melanin), ( 27 ), . It is possible that all eumelanin samples obtained until
now are artefacts ( breakdown of the benzenoid part ) produced by cellular H2O2
.
TABLE
II
Percentage of nitrogen , methoxyl goups in different methylated
pigments.
CO2 evolved during heating at 190-200°.
(Piattelli M.,Fattorusso E, Magno S.,Nicolaus
R.A. The structure of melanins and
melanogenesis II.Sepiomelanin and synthetic pigments. Tetrahedron 1962, 18,
941-949 ).
The methylated pigments are light
brown in colour,infusible and insoluble.
Methylated samples Free
samples
% N % OCH3 %
N % CO2
Sepiomelanin 7.4 18.8 8.5 9.1
DOPA-melanin (tyrosinase) 7.4 20.6 7.3 7.5
DOPA-melanin ( tyrosinase+catalase ) 6.5 19.6 6.3 5.2
DHI-melanin ( autoxidation ) 7.5 19.1 7.6 9.3
DHI-melanin (
tyrosinase ) 7.7 21.6 8.0 9.6
DHI-melanin
( tyrosinase + catalase ) 7.7 21.5 8.2 4.7
Pyrrole
black
14.0 8.6 13.8 4.9
____________________________________________________________________
BCM are particles derived from polyphenols .The
black particles discovered by M.R. Chedekel in
1992 ( 28 ) show
an interesting internal
organisation as reported by M.G.Bridelli and J.D.Simon ( 29-30 ) but results are still uncertain because the use of raw
material in the atomic force microscopy experiments. The particles are
formed from radical-polarone
oligomers of acetylene-black type, as
established by theorethical calculations ( 12
), ( 13 ) . They show high binding
power towards organic and inorganic compounds, to liquids and gases.These properties may influence or
distort the results of chemical and
physical analysis. The black particles are conductors showing the McGinness-Proctor ( 31 ) effect ( melanin exhibits the
unusual characteristics of an amorphous semiconductor with threshold switching
). Melanin may act as an innovative
sensor and energy generator, with the capacity of growing and shrinking in
length and volume, by electric stimulation.
It is interesting to note that the particle may exhibit non-invasive
control of the shape and growth of mammalian cells, as showed by D.E.Ingber
( 32
). Melanins show typical broad EPR, IR, solid state NMR ( spectra show an aliphatic part ) spectra (1a), ( 2 ), ( 4 ), ( 5a,5c
), ( 6a,6b ) ( 49). The MALDI procedures are not useful for molecular weight
determination as in the case of proteins. It is obvious that for a particle the
term “ molecular weight “, frequently reported in literature cannot be used in melanin chemistry. ( 33-34 ).
Particles
are formed by oligomers . It is interesting to note that in those oligomers the
system indicated by the red line in the formulae corresponds to the structure
of the acetylene-black and is present in
many BCM ( Black Cell Matter ) and BSM ( Black Synthetic Matter ) . Formation
of indolequinone hydrate was observed in the polymerization process of dopamine
or DHI ( 5,6-dihydroxyindole ) ( 35 ) . The oligomeric indole units may form a graphite-like stack with spacing
of 3.4 Å, a fullerene structure or,
according to recent molecular mechanics
calculations, they may have a helical structure ( 33 -34 ) .
It seems that indole oligomers may
form particles of different size and shape due to the preparation method.The
size and shape, type of oligomers may
influence some physical properties, like conductivity.
-------------------------------------------------------------
TABLE III
DHI-melanin and neuromelanin oligomers
DHI-melanin
Dopamine-black
( neuromelanin ? ) in vitro
--------------------------------------------------------------------
The structures show ( TABLE III ) neuromelanin oligomers compared with
acetylene black system . Dopamine units predominate in
neuromelanin in vitro ( 5-6, 11, 36 ). The structure of neuromelanin in
vivo is unknown but is probably a
mixture of dopamine-melanin , DHI-melanin, cysteinyldopamine-melanin .
Also to remember is that
adrenalin forms in presence or absence of oxygen a melanin. ( 4-5, 36 ) Adrenalin-melanin is different from
neuromelanin . Generally melanins have
about one oxygen more than the corresponding precursors.
