Study on the Enzyme Action Mechanism in the Phospholipid Hydrolysis by Means of small Molecular Inhibitors
Study on the Enzyme Action Mechanism in the Phospholipid Hydrolysis by Means of small Molecular Inhibitors
批准号:
09480145
负责人:
KATSUMURA Shigeo
金额:
$3.46万
依托单位国家:
日本
项目类别:
Grant-in-Aid for Scientific Research (B)
财政年份:
1997
资助国家:
日本
项目状态:
已结题
起止时间:
1997 至 1999
中文摘要
Phospholipids are classified into glycerophospholipids and sphingophospholipids.Phospholipase A-D 22-D-2(PLA-D 22-D 2)catalyzes the hydrolysis of the ester linkage at the sn-2 position of glycerophospholipids and responsibles for the metabolism of unsaturated fatty acids.Meanwhile,sphingomyelinase is the general term of the enzyme which catalyzes the hydrolysis of the phosphoester linkage of sphingomyelin to produce ceramide,which has been known as a lipid second messenger in mammalian cell membranes.We found that3-methoxycarbonyl-2,4,6-trienal(A)strongly inactivated phospholipase A i D22ee D2 which wisolated from bine bine pancas.The inactivation mechanism of PLA I D22文件D2 by the compound A was elucidated by means of the stereocontrolled synthesis of the derivatives of A,structure activity relationship,amino acid analysis of the complex with PLA文件D22文件D2,and model reactions with amines.Thus,the compound A was found to selectively modify Lys-56which is included in the…More interfacial recognition site of bovine pancreatic PLA-D 22-D-D2,by the MALDI-TOF-Mass peptide mapping analyses of the complex.We also synthesized the new cyclic amide analog as the second-generation inhibitor having an oxazolidinone ring,because we had previously synthesized the oxazolidinone the second-generation inhibitor having an oxazolidinone ring,because we had previously synthesized the oxazolidinone phospholipid analog which competitively acted on the catalytic site of PLA D 22 the stomy and the stomy of the stomy of the stomy,the stomiesin,the stomy of the stomy,the stomyy,the the.And found that(D)-erythro stereochemistry is essentially important as the substrate for sphingomyelinase and the double bond in the backbone skeleton was not essential for the hydrolysis by B.cereus sphingomyelinase。Furthermore,we established the stereocontrolled efficient synthesis of sphingomyelin methylene and ethylene analogs,which are the first substrate-analog inhibitors,and they actually inhibited the hydrolytic ability of the enzyme.These analog inhibitors might be useful for the elucidation of the sphingomyelinase hydrolytic mechanism.Less:Less
英文摘要
Phospholipids are classified into glycerophospholipids and sphingophospholipids. Phospholipase AィイD22ィエD2 (PLAィイD22ィエD2) catalyzes the hydrolysis of the ester linkage at the sn-2 position of glycerophospholipids and responsibles for the metabolism of unsaturated fatty acids. Meanwhile, sphingomyelinase is the general term of the enzyme which catalyzes the hydrolysis of the phosphoester linkage of sphingomyelin to produce ceramide, which has been known as a lipid second messenger in mammalian cell membranes.We found that 3-methoxycarbonyl-2, 4, 6-trienal (A) strongly inactivated phospholipase AィイD22ィエD2 which was isolated from bovine pancreas. The inactivation mechanism of PLAィイD22ィエD2 by the compound A was elucidated by means of the stereocontrolled synthesis of the derivatives of A, structure activity relationship, amino acid analysis of the complex with PLAィイD22ィエD2, and model reactions with amines. Thus, the compound A was found to selectively modify Lys-56 which is included in the … More interfacial recognition site of bovine pancreatic PLAィイD22ィエD2, by the MALDI-TOF-Mass peptide mapping analyses of the complex.We also synthesized the new cyclic amide analog as the second-generation inhibitor having an oxazolidinone ring, because we had previously synthesized the oxazolidinone phospholipid analog which competitively acted on the catalytic site of