Thermodynamic and structural study on the interaction of an enzyme and a substrate analogue for development of new therapy for lysosomal diseases
| Project/Area Number |
21390314
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Meiji Pharmaceutical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
TOGAWA Tadayasu 明治薬科大学, 薬学部, 教授 (80260983)
TSUKIMURA Takahiro 明治薬科大学, 薬学部, 助教 (50632783)
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| Co-Investigator(Renkei-kenkyūsha) |
TOGAWA Tadayasu 明治薬科大学, 薬学部, 教授 (80260983)
TSUKIMURA Takahiro 明治薬科大学, 薬学部, 助教 (50632783)
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| Project Period (FY) |
2009 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000)
Fiscal Year 2012: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
Fiscal Year 2011: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2010: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2009: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
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| Keywords | リソソーム病 / ファブリー病 / ポンペ病 / α‐ガラクトシダーゼ A / 酸性α-グル コシダーゼ / α-ガラクトシダーゼ / α-グルコシダーゼ / リソソーム酵素 / 基質類似体 / 酵素増強療法 / 分子間相互作用 |
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| Research Abstract |
To obtain basic information useful for development of chaperone therapy for Fabry disease and Pompe disease, we examined the molecular interactions between α-galactosidase A /acid α-glucosidase and their substrate analogues by means of isothermal titration calorimetry and surface plasmon resonance biosensor assays, and first determined the thermodynamic and binding-kinetics parameters. Furthermore, the structural analysis in silico revealed that the chemicals fit into the active site pocket of the enzyme molecule and undergo hydrogen bonding with residues comprising the pocket. The side chain of the chemicals is thought to be oriented towards the entrance of the pocket. On the basis of the results, we designed a new chemical that strongly stabilizes a mutant enzyme. Thermodynamic and structural studies should provide us with a lot of information for improving chaperone therapy for Fabry disease and Pompe disease.
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Report
(5 results)
Research Products
(62 results)
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[Journal Article] Mutant α-galactosidaseA with M296I does not cause elevationof the plasmaglobotriaosylsphingosine level.2012
Author(s)
Mitobe S., Togawa T., Tsukimura T., Kodama T., Tanaka T., Doi K., Noiri E.,Akai Y., Saito Y., Yoshino M.,Takenaka T., Saito S., Ohno K.,Sakuraba H.
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Journal Title
Mol.Genet. Metab.
Volume: 107
Pages: 623-626
Related Report
Peer Reviewed
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[Journal Article] Fabry disease: Biochemical, pathological and structural studies of the α-galactosidase A with E66Q amino acid substitution.2012
Author(s)
Togawa T., Tsukimura T., Kodama T., Tanaka T., Kawashima I., Saito S., Ohno K., Fukushige T., Kanekura T., Satomura A., D.-H. Kang, B. H. Lee, H.-W. Yoo, Doi K., Noiri E., SakurabaH.
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Journal Title
Mol. Genet. Metab.
Volume: 105
Pages: 615-620
Related Report
Peer Reviewed
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[Journal Article] Efficient uptakeof recombinant α-galactosidase A produced with a gene-manipulated yeast by Fabry mice kidneys.2012
Author(s)
Tsukimura T., Kawashima I., Togawa T., Kodama T., Suzuki T., Watanabe T., Chiba Y., Jigami Y., Fukushige T., Kanekura T., Sakuraba H.
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Journal Title
Mol. Med.
Volume: 18
Pages: 76-82
Related Report
Peer Reviewed
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[Journal Article] Lyso-GM2 ganglioside: A possible biomarker ofTay-Sachs disease and Sandhoff disease.2011
Author(s)
Kodama T., Togawa T., Tsukimura T., Kawashima I., Matsuoka K., Kitakaze K., Tsuji D., Itoh K., Ishida Y., Suzuki M., Suzuki T., Sakuraba H.
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Journal Title
Related Report
Peer Reviewed
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