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21.
22.
Members of the HhH-GPD superfamily of DNA glycosylases are responsible for the recognition and removal of damaged nucleobases from DNA. The hallmark of these proteins is a motif comprising a helix-hairpin-helix followed by a Gly/Pro-rich loop and terminating in an invariant, catalytically essential aspartic acid residue. In this study, we have probed the role of this Asp in human 8-oxoguanine DNA glycosylase (hOgg1) by mutating it to Asn (D268N), Glu (D268E), and Gln (D268Q). We show that this aspartate plays a dual role, acting both as an N-terminal alpha-helix cap and as a critical residue for catalysis of both base excision and DNA strand cleavage by hOgg1. Mutation of this residue to asparagine, another helix-capping residue, preserves stability of the protein while drastically reducing enzymatic activity. A crystal structure of this mutant is the first to reveal the active site nucleophile Lys249 in the presence of lesion-containing DNA; this structure offers a tantalizing suggestion that base excision may occur by cleavage of the glycosidic bond and then attachment of Lys249. Mutation of the aspartic acid to glutamine and glutamic acid destabilizes the protein fold to a significant extent but, surprisingly, preserves catalytic activity. Crystal structures of these mutants complexed with an unreactive abasic site in DNA reveal these residues to adopt a sterically disfavored helix-capping conformation. 相似文献
23.
Product-assisted catalysis in base-excision DNA repair 总被引:7,自引:0,他引:7
Most spontaneous damage to bases in DNA is corrected through the action of the base-excision DNA repair pathway. Base excision repair is initiated by DNA glycosylases, lesion-specific enzymes that intercept aberrant bases in DNA and catalyze their excision. How such proteins accomplish the feat of catalyzing no fewer than five sequential reaction steps using a single active site has been unknown. To help answer this, we report the structure of a trapped catalytic intermediate in DNA repair by human 8-oxoguanine DNA glycosylase. This structure and supporting biochemical results reveal that the enzyme sequesters the excised lesion base and exploits it as a cofactor to participate in catalysis. To our knowledge, the present example represents the first documented case of product-assisted catalysis in an enzyme-catalyzed reaction. 相似文献
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25.
Rick PD; Hubbard GL; Kitaoka M; Nagaki H; Kinoshita T; Dowd S; Simplaceanu V; Ho C 《Glycobiology》1998,8(6):557-567
The polysaccharide chains of enterobacterial common antigen (ECA) consist
of linear trisaccharide repeat units with the structure -->3)-
alpha-d-Fuc4NAc-(1-->4)-beta-d-ManNAcA-(1-->
4)-alpha-d-GlcNAc-(1-->, where Fuc4NAc is 4-acetamido-4,
6-dideoxy-d-galactose, ManNAcA is N - acetyl-d- mannosaminuronic acid, and
GlcNAc is N -acetyl-d-glucosamine. The major form of ECA (ECAPG) consists
of polysaccharide chains that are believed to be covalently linked to
diacylglycerol through phosphodiester linkage; the phospholipid moiety
functions to anchor molecules in the outer membrane. The ECA trisaccharide
repeat unit is assembled as a polyisoprenyl-linked intermediate which has
been tentatively identified as Fuc4NAc-ManNAcA-GlcNAc-
pyrophosphorylundecaprenol (lipid III). Subsequent chain-elongation
presumably occurs by a block-polymerization mechanism. However, the
identity of the polyisoprenoid carrier-lipid has not been established.
