Influence of N‐glycan processing disruption on tyrosinase and melanin synthesis in HM3KO melanoma cells

Abstract

Tyrosinase, a type I membrane glycoprotein, is synthesized and glycosylated in the endoplasmic reticulum (ER) and Golgi. The enzyme is subsequently transported to melanosomes where it participates in melanogenesis. Previous studies showed that the disruption of early ER N-glycan processing by deoxynojirimycin (DNJ), an inhibitor of alpha-glucosidase, suppresses tyrosinase enzymatic activity and melanogenesis. However, the disruption of late glycan processing, mainly performed by ER and Golgi alpha-1,2-mannosidases, on tyrosinase enzymatic activity and melanogenesis remains to be investigated. Following treatment of HM3KO human melanoma cells with deoxymannojirimycin (DMJ), an inhibitor of alpha-1,2-mannosidase, transport of tyrosinase to the melanosome, enzymatic activity, and melanogenesis were reduced in a dose-dependent manner. However, DMJ did not directly inhibit tyrosinase enzymatic activity and expression. Interestingly, an extract of Streptomyces subrutilus culture medium (ESSCM) containing DMJ and DNJ as the main components inhibited glycosylation and transport of tyrosinase to the melanosome as well as melanin synthesis, but with no negative effects on cell viability. These inhibitory effects of ESSCM were stronger than those of DMJ or DNJ alone. Tyrosinase glycosylation and melanogenesis in HM3KO melanoma cells were more effectively inhibited by DMJ and DNJ combined than DMJ or DNJ alone. Accordingly, we propose that ESSCM is a potential candidate for treating undesirable hyperpigmentation conditions, such as melasma, postinflammatory melanoderma, and solar lentigo.

Identifying mRNA, MicroRNA and Protein Profiles of Melanoma Exosomes

“…Those differentially expressed genes were involved in N-glycan biosynthesis (statistical score = 11.505), sphingolipid metabolism (statistical score = 8.148), and antigen presentation pathways (statistical score = 6.1) (Figure S1D). Among these identified pathways, the N-glycan pathway has been shown to be involved in tyrosinase and melanin synthesis in melanoma cells as well as melanoma cell metastasis [25], [26]. Sphingolipid has been involved in a lipogenic pathway to boost Akt signaling [27].…”

Mechanisms Regulating Skin Pigmentation: The Rise and Fall of Complexion Coloration

“…As other active derivatives of the compound cause an increase in protein glycosylation in B16 melanoma cells, the authors hypothesize that the test compound inhibited tyrosinase by modifying the sugar moieties of the enzyme [40,41]. In a distinct study by Choi et al , treatment of HM3KO melanoma cells with deoxynojirimycin, a α-glucosidase inhibitor that disrupts early ER N -glycan processing, and deoxymannojirimycin, an inhibitor of α-1,2-mannosidase which are thought to be responsible for late glycan processing, showed inhibition of glycosylation, transportation of tyrosinase to the melanosome and melanin synthesis [42]. Other factors explored for their ability to modulate tyrosinase glycosylation include calcium d -pantetheine- S -sulfonate [43], ferritin [44] and glutathione [45].…”

Novel inhibitory effect of the antidiabetic drug voglibose on melanogenesis

“…Tyrosinase is a glycoprotein that requires N‐glycan for functionality and proper localization . The N‐glycan processing of tyrosinase is performed by intracellular α‐glucosidase and α‐mannosidases in the endoplasmic reticulum (ER) and Golgi apparatus .…”

“…The N‐glycan processing of tyrosinase is performed by intracellular α‐glucosidase and α‐mannosidases in the endoplasmic reticulum (ER) and Golgi apparatus . If these enzymes are inhibited, tyrosinase is aberrantly folded and does not become mature, resulting in hypopigmentation . Among the general inhibitors of glycosylation, glucosamine and tunicamycin inhibit melanin production without decreasing the tyrosinase protein level .…”

“…Among the general inhibitors of glycosylation, glucosamine and tunicamycin inhibit melanin production without decreasing the tyrosinase protein level . Two specific inhibitors, deoxynojirimycin (DNJ), an α‐glucosidase inhibitor, and deoxymannojirimycin (DMJ), an α‐mannosidase inhibitor, are also direct inhibitors of melanin production that do not affect the tyrosinase protein level .…”