Oxidative Polymerization of the Pheomelanin Precursor 5-Hydroxy-1,4-benzothiazinylalanine:  A New Hint to the Pigment Structure

Abstract

Biosynthetic studies have shown that pheomelanins, the distinctive pigments of red human hair, arise from oxidative polymerization of cysteinyldopas via 1,4-benzothiazinylalanine intermediates. However, the mode of formation of the pigment polymer remains controversial. To address this point, we have investigated the conversion of the major biosynthetic precursor 5-S-cysteinyldopa (2a) to pheomelanin under biomimetic conditions. Peroxidase/H(2)O(2) oxidation of 2a was shown to lead in the early stages to the 1,4-benzothiazinylalanine 8a, which rapidly declines with concomitant formation of a distinct pattern of oligomeric products. Reduction of the reaction mixture at this stage allowed the isolation of dimer 17 in 10% yield, along with trimers 18 and 19 in smaller amounts. A restricted rotation about the ethereal C-O bond of 17 was apparent by the presence of two NMR-detectable conformational isomers, separated by an activation energy barrier of 17.83 +/- 0.03 kcal mol(-)(1). Under similar oxidation conditions, the model catechol 2b gave the related dimers 15 and 16. The structure of oligomers 17-19, all characterized by C-C and C-O bonds between the benzothiazine units, would suggest that the peroxidase-promoted polymerization proceeds by phenol-type coupling of an aryloxy radical generated by initial one-electron oxidation of 8a. Overall, these results point to a structural model for the pheomelanin polymer which is basically different from that proposed on the basis of degradative studies.

Chemical analysis of late stages of pheomelanogenesis: conversion of dihydrobenzothiazine to a benzothiazole structure

“…A coupling reaction between QI and DHBTCA may thus be favored under such a situation. The C-C bond formation between the C6 or C8 atom of QI with the C6 atom of DHBTCA would be possible as has been reported previously (Napolitano et al, 1996).…”

Chemistry of Mixed Melanogenesis—Pivotal Roles of Dopaquinone†

“…1) for pheomelanin that consists mostly of benzothiazine units with minor contributions from benzothiazole and isoquinoline units. Some of these monomer units may be connected by ether bonds (29,30). However, the contribution of ether bonds should be minimal as monomer units connected by ether bonds should be colorless, which is not consistent with the yellow‐red color of natural pheomelanin.…”

Red human hair pheomelanin is a potent pro‐oxidant mediating UV‐independent contributory mechanisms of melanomagenesis

“…Formation of pheomelanin from its precursors in the presence of preformed pheomelanin in air settles the issue of what actually brings about pheomelanin synthesis in the absence of enzymatic assistance. glutathione (GSH) and cysteine and leads to the formation of 5-S-cysteinyldopa (5SCD) from which pheomelanins are generated via benzothiazine intermediates (Napolitano et al, 1996a (Figure 1). In addition, the activation effects of MC1R in DNA repair and antioxidant pathways would point to MC1R as a melanoma susceptibility gene, but the question as to how eumelanin and pheomelanin may have a direct role in melanoma has remained open (Abdel-Malek and Ito, 2013).…”

“…Failure of MC1R to properly stimulate production of the dark photoprotective eumelanin pigments via the antioxidant 5,6‐dihydroxyindole‐2‐carboxylic acid (DHICA) (Panzella et al., ; Kovacs et al., ) pathway results in a switch of melanocyte activity toward formation of the reddish/yellow pheomelanins. Such a switch depends on the availability of glutathione (GSH) and cysteine and leads to the formation of 5‐S‐cysteinyldopa (5SCD) from which pheomelanins are generated via benzothiazine intermediates (Napolitano et al., , ) (Figure ). In addition, the activation effects of MC1R in DNA repair and antioxidant pathways (Kadekaro et al., ) would point to MC1R as a melanoma susceptibility gene, but the question as to how eumelanin and pheomelanin may have a direct role in melanoma has remained open (Abdel‐Malek and Ito, ).…”