78
3 Dopaquinone Conversion and Related Reactions
and C1, were found. In particular, we found that the newly identified C3–C4 bridge
is the energetically favorable site more than the previously thought C5 and C2.
The C6-bound structure showed higher binding energy than the C2-bound structure,
indicating the experimentally observed preference of C2 over C6 cannot be explained
by the energetic stability of these bound structures. Based on the obtained results,
we proposed that cysteine is initially bound onto C3–C4 bridge, and then migrates
to the adjacent C5 or C2 as the mechanism for the initial step of cysteine binding.
These findings are in agreement with the experimental results [1, 2, 7], and
explains the tendency of cyclization/thiol-binding competition of dopaquinone and
RD-quinone [2, 7] and cyclization rates of dopaquinone analogs [1] at the atomic
level. Furthermore, beyond the extent of experimental findings, we pointed out
that RD-quinone in the electroneutral structure does not form a cyclic bond in a
straightforward manner, and that cysteine is strongly attracted by C3–C4 bridge in
dopaquinone so that adjacent C5 and C2 can be the subsequent reaction sites.
References
1. E.J. Land, C.A. Ramsden, P.A. Riley, ortho-Quinone amines and derivatives: the influence of
structure on the rates and modes of intramolecular reaction. Arkivoc. xi, 23–36 (2007)
2. S. Ito, A Chemist’s view of melanogenesis. Pigment Cell Res. 16, 230–236 (2003)
3. W.D. Bush, J. Garguilo, F.A. Zucca, A. Albertini, L. Zecca, G.S. Edwards, R.J. Nemanich, J.D.
Simon, The surface oxidation potential of human neuromelanin reveals a spherical architecture
with a pheomelanin core and a eumelanin surface. Natl. Acad. Sci. 103, 14785–14789 (2006)
4. S. Ito, Encapsulation of a reactive core in neuromelanin. Proc. Natl. Acad. Sci. 103, 14647–
14648 (2006)
5. S. Ito, T. Kato, K. Fujita, Covalent binding of catechols to proteins through the sulphydryl
group. Biochem. Pharmacol. 37, 1707–1710 (1988)
6. K. Hasegawa, S. Ito, S. Inoue, K. Wakamatsu, H. Ozeki, I. Ishiguro, Dihydro-1,4benzothiazine-6,7-dione, the ultimate toxic metabolite of 4-S-cysteaminylphenol and 4-Scysteaminylcatechol. Biochem. Pharmacol. 53, 1435–1444 (1997)
7. S. Ito, M. Ojika, T. Yamashita, K. Wakamatsu, Tyrosinase-catalyzed oxidation of rhododendrol
produces 2-methylchromane-6,7-dione, the putative ultimate toxic metabolite: implications for
melanocyte toxicity. Pigment Cell Melanoma Res. 27, 744–753 (2014)
8. A. Thompson, E.J. Land, M.R. Chedekel, K.V. Subbarao, T.G. Truscott, A pulse radiolysis
investigation of the oxidation of the melanin precursors 3,4-dihydroxyphenylalanine (dopa)
and the cysteinyldopas. Biochim. Biophys. Acta 843, 49–57 (1985)
9. M.D. Hawley, S.V. Tatawawadi, S. Piekarski, R.N. Adams, Electrochemical studies of the
oxidation pathways of catecholamines. J. Am. Chem. Soc. 89, 447–450 (1967)
10. J. Borovansky, R. Edge, E.J. Land, S. Navaratnam, S. Pavel, C.A. Ramsden, P.A. Riley, N.P.M.
Smit, Mechanistic studies of melanogenesis: the influence of N-substitution on dopamine
quinone cyclization. Pigment Cell Melanoma Res. 19, 170–178 (2006)
11. T.E. Young, J.R. Griswold, M.H. Hulbert, Melanin. I. Kinetics of the oxidative cyclization of
dopa to dopaquinone. J. Org. Chem. 39, 1980–1982 (1974)
12. J. Cabanes, F. García-Cánovas, J.A. Lozano, F. García-Carmona, A kinetic study of the
melanization pathway between L-tyrosine and dopachrome. Biochim. Biophys. Acta 923,
187–195 (1987)
3 Dopaquinone Conversion and Related Reactions
and C1, were found. In particular, we found that the newly identified C3–C4 bridge
is the energetically favorable site more than the previously thought C5 and C2.
