An updated review of tyrosinase inhibitors

Abstract

Tyrosinase is a multifunctional, glycosylated, and copper-containing oxidase, which catalyzes the first two steps in mammalian melanogenesis and is responsible for enzymatic browning reactions in damaged fruits during post-harvest handling and processing. Neither hyperpigmentation in human skin nor enzymatic browning in fruits are desirable. These phenomena have encouraged researchers to seek new potent tyrosinase inhibitors for use in foods and cosmetics. This article surveys tyrosinase inhibitors newly discovered from natural and synthetic sources. The inhibitory strength is compared with that of a standard inhibitor, kojic acid, and their inhibitory mechanisms are discussed.

Keywords: browning; inhibitors; melanogenesis; tyrosinase.

Figure 1.

Biosynthetic pathway of melanin [–4]. TYR, tyrosinase; TRP; tyrosinase related protein; dopa, 3,4-dihydroxyphenylalanine; DHICA, 5,6-dihydroxyindole-2-carboxylic acid; DHI, 5,6-dihydroxyindole; ICAQ, indole-2-carboxylic acid-5,6-quinone; IQ, indole-5,6-quinone; HBTA, 5-hydroxy-1,4-benzothiazinylalanine.

Figure 2.

Catalytic cycles of the hydroxylation of monophenol and oxidation of o-diphenol to o-quinone by tyrosinase [–24]. E_oxy, E_met, and E_deoxy are the three types of tyrosinase, respectively. E_oxyD, E_oxyM, and E_metM are E_oxy-Diphenol, E_oxy-Monophenol, and E_met-Monophenol complexes, respectively.

Figure 3.

Chemical structures of selected tyrosinase inhibitors belonging to some standard ones (a), flavonoids (b–j) or N-benzylbenzamides analogs (k). RA^a and RA^b are the relative diphenolase and monophenolase inhibitory activity, respectively, against mushroom tyrosinase compared to the standard kojic acid, where 1.0F means one time activity of kojic acid.

Figure 4.

Chemical structures of selected tyrosinase inhibitors belonging to stilbenes (a), bibenzyl derivatives (b), coumarins (c), and benzaldehyde derivatives (d). RA^a and RA^b have the same meanings as those of Figure 3.

Figure 5.

Chemical structures of selected tyrosinase inhibitors belonging to long-chain lipids (a) or steroids (b). RA^a and RA^b have the same meanings as those of Figure 3.

Figure 6.

Chemical structures of other tyrosinase inhibitors from natural (a) or synthetic (b) sources. RA^a and RA^b have the same meanings as those of Figure 3.

Figure 7.

Chemical structures of irreversible tyrosinase inhibitors.

Figure 8.

Molecular reaction mechanism of suicide inactivation of tyrosinase by the oxidation of an o-diphenol substrate. The curly arrows shows the effect of deprotonation leading to the reduction of copper from bivalent to zero-valent form, elimination of an o-quinone and inactivated tyrosinase [168].

Scheme 1.

Action mechanism of reversible inhibitors. E, S, I, and P are the enzyme, substrate, inhibitor, and product, respectively; ES is the enzyme-substrate complex, and EI and ESI are the enzyme-inhibitor and enzyme-substrate-inhibitor complexes, respectively.

Scheme 2.

Reaction mechanism of irreversible inhibitors. E and E_i are the enzyme and the inactivated enzyme, respectively; S, I, and P are the substrate, inhibitor, and product, respectively; ES, EI and ESI are the intermediates.

Scheme 3.

Action mechanism for suicide substrate. E and E_i are the enzyme and inactivated enzyme, respectively; P is the product; X is the first intermediate, and Y is another intermediate.