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Repigmentation in Vitiligo
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Bharat Bhushan Mahajan, Richa Nagpal
Dopaquinone is a highly reactive intermediate, and in the absence of sulfhydryl compounds it forms cyclodopa. The redox exchange between cyclodopa and dopaquinone then gives rise to the red intermediate Dopachrome and DOPA. Dopachrome then rearranges to 5,6-dihydroxyindole (DHI) and to a lesser extent to 5,6-dihydroxyindole carboxylic acid (DHICA). Finally, these two compounds are oxidized and polymerized to produce eumelanins.
Melanin
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
M. Badawy Abdel-Naser, Sabine Krueger-Krasagakis, Konstantinos Krasagakis
Eumelanogenesis involves the further transformation of dopaquinone to leukodopachrome, followed by a series of oxidoreduction reactions with production of the intermediates dihydroxyindole (DHI) and DHI carboxylic acid (DHICA), with ultimate polymerization to form eumelanin (Figure 3.1).11,15,16 Eumelanins are black to brown, insoluble in most solvents, and more abundant in human beings, especially in dark-skinned individuals. A unique character of eumelanin is its stable paramagnetic state exerted by its semiquinone units, which are also responsible for eumelanin redox properties.17 In Caucasians, localized high cutaneous concentrations of eumelanin can be found in moles, macules, nevi, or lentigos.13 Eumelanins act as polyanions and can reversibly bind cations, anions, and polyamines.15
Roles of macrophage migration inhibitory factor in Guillain-Barré syndrome and experimental autoimmune neuritis: beneficial or harmful?
Published in Expert Opinion on Therapeutic Targets, 2018
Donghui Shen, Yue Lang, Fengna Chu, Xiujuan Wu, Ying Wang, Xiangyu Zheng, Hong-Liang Zhang, Jie Zhu, Kangding Liu
MIF exhibits 4-oxalocrotonate tautomerase, 5-carboxymethyl-2-hydroxymuconate isomerase, D-dopachrome tautomerase, and phenylpyruvate tautomerase catalytic activities [21]. Similar to the activities of a bacterial enzyme, 4-oxalocrotonate tautomerase, MIF converts d-l-dopachrome to 5, 6-dihydroxy-2-carboxylic acid (DHICA), and acts as a phenylpyruvate tautomerase when phenylpyruvate and p-hydroxyphenylpyruvate are used as substrates, by interconverting enol and keto groups [7]. The N-terminal proline is crucial for the phenylpyruvate tautomerase and D-dopachrome tautomerase activities, since it functions as both general acids and base catalyst. MIF converts toxic products of catecholamine to hydroxyindole derivatives due to its D-dopachrome tautomerase activity [26]. Pro-1 to glycine mutation or the insertion of an alanine between Pro-1 and Met-2 reduces the catalytic activity of MIF. Therefore, the active site of MIF dopachrome tautomerase has been used for the small-molecule MIF inhibitors development [27]. However, MIF’s enzymatic activities in various diseases have not been elucidated.
Tetralone derivatives are MIF tautomerase inhibitors and attenuate macrophage activation and amplify the hypothermic response in endotoxemic mice
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
János Garai, Marcell Krekó, László Őrfi, Péter Balázs Jakus, Zoltán Rumbus, Patrik Kéringer, András Garami, Eszter Vámos, Dominika Kovács, Viola Bagóné Vántus, Balázs Radnai, Tamás Lóránd
More than twenty years ago Rorsman et al. reported that recombinant MIF catalyses the tautomerisation of the non-naturally occurring d-dopachrome, transforming the coloured compound to the colourless dihydroindole carboxylic acid (DHICA)12, however, l-dopachrome methyl ester (a melanin precursor) have also been found a suitable substrate. This was soon followed by the identification of phenylpyruvate and p-hydroxyphenylpyruvate as alternate substrates for the tautomeric activity of MIF13. In the homotrimeric MIF, the catalytic site is located between each of two adjacent monomers. Acidic pKa of the N-terminal proline of each MIF monomer is thought to play a crucial role in the keto-enol tautomerisation reaction7. A direct link between cytokine activity and tautomerase catalytic site of MIF has been reported14, although a “true” endogenous small molecule ligand has yet to be found. Blocking of endogenous MIF by a small molecule such as “ISO-1” and neutralisation of MIF by anti-MIF antibodies or by plant-derived MIF inhibitors reduces the manifestations of inflammatory conditions such as type II collagen-induced arthritis, immunologically induced kidney disease, experimental autoimmune encephalomyelitis, experimental allergic neuritis, immunoinflammatory diabetes, experimental autoimmune myocarditis, irradiation-induced acute pneumonitis, sepsis, and ischemia–reperfusion injury15–18. Therefore, inhibitors of MIF tautomerase hold promise for prospective clinical use in many pathologic conditions19. Development of individualised therapy targeting MIF in these conditions is expected based on the human genetic data supporting the role of high-expression MIF alleles in the clinical severity and end-organ complications of a number of inflammatory disorders20.