The C6-bound structure showed higher binding energy than the C2-bound structure,
indicating the experimentally observed preference of C2 over C6 cannot be explained
by the energetic stability of these bound structures. Based on the obtained results,
we proposed that cysteine is initially bound onto C3–C4 bridge, and then migrates
to the adjacent C5 or C2 as the mechanism for the initial step of cysteine binding.
These findings are in agreement with the experimental results [1, 2, 7], and
explains the tendency of cyclization/thiol-binding competition of dopaquinone and
RD-quinone [2, 7] and cyclization rates of dopaquinone analogs [1] at the atomic
level. Furthermore, beyond the extent of experimental findings, we pointed out
that RD-quinone in the electroneutral structure does not form a cyclic bond in a
straightforward manner, and that cysteine is strongly attracted by C3–C4 bridge in
dopaquinone so that adjacent C5 and C2 can be the subsequent reaction sites.
References
1. E.J. Land, C.A. Ramsden, P.A. Riley, ortho-Quinone amines and derivatives: the influence of
structure on the rates and modes of intramolecular reaction. Arkivoc. xi, 23–36 (2007)
2. S. Ito, A Chemist’s view of melanogenesis. Pigment Cell Res. 16, 230–236 (2003)
3. W.D. Bush, J. Garguilo, F.A. Zucca, A. Albertini, L. Zecca, G.S. Edwards, R.J. Nemanich, J.D.
Simon, The surface oxidation potential of human neuromelanin reveals a spherical architecture
with a pheomelanin core and a eumelanin surface. Natl. Acad. Sci. 103, 14785–14789 (2006)
4. S. Ito, Encapsulation of a reactive core in neuromelanin. Proc. Natl. Acad. Sci. 103, 14647–
14648 (2006)
5. S. Ito, T. Kato, K. Fujita, Covalent binding of catechols to proteins through the sulphydryl
group. Biochem. Pharmacol. 37, 1707–1710 (1988)
6. K. Hasegawa, S. Ito, S. Inoue, K. Wakamatsu, H. Ozeki, I. Ishiguro, Dihydro-1,4benzothiazine-6,7-dione, the ultimate toxic metabolite of 4-S-cysteaminylphenol and 4-Scysteaminylcatechol. Biochem. Pharmacol. 53, 1435–1444 (1997)
7. S. Ito, M. Ojika, T. Yamashita, K. Wakamatsu, Tyrosinase-catalyzed oxidation of rhododendrol
produces 2-methylchromane-6,7-dione, the putative ultimate toxic metabolite: implications for
melanocyte toxicity. Pigment Cell Melanoma Res. 27, 744–753 (2014)
8. A. Thompson, E.J. Land, M.R. Chedekel, K.V. Subbarao, T.G. Truscott, A pulse radiolysis
investigation of the oxidation of the melanin precursors 3,4-dihydroxyphenylalanine (dopa)
and the cysteinyldopas. Biochim. Biophys. Acta 843, 49–57 (1985)
9. M.D. Hawley, S.V. Tatawawadi, S. Piekarski, R.N. Adams, Electrochemical studies of the
oxidation pathways of catecholamines. J. Am. Chem. Soc. 89, 447–450 (1967)
10. J. Borovansky, R. Edge, E.J. Land, S. Navaratnam, S. Pavel, C.A. Ramsden, P.A. Riley, N.P.M.
Smit, Mechanistic studies of melanogenesis: the influence of N-substitution on dopamine
quinone cyclization. Pigment Cell Melanoma Res. 19, 170–178 (2006)
11. T.E. Young, J.R. Griswold, M.H. Hulbert, Melanin. I. Kinetics of the oxidative cyclization of
dopa to dopaquinone. J. Org. Chem. 39, 1980–1982 (1974)
12. J. Cabanes, F. García-Cánovas, J.A. Lozano, F. García-Carmona, A kinetic study of the
melanization pathway between L-tyrosine and dopachrome. Biochim. Biophys. Acta 923,
187–195 (1987)