Accordingly, the current studies were conducted in an effort to
structurally characterize the polyisoprenyl lipid-carrier involved in ECA
synthesis. Isolation and characterization of the lipid carrier was
facilitated by the accumulation of a ManNAcA-GlcNAc-
pyrophosphorylpolyisoprenyl lipid (lipid II) in mutants of Salmonella
typhimurium defective in the synthesis of TDP-Fuc4NAc, the donor of Fuc4NAc
residues for ECA synthesis. Analyses of lipid II preparations by fast atom
bombardment tandem mass spectroscopy (FAB-MS/MS) resulted in the
identification of the lipid-carrier as the 55-carbon polyisoprenyl alcohol,
undecaprenol. These analyses also resulted in the identification of a novel
glycolipid which copurified with lipid II. FAB-MS/MS analyses of this
glycolipid revealed its structure to be 1,2-diacyl- sn
-glycero-3-pryophosphoryl-GlcNAc-ManNAcA (DGP- disaccharide). An
examination of purified ECAPGby phosphorus-31 nuclear magnetic resonance
spectroscopy confirmed that the polysaccharide chains are linked to
diacylglycerol through phosphodiester linkage. Thus, DGP-disaccharide does
not appear to be an intermediate in ECAPGsynthesis. Nevertheless, although
the available evidence clearly indicate that lipid II is a precursor of
DGP-disaccharide, the function of this novel glycolipid is not yet known,
and it may be an intermediate in the biosynthesis of a molecule other than
ECAPG.
相似文献
26.
角质形成细胞生长因子(KGF)在喉粘膜良性、癌前及恶性病变中的mRNA水平分析 总被引:1,自引:0,他引:1
利用原位杂交的方法检测KGFmRNA在正常喉粘膜上皮(N)、慢性非特异性炎症(IF)、不典型增生(DYS)及鳞癌(SCC)中的转录水平,探讨KGF在喉粘膜良性及恶性病变中的分布和可能的作用。结果表明,KGFmRNA不仅在间质中的成纤维细胞中表达,少量的炎细胞及血管内皮细胞中亦表达,而且从N、IF、DYS到SCC、KGFmRNA转录水平逐渐增强;上皮细胞及肿瘤性上皮细胞不表达KGFmRNA,KGFmRNA在分化差的SCC周围间质中表达较分化好的SCC周围间质增多。结论:KGF在上皮与间充质细胞的交互作用中发挥着重要的作用,对维持喉粘膜正常结构、代谢及喉癌的发生发展具有重要意义。 相似文献
27.
DNA glycosylase recognition and catalysis 总被引:5,自引:0,他引:5
DNA glycosylases are the enzymes responsible for recognizing base lesions in the genome and initiating base excision DNA repair. Recent structural and biochemical results have provided novel insights into DNA damage recognition and repair. The basis of the recognition of the oxidative lesion 8-oxoguanine by two structurally unrelated DNA glycosylases is now understood and has been revealed to involve surprisingly similar strategies. Work on MutM (Fpg) has produced structures representing three discrete reaction steps. The NMR structure of 3-methyladenine glycosylase I revealed its place among the structural families of DNA glycosylases and the X-ray structure of SMUG1 likewise confirmed that this protein is a member of the uracil DNA glycosylase superfamily. A novel disulfide cross-linking strategy was used to obtain the long-anticipated structure of MutY bound to DNA containing an A*oxoG mispair. 相似文献
28.
29.
Excision of deaminated cytosine from the vertebrate genome: role of the SMUG1 uracil-DNA glycosylase 总被引:1,自引:0,他引:1
Nilsen H Haushalter KA Robins P Barnes DE Verdine GL Lindahl T 《The EMBO journal》2001,20(15):4278-4286
Gene-targeted mice deficient in the evolutionarily conserved uracil-DNA glycosylase encoded by the UNG gene surprisingly lack the mutator phenotype characteristic of bacterial and yeast ung(-) mutants. A complementary uracil-DNA glycosylase activity detected in ung(-/-) murine cells and tissues may be responsible for the repair of deaminated cytosine residues in vivo. Here, specific neutralizing antibodies were used to identify the SMUG1 enzyme as the major uracil-DNA glycosylase in UNG-deficient mice. SMUG1 is present at similar levels in cell nuclei of non-proliferating and proliferating tissues, indicating a replication- independent role in DNA repair. The SMUG1 enzyme is found in vertebrates and insects, whereas it is absent in nematodes, plants and fungi. We propose a model in which SMUG1 has evolved in higher eukaryotes as an anti-mutator distinct from the UNG enzyme, the latter being largely localized to replication foci in mammalian cells to counteract de novo dUMP incorporation into DNA. 相似文献
30.