Crystal structures of malonyl-coenzyme A decarboxylase provide insights into its catalytic mechanism and disease-causing mutations.
Crystal structures of malonyl-coenzyme A decarboxylase provide insights into its catalytic mechanism and disease-causing mutations.
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DOI：
10.1016/j.str.2013.05.001
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发表时间：
2013-07-02
期刊：
影响因子：
5.7
通讯作者：
Tong, Liang
中科院分区：
文献类型：
--
作者：
Froese, D. Sean;Forouhar, Farhad;Tran, Timothy H.;Vollmar, Melanie;Kim, Yi Seul;Lew, Scott;Neely, Helen;Seetharaman, Jayaraman;Shen, Yang;Xiao, Rong;Acton, Thomas B.;Everett, John K.;Cannone, Giuseppe;Puranik, Sriharsha;Savitsky, Pavel;Krojer, Tobias;Pilka, Ewa S.;Kiyani, Wasim;Lee, Wen Hwa;Marsden, Brian D.;von Delft, Frank;Allerston, Charles K.;Spagnolo, Laura;Gileadi, Opher;Montelione, Gaetano T.;Oppermann, Udo;Yue, Wyatt W.;Tong, Liang
丙二酰辅酶A脱羧酶（Malonyl-coenzyme A decarboxylase， MCD）从细菌到人类都有发现，在调节脂肪酸代谢和食物摄入中起着重要作用，是一个有吸引力的药物开发靶点。我们在这里报道了四种MCD晶体结构，分别来自人类，古红假单胞菌，葡萄农杆菌和金属铜杆菌，分辨率高达2.3 Å。MCD单体包含一个参与寡聚化的n端螺旋结构域和一个c端催化结构域。这四种结构在螺旋结构域的组织中表现出实质性的差异，因此，寡聚态和亚基间界面。出乎意料的是，MCD催化结构域在结构上与gcn5相关的n -乙酰基转移酶超家族同源，特别是curacin A聚酮合成酶催化模块，具有保守的His-Ser/Thr对催化很重要。我们的结构，以及诱变和动力学研究，为理解致病突变和催化提供了分子基础，也为基于结构的药物设计提供了模板。在2.3 Å分辨率下测定了人类和细菌MCD的结构，观察到不同的四聚体和二聚体MCD寡聚与GNAT超家族的意外同源性，为MCD致病突变提供了分子基础，丙二酰辅酶a脱羧酶（MCD）在脂肪酸代谢中很重要。Froese等人报道了几种MCD的结构，并表明MCD催化结构域与GNAT超家族具有结构同源性。这些结构进一步加深了我们对催化、致病突变和药物设计的理解。
Malonyl-coenzyme A decarboxylase (MCD) is found from bacteria to humans, has important roles in regulating fatty acid metabolism and food intake, and is an attractive target for drug discovery. We report here four crystal structures of MCD from human, Rhodopseudomonas palustris, Agrobacterium vitis, and Cupriavidus metallidurans at up to 2.3 Å resolution. The MCD monomer contains an N-terminal helical domain involved in oligomerization and a C-terminal catalytic domain. The four structures exhibit substantial differences in the organization of the helical domains and, consequently, the oligomeric states and intersubunit interfaces. Unexpectedly, the MCD catalytic domain is structurally homologous to those of the GCN5-related N-acetyltransferase superfamily, especially the curacin A polyketide synthase catalytic module, with a conserved His-Ser/Thr dyad important for catalysis. Our structures, along with mutagenesis and kinetic studies, provide a molecular basis for understanding pathogenic mutations and catalysis, as well as a template for structure-based drug design. Structures of human and bacterial MCDs were determined at up to 2.3 Å resolution Distinct tetrameric and dimeric MCD oligomerizations were observed Unexpected homology to the GNAT superfamily gives insights into catalytic mechanism The structures provide the molecular basis for the disease-causing mutations in MCD Malonyl-CoA decarboxylase (MCD) is important in fatty acid metabolism. Froese et al. report structures of several MCDs and show that the MCD catalytic domain shares structural homology with GNAT superfamily. The structures further our understanding of catalysis, pathogenic mutations, and drug design.
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影响因子：
37.8
作者：
Dyck, Jason R. B.;Hopkins, Teresa A.;Lopaschuk, Gary D.
通讯作者：
Lopaschuk, Gary D.
DOI：
10.1107/s0907444998003254
发表时间：
1998-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
Brunger, AT;Adams, PD;Warren, GL
通讯作者：
Warren, GL
DOI：
10.1107/s0907444994003112
发表时间：
1994-09-01
期刊：
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY
影响因子：
--
作者：
BAILEY, S
通讯作者：
BAILEY, S
影响因子：
2.9
作者：
Benning, MM;Haller, T;Holden, HM
通讯作者：
Holden, HM
影响因子：
8
作者：
Goldschmidt, Lukasz;Cooper, David R.;Eisenberg, David
通讯作者：
Eisenberg, David