Density functional theory-based calculation shed new light on the bizarre addition of cysteine thiol to dopaquinone

Ryo Kishida, Shosuke Ito, Manickam Sugumaran, Ryan Lacdao Arevalo, Hiroshi Nakanishi, Hideaki Kasai

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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 pre-ferred 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).

Original languageEnglish
Article number1373
Pages (from-to)1-16
Number of pages16
JournalInternational journal of molecular sciences
Volume22
Issue number3
DOIs
Publication statusPublished - Feb 1 2021

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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