The effect of alpha-ketoglutaric acid on tyrosinase activity and conformation: Kinetics and molecular dynamics simulation study

被引:17
|
作者
Gou, Lin [1 ]
Lee, Jinhyuk [2 ,3 ]
Yang, Jun-Mo [4 ]
Park, Yong-Doo [5 ]
Zhou, Hai-Meng [5 ]
Zhan, Yi [6 ]
Lu, Zhi-Rong [5 ]
机构
[1] Sichuan Agr Univ, Coll Biol & Sci, Chengdu 611130, Sichuan, Peoples R China
[2] Korean Bioinformat Ctr KOBIC, Korea Res Inst Biosci & Biotechnol, Daejeon 305806, South Korea
[3] Univ Sci & Technol, Dept Nanobiotechnol & Bioinformat, Daejeon 305350, South Korea
[4] Sungkyunkwan Univ, Dept Dermatol, Samsung Med Ctr, Sch Med, Seoul 135710, South Korea
[5] Tsinghua Univ, Zhejiang Prov Key Lab Appl Enzymol, Yangtze Delta Reg Inst, Jiaxing 314006, Peoples R China
[6] Zhejiang Sci Tech Univ, Coll Life Sci, Hangzhou 310018, Zhejiang, Peoples R China
关键词
Tyrosinase; Alpha-ketoglutaric acid; Inhibition; CRYSTAL-STRUCTURE; INHIBITION; ENZYMES; RATS;
D O I
10.1016/j.ijbiomac.2016.12.015
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Alpha-ketoglutaric acid (AKG) is naturally found in organisms and is a well-known intermediate in the production of ATP or GTP in the Krebs cycle. We elucidated the effects of AKG on tyrosinase activity and conformation via methods of inhibition kinetics integrated with molecular dynamics (MD) simulations. AKG was found to be a reversible inhibitor of tyrosinase (IC50 = 15 +/- 0.5 mM) and induced parabolic slope mixed-type inhibition. Based on our newly established equation, the dissociation constant (K-islope) was determined to be 7.93 +/- 0.31 mM. The spectrofluorimetry studies showed that AKG mainly induced regional changes in the active site of tyrosinase, which reflects the flexibility of the active site. The computational docking and molecular dynamics (MD) simulations further demonstrated that AKG could interact with several residues near the substrate-binding site located in the tyrosinase active site pocket. Our study provides insight into the mechanism by which energy-producing intermediates such as AKG inhibit tyrosinase through its ketone groups. Also, AKG could be a potential natural antipigmentation agent due to its non-toxic property. (C) 2016 Elsevier B.V. All rights reserved.
引用
收藏
页码:1654 / 1662
页数:9
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