---------------------------------------------------------------------------
DHI (
.5,6-Dihydroxyindole ), whih may
obtained also by melanin degradation, is
generally considered the precursor of eumelanin . Differences between DHI-melanin
and the natural pigment are
observed in IR,
TABLE IV
MALDI
spectra
Sepiomelanin
273, 313,
335, 349, 363, 369, 373, 391, 450, 526, 552, 685.
DHI-melanin
( autoxidation)
497, 516,
542, 572, 579, 692, 722, 744, 778, 874, 930, 983, 1047, 1080, 1136.
DHI-melanin
( peroxidase )
497, 524,
540, 552, 572, 703, 714, 731, 868
--------------------------------------------------------------------------------------------------------------------
This fragmentation, which occurs both in
vitro and in vivo was discovered by D.I.McAuliffe ( 37 ) and resembles the LASER graphite fission . Sepiomelanin
and DHI-melanin methylated with diazomethane have similar percentages of -OCH3
groups as reported by R.A.Nicolaus ( 26-27
) The methoxy group value is different from the theoretical values. An interpretation given by A.Bolognese ( 34 )
suggest that about half of the hydroxyls present are masked and not
methylable. The black particles have
a structure (internal) organisation
which may explain the binding effect of
solid, liquid and gases observed by H.Rorsman ( 38 ) . Natural and synthetic melanins are still today considered
polyindolequinones, justifying the difference between the found (three oxygen for every indole unit) and calculated values of polymer analysis by the
presence of molecules of water ( 39 ). Thermogravimetric analysis
performed on freshly prepared sepiomelanin samples recorded two transition
temperatures of about 100° and 150° according to the loss of two possibly
different kinds of water ( 40 ).In conclusion chemistry only plays a
small role in the determination of chemical structure of
melanins. Degradation products and analysis show sepiomelanin
oligomers to be chiefly formed by DHI and DHICA units. Pyrrole units are
present.The study of
the solid state seems more promising. It is
necessary to work on purified and analytically tested melanin samples ( recommended
elemental analysis for C , H, N, S, Cu, Fe, Ni, Zn ).
THE INK GLAND
This
pigment, contained in the ink gland of Sepia officinalis was well studied from a chemical point of
view. The ink gland described by A.Palumbo ( 41 - 42 ) is a highly specialized organ with immature cells in the inner portion , from
where the cells gradually mature, migrate towards the outer portion of the gland
and become competent to produce melanin giving rise to mature particles (melanosomes ). When cell maturation is complete, melanin is secreted into the lumen of the gland, accumulated into the
ink sac and ejected on demand . The pigment samples were found to differ in
properties and chemical composition depending to the mode of extraction and storage time. Fresh ejected ink differs
from the ink remaining into the sack. Simple
extraction can induce some transformations, like morphology, hydroxylation
processes, further oxidation, benzenoid ring breakdown.
COLOURATION
The
methylether obtained treating the pigment with diazomethane was in the form of
an infusible light brown powder The change of
“colour” indicates that a physical “colour” contributes to the black
“colouration” of the particle. In
1987 a
unified physical model of pigment “colour” was presented The model
is based on measurements of the
optical constants of eumelanin and
pheomelanin. Using the results of exact Mie calculations of the scattering and absorption cross- sections for
individual pigment granules, it was
shown that the colours produced by dispersions of
eumelanin or pheomelanin granules
are strongly dependent on the pigment
granule size as reported by L.Wolfram ( 46 ), ( 47 ).In conclusion chemistry only plays a small role in the determination of chemical structure of
melanins. The study of the solid
state seems more promising. It is
necessary to work on purified and analytically tested melanin samples ( recommended
elemental analysis for C , H, N, S, Cu, Fe, Ni, Zn ).