PLAィイD22ィエD2.On the other hand, in the study of sphingomyelinase, we achieved the efficient synthesis of (D)-erythro-sphigomyelin, and found that (D)-erythro stereochemistry is essentially important as the substrate for sphingomyelinase and the double bond in the backbone skeleton was not essential for the hydrolysis by B. cereus sphingomyelinase. Furthermore, we established the stereocontrolled efficient synthesis of sphingomyelin methylene and ethylene analogs, which are the first substrate-analog inhibitors, and they actually inhibited the hydrolytic ability of the enzyme. These analog inhibitors might be useful for the elucidation of the sphingomyelinase hydrolytic mechanism. Less
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Murakami, M. et al.: "An Efficient Synthesis of Short-chain Spingomyelin Analogs and their Susceptibility to Hydrolysis Catalyzed by Spingomyelinase"Bioorg. Medic. Chem. Lett.. 7. 1725-1728 (1997)
Murakami,M.等:“短链鞘磷脂类似物的有效合成及其对鞘磷脂酶催化水解的敏感性”Bioorg。
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Fujii,S.;Tani,T.:Inoue,S.;Iwama,S.;Katsumura,S.;Ikeda,K.: "pH Dependence of the Reaction Rate of p-Bromophenacyl Bromide and of the Binding Constant of Ca^<2+> and an Amide-Type Substrate Analog to Bovine Panacreatic Phospholopase A_2," Arch.Biochem.Bioph
Fujii,S.;Tani,T.:Inoue,S.;Iwama,S.;Katsumura,S.;Ikeda,K.:“对溴苯甲酰溴反应速率和 Ca^ 结合常数的 pH 依赖性
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Tanaka, K.; Kamatani, M.; Mori, H.; Fujii, S.; Ikeda, K.; katsumura, S.: "The Inhibitory Mechanism of Bovine Pancreatic Phospholipase AィイD22ィエD2 by Aldehyde Terpenoids."Tetrahedron. 55. 1657-1686 (1999)
Tanaka,K.;Kamatani,H.;Fujii,S.;katsumura,S.:“醛类萜的抑制机制”。 1686 (1999)
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Tomoo,K.: "X-Ray Crystal Structure Determination and Molecular Dynamics Simulation of Phospholipase A_2 Inhibited by Amide-type Substrate Analogues." Biochimimica et Biophysica Acta. 1340. 178-186 (1997)
Tomoo,K.:“酰胺型底物类似物抑制磷脂酶 A_2 的 X 射线晶体结构测定和分子动力学模拟。”
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共 32 条
An Approach from Organic Synthesis Toward Elucidating the Mechanism of Super Energy Transfer Efficiencies of Carotenoids in Photosynthesis
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批准号:22550160
-
项目类别:Grant-in-Aid for Scientific Research (C)
-
资助金额:$2.91万
-
财政年份:2010
-
负责人:KATSUMURA Shigeo
-
依托单位:
Practical Alkaloid Synthesis on the axis of Asymmetric Azaelectrocyclization
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批准号:16510169
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项目类别:Grant-in-Aid for Scientific Research (C)
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资助金额:$2.37万
-
财政年份:2004
-
负责人:KATSUMURA Shigeo
-
依托单位:
Development of a New Synthetic Strategy Utilizing 6π-Azaelectrocyclization and its Synthetic Application
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批准号:13680679
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项目类别:Grant-in-Aid for Scientific Research (C)
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资助金额:$2.24万
-
财政年份:2001
-
负责人:KATSUMURA Shigeo
-
依托单位:
New Chiral Synthons from Glcidol and their Applications to Natural Products Synthesis.
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批准号:04640533
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项目类别:Grant-in-Aid for General Scientific Research (C)
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资助金额:$1.34万
-
财政年份:1992
-
负责人:KATSUMURA Shigeo
-
依托单位:
国内基金
海外基金
酸性鞘磷脂酶缺陷导致神经退行性病变的分子机制
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批准号:30700219
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项目类别:青年科学基金项目
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资助金额:19.0万元
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批准年份:2007
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负责人:刘忠华
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依托单位: