Effects of L-Malic Acid on Alpha-Glucosidase: Inhibition Kinetics and Computational Molecular Dynamics Simulations

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• 作者：Lin Gou (1)
  Yi Zhan (2) (3)
  Jinhyuk Lee (4) (5)
  Xuan Li (6)
  Zhi-Rong L眉 (3)
  Hai-Meng Zhou (2) (3)
  Hang Lu (7)
  Xi-Yao Wang (8)
  Yong-Doo Park (3)
  Jun-Mo Yang (9)
  
  1. College of Biology and Science ; Sichuan Agriculture University ; Chengdu ; 611130 ; People鈥檚 Republic of China
  2. School of Life Science ; Tsinghua University ; Zhongguancun Street ; Beijing ; 100084 ; People鈥檚 Republic of China
  3. Zhejiang Provincial Key Laboratory of Applied Enzymology ; Yangtze Delta Region Institute of Tsinghua University ; Jiaxing ; 314006 ; People鈥檚 Republic of China
  4. Korean Bioinformation Center (KOBIC) ; Korea Research Institute of Bioscience and Biotechnology ; Daejeon ; 305-806 ; Republic of Korea
  5. Department of Bioinformatics ; University of Sciences and Technology ; Daejeon ; 305-350 ; Republic of Korea
  6. College of Life Sciences ; Zhejiang Sci-Tech University ; Hangzhou ; 310018 ; People鈥檚 Republic of China
  7. College of Landscape Architecture ; Sichuan Agriculture University ; Cheng Du ; 611130 ; People鈥檚 Republic of China
  8. College of Agronomy ; Sichuan Agriculture University ; Cheng Du ; 611130 ; People鈥檚 Republic of China
  9. Department of Dermatology ; Sungkyunkwan University School of Medicine ; Samsung Medical Center ; Seoul ; 135-710 ; Republic of Korea
  
• 关键词：Alpha ; glucosidase ; Malic acid ; Inhibition
• 刊名：Applied Biochemistry and Biotechnology
• 出版年：2015
• 出版时间：February 2015
• 年：2015
• 卷：175
• 期：4
• 页码：2232-2245
• 全文大小：1,222 KB
• 参考文献：1. Konya, H., Katsuno, T., Tsunoda, T., Yano, Y., Kamitani, M., Miuchi, M., Hamaguchi, T., Miyagawa, J. I., & Namba, M. (2013). Effects of combination therapy with mitiglinide and voglibose on postprandial plasma glucose in patients with type 2 diabetes mellitus. / Diabetes Metabolic Syndrome Obesity, 6, 317鈥?25. CrossRef
  2. van de Laar, F. A. (2008). Alpha-glucosidase inhibitors in the early treatment of type 2 diabetes. / Vascular Health and Risk Management, 4, 1189鈥?195.
  3. Chiba, S. (1997). Molecular mechanism in alpha-glucosidase and glucoamylase. / Bioscience, Biotechnology, and Biochemistry, 61, 1233鈥?239. CrossRef
  4. Etienne, A., G茅nard, M., Lobit, P., Mbegui茅-A-Mb茅gui茅, D., & Bugaud, C. (2013). What controls fleshy fruit acidity? A review of malate and citrate accumulation in fruit cells. / Journal of Experimental Botany, 64, 1451鈥?469. CrossRef
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  7. G贸mez-Moreno, G., Guardia, J., Aguilar-Salvatierra, A., Cabrera-Ayala, M., de-Val Mat茅-S谩nchez, J. E., & Calvo-Guirado, J. L. (2013). Effectiveness of malic acid 1聽% in patients with xerostomia induced by antihypertensive drugs. / Medicina Oral, Patolog铆a Oral y Cirug铆a Bucal, 18, e49鈥揺55. CrossRef
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  11. Zeng, Y. F., L眉, Z. R., Yan, L., Oh, S., Yang, J. M., Lee, J., & Ye, Z. M. (2012). Towards alpha-glucosidase folding induced by trifluoroethanol: kinetics and computational prediction. / Process Biochemistry, 47, 2284鈥?290. CrossRef
  12. Wu, X. Q., Wang, J., L眉, Z. R., Tang, H. M., Park, D., Oh, S. H., Bhak, J., Shi, L., Park, Y. D., & Zou, F. (2010). Alpha-glucosidase folding during urea denaturation: enzyme kinetics and computational prediction. / Applied Biochemistry and Biotechnology, 160, 1341鈥?355. CrossRef
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• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Biotechnology
  Biochemistry
  
• 出版者：Humana Press Inc.
• ISSN：1559-0291

文摘

The inhibitory effect of L-malic acid (MA) on alpha-glucosidase (EC 3.2.1.20) was investigated by combination study between inhibition kinetics and computational simulations. The results from the serial kinetics demonstrated that MA could directly inactivate the enzyme activity in a dose-dependent manner and a typical non-competitive type, as well as in a fast inactivate process without detectable time course. The tertiary conformation study with an application of spectrofluorimetry showed that MA modulated the tertiary structural conformation of alpha-glucosidase both on the overall and on regional active site pocket, which monitored by red-shift intrinsic fluorescence peak with decreases intensities, and the significant intensity increasing of 1-anilinonaphthalene-8-sulfonate (ANS)-binding fluorescence, respectively. To have more insight, we also adapted the computational molecular dynamics (MD) simulations. The results showed that MA was located in the entrance of active pocket for the catalytic reaction and blocked the passage of substrate. It confirmed that MA inhibits as a non-competitive type, not direct docking to the glucose binding site. Our study provides important molecular mechanisms to figure out alpha-glucosidase inhibition that might associate to development of type 2 diabetes mellitus drug.