HELICOIDAL STRUCTURE OF OLIGOMERS
Molecular modelling studies on the 5,6-indole-dione
monohydrate at 5 position showed that linear dimeric, trimeric, tetrameric,
pentameric, etc. forms may assume two low energy conformations sheets and
helixes . The first conformation, sheet,
shows two areas with different polarity, the second
one is like a helix was observed by A.Bolognese ( 36, 40
) .Constrained by steric hindrance, the alternated, pleated sheet and the helix
are held in their shapes by hydrogen bonds between a hydroxyl group and the
heterocyclic nitrogen. The hydroxyl group over (or under) the indolic plane and
the heterocyclic nitrogen generate the helix, whereas a bond between the
hydroxyl group, alternatively, over and under the indole plane and the
heterocyclic nitrogen determines the alternated pleated sheet. Whenever the
helix behaves as an organic conductor, according to reported acquisitions on
acetylene-black, it could constitute a very long solenoid able to generate a
magnetic field at the far end of the molecule with the long axis of the helix
coiling around the backbone formed by double bond linking 4 and 7 positions of
starting 5,6-indol-di-one monohydrate.Even if the unsaturated carbon backbone
is not completely planar as reported on the acetylene black, nevertheless
partial orbital overlapping is possible, as the bond length between the two
junction carbons of the dienic unit demonstrates 1.49 Å. This distance is very close
to the length of an aromatic conjugate C-C bond. Both proposed conformations
can satisfy the properties and different
roles of melanin in the animal kingdom. It is to note that reactions involving
the radical or the cation site of the melanin radical-polarone produce a local
carbon hybrid change and determine variation of the strand orientation in space. This response to chemical radical
attack could determinate abrupt conductivity changes and indicate a possible chemical switching
function of this pigments. On this topic, it was reported that melanins respond
to a critical applied field by changing their conductivity and that the nature
of response depends on hydration and temperature of sample and on external
circuitry Melanin exhibits two separate
current-voltage characteristics, the on and off state. Experiments have
demonstrated that their switching depends on hydratation (gem-diol formation).
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proven methods
and their application in chemistry, natural science and medicine, Vol.11, Part 3, Ed.
Friedheim Korte, Academic Press New York, Georg Thieme Stuttgart,
Maruzen Co.
b.
Nicolaus R.A. La Chimica delle Melanine Accademia Nazionale dei Lincei, Fondazione Donegani,III° Corso
Estivo di Chimica, Varenna 23 settembre-7 ottobre 1958, 261-275.
Nicolaus
R.A., Piattelli M. Narni G. The structure
of sepiomelanin Tetrahedron Letters
1959, 22, 14-17.
c. Nicolaus RA, Piattelli M., Narni G. Sulla struttura della sepiomelanina Rend.acc.sci.fis.mat.
1960 Vol XXVII, 1-12
d. Nicolaus R.A. Piattelli M. Structure of melanins and melanogenesis J.Polym.Science 1962, 158,
1133-1140.
e
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delle melanine Accademia Nazionale dei Lincei , Fondazione
Donegani, VII Corso estivo di Chimica, Milano 21 Settembre-3 Ottobre 1962
pp.291-319.
Fattorusso E. Piattelli M. Nicolaus
R.A. Su
alcuni neri naturali Rend.Acc.Sci.Fis.Mat.
1965, Vol.XXXII, 3-4 .
f. Nicolaus R.A. Piattelli M. Progress
in the Chemistry of Natural Black Pigments
Rend.Acc.Sci.Fis.Mat. 1965, Vol.XXXII, 3-17.
g.
Fattorusso E. Piattelli M. Nicolaus R.A.
Su alcune melanine naturali Rend.Acc.Sci.Fis.Mat. 1965, Vol.XXXII,
200-20
h.
Prota G.Piattelli M. Nicolaus R.A.
Preliminary
results in the study of phaeomelanins Rend.Acc.Sci.Fis.Mat.
1966, Vol.XXXIII, 146-150.
i.
Fattorusso E. Cimino G. Ulteriori ricerche sulla sepiomelanina Rend.Acc.Sci.Fis.Mat. 1966,Vol.XXXIII,
378-380.
l. Nicolaus R.A. Comments
on Howard S.Mason Paper.The structure of Melanin in Advances in Biology of Skin-Volume
VIII The Pigmentary System. Proceedings of a Symposium held at The University
of Oregon Medical School 1966. Pergamon
Press 1967.
m.
Fattorusso E. Minale L. Sodano G. Feomelanine
ed eumelanine da nuove fonti naturali Gazz.Chim.Ital.
1970, 100, 452-460.
n.
Nicolaus R.A. The Nature of Mammalian Colors La Chimica e l’Industria 1972, 54, 427-433.
o .
Piattelli M. Nicolaus R.A. Struttura e biogenesi delle melanine Rend.Acc.Sci.Fis.Mat. 1960, Vol.XXVII,
499-502 .
2 ) .
