title: Discovery of Potent Cysteine-Containing Dipeptide Inhibitors against Tyrosinase: A Comprehensive Investigation of 20 × 20 Dipeptides in Inhibiting Dopachrome Formation.
abstract: Tyrosinase is an essential copper-containing enzyme required for melanin synthesis. The overproduction and abnormal accumulation of melanin cause hyperpigmentation and neurodegenerative diseases. Thus, tyrosinase is promising for use in medicine and cosmetics. Our previous study identified a natural product, A5, resembling the structure of the dipeptide WY and apparently inhibiting tyrosinase. Here, we comprehensively estimated the inhibitory capability of 20 × 20 dipeptides against mushroom tyrosinase. We found that cysteine-containing dipeptides, directly blocking the active site of tyrosinase, are highly potent in inhibition; in particular, N-terminal cysteine-containing dipeptides markedly outperform the C-terminal-containing ones. The cysteine-containing dipeptides, CE, CS, CY, and CW, show comparative bioactivities, and tyrosine-containing dipeptides are substrate-like inhibitors. The dipeptide PD attenuates 16.5% melanin content without any significant cytotoxicity. This study reveals the functional role of cysteine residue positional preference and the selectivity of specific amino acids in cysteine-containing dipeptides against tyrosinase, aiding in developing skin-whitening products.
authors.affiliation: †Institute of Biotechnology, National Changhua University of Education, Changhua, Taiwan.
authors.forename: Tien-Sheng
authors.initials: TS
authors.lastname: Tseng
authors.affiliation: ‡National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan.
authors.forename: Keng-Chang
authors.initials: KC
authors.lastname: Tsai
authors.affiliation: §The School of Chinese Medicine for Post Baccalaureate, I-Shou University, Kaohsiung, Taiwan.|#Department of Chinese Medicine, E-Da Hospital, Kaohsiung, Taiwan.
authors.forename: Wang-Chuan
authors.initials: WC
authors.lastname: Chen
authors.affiliation: ⊥Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yeng-Tseng
authors.initials: YT
authors.lastname: Wang
authors.affiliation: ΔThe Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan.|⊗Ph.D. Program for Biotechnology in Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Yu-Ching
authors.initials: YC
authors.lastname: Lee
authors.affiliation: ‡National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan.
authors.forename: Chung-Kuang
authors.initials: CK
authors.lastname: Lu
authors.affiliation: ‡National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan.
authors.forename: Ming-Jaw
authors.initials: MJ
authors.lastname: Don
authors.affiliation: ΠDepartment of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan.
authors.forename: Chang-Yu
authors.initials: CY
authors.lastname: Chang
authors.affiliation: ΠDepartment of Medical Technology, Jen-Teh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan.
authors.forename: Ching-Hsiao
authors.initials: CH
authors.lastname: Lee
authors.affiliation: †Institute of Biotechnology, National Changhua University of Education, Changhua, Taiwan.|‡National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan.
authors.forename: Hui-Hsiung
authors.initials: HH
authors.lastname: Lin
authors.affiliation: ‡National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan.
authors.forename: Hung-Ju
authors.initials: HJ
authors.lastname: Hsu
authors.affiliation: †Institute of Biotechnology, National Changhua University of Education, Changhua, Taiwan.
authors.forename: Nai-Wan
authors.initials: NW
authors.lastname: Hsiao
mesh_terms: D000363:Agaricales / Q000201:enzymology*; D002460:Cell Line; D003545:Cysteine / Q000032:analysis / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D045563:Indolequinones / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D062105:Molecular Docking Simulation; D014442:Monophenol Monooxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D004151:Dipeptides; D004791:Enzyme Inhibitors; D045563:Indolequinones; D008543:Melanins; C001123:dopachrome; D014442:Monophenol Monooxygenase; D003545:Cysteine
keywords: dopachrome; eumelanin formation; melanin; molecular docking; peptide; tyrosinase