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Article

Density Functional Theory-Based Calculation Shed New Light on the Bizarre Addition of Cysteine Thiol to Dopaquinone

1
Department of Biomaterials, Faculty of Dental Science, Kyushu University, Maidashi, Fukuoka 812-8582, Japan
2
Institute for Melanin Chemistry, Fujita Health University, Toyoake, Aichi 470-1192, Japan
3
Department of Biology, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125-3393, USA
4
Department of Physics, Talamban Campus, University of San Carlos, Cebu City 6000, Philippines
5
National Institute of Technology, Akashi College, Akashi, Hyogo 674-8501, Japan
6
Institute of Industrial Science, The University of Tokyo, Meguro, Tokyo 153-8505, Japan
7
Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
*
Author to whom correspondence should be addressed.
Academic Editor: Michele Navarra
Int. J. Mol. Sci. 2021, 22(3), 1373; https://doi.org/10.3390/ijms22031373
Received: 30 December 2020 / Revised: 24 January 2021 / Accepted: 27 January 2021 / Published: 29 January 2021
(This article belongs to the Special Issue Melanins and Melanogenesis 2.0: From Nature to Applications)
Two types of melanin pigments, brown to black eumelanin and yellow to reddish brown pheomelanin, are biosynthesized through a branched reaction, which is associated with the key intermediate dopaquinone (DQ). In the presence of l-cysteine, DQ immediately binds to the –SH group, resulting in the formation of cysteinyldopa necessary for the pheomelanin production. l-Cysteine prefers to bond with aromatic carbons adjacent to the carbonyl groups, namely C5 and C2. Surprisingly, this Michael addition takes place at 1,6-position of the C5 (and to some extent at C2) rather than usually expected 1,4-position. Such an anomaly on the reactivity necessitates an atomic-scale understanding of the binding mechanism. Using density functional theory-based calculations, we investigated the binding of l-cysteine thiolate (Cys–S) to DQ. Interestingly, the C2–S bonded intermediate was less energetically stable than the C6–S bonded case. Furthermore, the most preferred Cys–S-attacked intermediate is at the carbon-carbon bridge between the two carbonyls (C3–C4 bridge site) but not on the C5 site. This structure allows the Cys–S to migrate onto the adjacent C5 or C2 with small activation energies. Further simulation demonstrated a possible conversion pathway of the C5–S (and C2–S) intermediate into 5-S-cysteinyldopa (and 2-S-cysteinyldopa), which is the experimentally identified major (and minor) product. Based on the results, we propose that the binding of Cys–S to DQ proceeds via the following path: (i) coordination of Cys–S to C3–C4 bridge, (ii) migration of Cys–S to C5 (C2), (iii) proton rearrangement from cysteinyl –NH3+ to O4 (O3), and (iv) proton rearrangement from C5 (C2) to O3 (O4). View Full-Text
Keywords: dopaquinone; cysteine; melanin; density functional theory; quinone reactions; thiol addition to quinone dopaquinone; cysteine; melanin; density functional theory; quinone reactions; thiol addition to quinone
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MDPI and ACS Style

Kishida, R.; Ito, S.; Sugumaran, M.; Arevalo, R.L.; Nakanishi, H.; Kasai, H. Density Functional Theory-Based Calculation Shed New Light on the Bizarre Addition of Cysteine Thiol to Dopaquinone. Int. J. Mol. Sci. 2021, 22, 1373. https://doi.org/10.3390/ijms22031373

AMA Style

Kishida R, Ito S, Sugumaran M, Arevalo RL, Nakanishi H, Kasai H. Density Functional Theory-Based Calculation Shed New Light on the Bizarre Addition of Cysteine Thiol to Dopaquinone. International Journal of Molecular Sciences. 2021; 22(3):1373. https://doi.org/10.3390/ijms22031373

Chicago/Turabian Style

Kishida, Ryo; Ito, Shosuke; Sugumaran, Manickam; Arevalo, Ryan L.; Nakanishi, Hiroshi; Kasai, Hideaki. 2021. "Density Functional Theory-Based Calculation Shed New Light on the Bizarre Addition of Cysteine Thiol to Dopaquinone" Int. J. Mol. Sci. 22, no. 3: 1373. https://doi.org/10.3390/ijms22031373

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