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中文摘要
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我们建议详细研究功能相关的分子/电子结构和动力学
英文摘要
We propose the detailed study of functionally relevant molecular/electronic structural and dynamic properties of a series of heme oxygenase, HO, enzymes and their complexes with substrate/reaction intermediates in variable oxidation/spin/liagtion states, using high resolution solution 2D/3D NMR. HO, found in vertebrates, plants and bacteria, acts by a common mechanism and set of intermediates, using heme as both substrate and cofactor, to stereoselectively cleave heme into a-biliverdin, iron and CO. HO is unique in using the hydrpperoxy species as its activated form, and the structural properties of the active site that stabilize the species are not well understood except that ordered water molecules within a distal H-bond network are involved. We select three HOs, ispzyme #1 from human, hHO, and those from two pathogenic bacteria C. diphtheriae (CofHO) and N. meningitidis (NmHO), which share a common fold, but exhibit variable sequence homology for the residues involved in the H-bonding network. The target derivatives are substrate-free or app-HO, resting state HO-hemin-H/jO, HO-hemin-CN as a model for the unstable oxy complex, and HO-hemin-OH as a model for the reactive hydroperpxy species. Since all but one targeted HO derivative are paramagnetic, emphasis is placed on utilizing appropriately tailored 1D/2D/3D NMR to extract the wealth of unique information in hyperfine shifts. We will develop a new and highly sensitive NMR probe that directly reflect the degree of H-bonding between axial ligand to the hemin and the distal ordered-water/H-bond network, using the pair of complex HO-hemin-H2O/-OH, and to use this probe, as well as previously established procedures, to provide a detailed characterization of the solution structure. Our interests focus on comparison of local solution with cryogenic crystallographic molecular structure, with particular attention paid to extended H-bond networks with some remarkably robust H-bonds, and the ordered water molecules within these networks. We emphasize comparative studies among the various derivatives of one HO, and among the different HOs for a given derivative, to elucidate the relationship between variable strength H-bonds and axial ligand properties. In addition, we will characterize the influence of HO, substrate or intermediates and their axial ligands on dynamic properties related to entry and exit of substrate. Lastly, for NmHO, we will characterize the influence of heme substituents on its seating in the active site, determine the structure of the crystallographically disordered C-terminus found folded into the active site in solution, and illuminate the role of the C-terminus and the unique active site Cys113 in multiple, functionally relevant, microheterogeneities. The detailed description of the molecular structural and dynamic properties of heme oxygenase will improve our understanding of the varied roles of mammalian enzymes. The elucidation of the similarities and differences between bacterial and mammalian heme oxygenase will improve prospects for the design of selective inhibitors for the enzyme in pathogenic bacteria.
期刊论文(20)
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1H NMR study of the influence of mutation on the interaction of the C-terminus with the active site in heme oxygenase from Neisseria meningitidis: implications for product release.
1H NMR 研究突变对脑膜炎奈瑟菌血红素加氧酶 C 末端与活性位点相互作用的影响:对产品释放的影响。
DOI: 10.1021/bi1000867
发表时间: 2010
期刊: Biochemistry
影响因子: 2.9
作者: [Peng,Dungeng, Ma,Li-Hua, Ogura,Hiroshi, Yang,En-Che, Zhang,Xuhong, Yoshida,Tadashi, LaMar,GerdN]
通讯作者: LaMar,GerdN
DOI: 10.1021/bi200978g
发表时间: 2011-10-18
期刊: BIOCHEMISTRY
影响因子: 2.9
作者: [Peng, Dungeng, Satterlee, James D., Ma, Li-Hua, Dallas, Jerry L., Smith, Kevin M., Zhang, Xuhong, Sato, Michihiko, La Mar, Gerd N.]
通讯作者: La Mar, Gerd N.
DOI: 10.1021/ja028108x
发表时间: 2002-11
期刊: Journal of the American Chemical Society
影响因子: 15
作者: [R. Syvitski;Yiming Li;K. Auclair;P. Ortiz de Montellano;G. L. La Mar]
通讯作者: R. Syvitski;Yiming Li;K. Auclair;P. Ortiz de Montellano;G. L. La Mar
Solution NMR study of environmental effects on substrate seating in human heme oxygenase: influence of polypeptide truncation, substrate modification and axial ligand.
环境对人血红素加氧酶底物定位影响的溶液核磁共振研究:多肽截短、底物修饰和轴向配体的影响。
DOI: 10.1016/j.jinorgbio.2005.08.010
发表时间: 2006
期刊: Journal of inorganic biochemistry
影响因子: 3.9
作者: [Zhu,Wenfeng, Li,Yiming, Wang,Jinling, OrtizdeMontellano,PaulR, LaMar,GerdN]
通讯作者: LaMar,GerdN
共 12 条
    Electronic/molecular structure of enzyme heme pockets
    Electronic/Molecular Structure of Enzyme Heme Pockets
    Electronic/molecular structure of enzyme heme pockets
    Electronic/Molecular Structure of Enzyme Heme Pockets
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