Benathan M. Contibution à l’analyse
quantitative des melanines. Application comparèe de methodes de caractèrisation
et de dègradation oxydative à la melanine de l’encre de seiche,à la mèlanine de
l’iris de bœuf et à la dopa-melanine Universitè de Lausanne, Facultè des Sciences,
Thèse de Doctorat , Imprivite S.A.,Lausanne 1980 .
3
) . Benathan M. Wyler H. Contribution
a l’analyse quantitative des melanines Yale
J. Biol.med.1980, 53, 389 (ABS) ;
4
) . Prota.G. (1992 )
Melanins and melanogenesis AP
5 ). a
Nicolaus R. A. (1968) Melanins in Chemistry of Natural Products, Series
edited by Edgar Lederer, Hermann, Paris
pp.1-305. .See also (1), (2), (9), (12), (19), (20).
b . Look at INTERNET the voices allomelanin, fungal melanin, microbial melanin, humin,
humic acids, fulvic acid.
c . Thomson R.H.
Melanins in Comparative
Biochemistry.Vol.III.Costituents of Life,-Part A, pp. 727-753. Ed. Florkin M. , Mason H.S. AP, 1962
6
) . a. Swan G.A. Structure
chemistry and biosynthesis of the melanins in Fort.Chem.Org.Nat., Vol 31 , 522-528 , SV
Wien 1974
b.
Nicolaus R.A.(1984) Melanine in Quaderni della Accademia Pontaniana n°4,
Ed.Giannini Napoli pp. 1-59. The most important papers of G.A.Swan are reported.
7 ). Hearing VJ. Lutzner MA. Mammalian
melanosomal proteins : Characterization by Polyacrylamide
Gel Electrophoresis. Yale Journal of
Biology and Medicine 1973,46, 553-559 ; Hearing V.G., Ekel T.M., Montague P.M.,
Nicholson J.M., BBA 1980, 611, 251-268
8 ) . Kushimoto T. Basur V. Valencia J.
Matsunaga J. Vieira WD Ferrarsi VJ. Muller J. Appella E. Hearing VJ.
A model for melanosome biogenesis based
on the purification and analysis of early melanosomes 2001 PNAS 98, 10698-10703
9 ) . a Santacroce C. Sica D. Prota G. Nicolaus R. A. Delta2,2 –BI (5
hydroxy-7-methyl-8-(2-hydroxy-4-methylphenoxy)-2H-1,4-benzothiazine) : an
interesting model compound for the study of chicken feather pigments
Rend.Acc.Sci.Fis.Mat 1968,Vol.XXXV, 3-5.
b. Thomson
R.H. The pigments of reddish hair and
feathers Angew. Chim. Int. Ed. English 1974; 13 ; 305 -312
10 ) . Kaul B.L. Studies
on Heterocyclic Colouring Matters.
Part II: ?2,2'-Bi(2H-1,4-benzothiazines),
Helv. Chem. Acta 1974; 57;
2664-2678 The chromophore of pheomelanin
was synthesed ; Prota G. Ponsiglione E. Ruggiero R. Synthesis and photochromism of Bi-(2H-1,4-benzothiazine)
Tetrahedron 1974, 30, 2781-2784.
11 ) . See (1), (41), (47).
12 ) . Medrano J. Dudis D. (1990) Quasi-Particles in Polymeric conductors in
organic superconductivity, Ed. Vladimir
Z. Kresin and William A. Little, Plenum Press pp 275-285
13 ) . Blumstein A. S.
Subramanyam S. (1990) Conjugated ionic polyacetylenes : novel
structures and model for a polymeric high Tc superconductor in Organic Superconductivity, edited by
Vladimir Z. Kresin and William A. Little, Plenum Press pp.335-341.
14
) a. Piattelli M. Fattorusso E . Magno
S. Nicolaus R.A. Alkali fusion of sepiomelanin : isolation of 5,6-dihydroxyindole Rend.Acc.Sci.Fis.Mat. 1962,
Vol.XXIX, 3-4 .
b
. Piattelli M.
Fattorusso E. Magno S. Alkali fusion of
sepiomelanin : identification of 5,6-dihydroxyindole-2-carboxylic acid Rend.Acc.Sci.Fis.Mat. 1962, Vol.XXIX,
1-2.
15
) . Fattorusso E. Nicolaus R.A. Sussman H. Kertesz
D. Sul processo di trasformazione del
5,6-diossindolo in melanina Rend.Acc.Sci.Fis.Mat.
1966, Vol.XXXIII, 372-377.
16
).a Nicolaus R. Sugli
acidi pirrolcarbonici .Nota I. Acido 2,3,5-pirroltricarbonico Gazz.Chim.Ital.
1953, 83, 239-251.
b. Binns F. Swan
G.A. Oxidation of some synthetic
melanins Chem.and Ind.1957, 396-404.
17
) . Nicolaus R. Sugli acidi pirrolcarbonici La ricerca scientifica 1953, 23,1836-1638
18
) . Nicolaus R., Oriente
G. Sugli acidi pirrolcarbonici : acido
2,3,4,5-pirroltetracarbonico Gazz.Chim.Ital.1954, 84, 230-241
19
) . Nicolaus R.A. Cromatografia
su carta dei prodotti di demolizione con H2O2 .di
melanine naturali e della tirosina melanina
Gazz.Chim.Ital. 1955, 85, 659-664 .
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Riassunto in lingua italiana
Circa
un anno fa è apparsa sulla rivista Pigment Cell Research 2004,17,422-424 una
lettera all’editore dal titolo ‘’ The
Chemical Structure of Melanin ‘’ del Dr.
W.L.Cheun ( College of Pharmacy St.John’s University,USA ) e una replica del Dr.J.D.Simon ( Duke
University, USA ) e del Dr.S.Ito ( Fujita Health University, Japan ).
Nella
lettera e la replica vi è poco per
quanto è stato fatto sulla struttura
chimica della melanina come indicato nel titolo, mentre vengono omessi
importanti riferimenti scientifici e bibliografici .Il contributo fondamentale
dato dalla ricerca italiana a partire da Angelo Angeli è quasi completamente
ignorato. Lo studio fondamentale sulla struttura della melanina di M.G.Peter
viene negletto. Gli studi ai raggi-X, la spettrometria di massa, la microscopia a forza atomica, lo studio analitico sulle eumelanine e
feomelanine ai quali gli autori fanno
riferimento in modo confuso sono ancora incerti a causa del materiale grezzo usato negli esperimenti
di laboratorio. Va inoltre considerato che gli studi chimici hanno dato
risultati poco soddisfacenti anche
per la scarsa conoscenza della scienza dello stato solido.
La attuale nota presentata per gli Atti della Accademia Pontaniana ha lo scopo di
cercare di colmare le lacune bibliografiche e scientifiche presenti nelle
lettere all’editore dei dottori Cheun, Simon ed Ito.
Le
melanine posseggono interessanti proprietà quali quelle di sequestrare molecole
organiche, ioni, liquidi e gas nonché
quella di condurre la corrente elettrica.Tutte le particelle nere a partire dal
carbone fino alla melanina del cervello o dello spazio hanno proprietà molto
simili e possono presentare gabbie
grafitiche, fullereniche o elicoidali.Le forme elicoidali potrebbero creare,al
passaggio della corrente, campi magnetici di interesse biologico.
Lo
studio con AFM della particella scoperta di recente e l’uso della spettrometria di massa quale
tecnica degradtiva sembrano oggi poter migliorare le nostre conoscenze della
struttura chimica della melanina . La particella melaninica mostra una
particolare organizzazione che può , fra l’altro, spiegare la sua capacità di
legare molecole, ioni, liquidi, gas.
E’ necessario , nello studio del
pigmento, usare campioni di melanina (
melanosomi ) purificati, ad esempio
secondo il procedimento di V.J.Hearing,
e corredati dalla analisi elementare per C, H, N, S, Cu, Fe, Ni, Cd.
Prof. Rodolfo Alessandro Nicolaus,
Accademia Pontaniana, Presidente della Classe di Scienze Naturali ,Via Mezzocannone
8, I-80134, Napoli. accponta@tin.it www.pontaniana.unina.it
rnicolaus@tightrope.it www.tightrope.it/nicolaus/index.htmScritto in Napoli il 25 Settembre
2005. . Approvato
per la pubblicazione sugli Atti della AccademiaPontaniana il 15 Dicembre 2005. Rispetto al lavoro presentato alla
Accademia Pontaniana , il testo è stato
revisionato ed illustrato nel Gennaio 2006.