共查询到20条相似文献,搜索用时 15 毫秒
1.
Yun Wang Jennifer M. Kavran Zan Chen Kannan R. Karukurichi Daniel J. Leahy Philip A. Cole 《The Journal of biological chemistry》2014,289(45):31361-31372
S-Adenosylhomocysteine hydrolase (SAHH) is an NAD+-dependent tetrameric enzyme that catalyzes the breakdown of S-adenosylhomocysteine to adenosine and homocysteine and is important in cell growth and the regulation of gene expression. Loss of SAHH function can result in global inhibition of cellular methyltransferase enzymes because of high levels of S-adenosylhomocysteine. Prior proteomics studies have identified two SAHH acetylation sites at Lys401 and Lys408 but the impact of these post-translational modifications has not yet been determined. Here we use expressed protein ligation to produce semisynthetic SAHH acetylated at Lys401 and Lys408 and show that modification of either position negatively impacts the catalytic activity of SAHH. X-ray crystal structures of 408-acetylated SAHH and dually acetylated SAHH have been determined and reveal perturbations in the C-terminal hydrogen bonding patterns, a region of the protein important for NAD+ binding. These crystal structures along with mutagenesis data suggest that such hydrogen bond perturbations are responsible for SAHH catalytic inhibition by acetylation. These results suggest how increased acetylation of SAHH may globally influence cellular methylation patterns. 相似文献
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Moon Woo Chun Hyuk Woo Lee Jin-Hee Kim Hea Ok Kim Kang Man Lee Shantanu Pal 《Nucleosides, nucleotides & nucleic acids》2013,32(6-7):729-732
Homo-apioneplanocin A (1) as a potential inhibitor of S-adenosylhomocysteine hydrolase was synthesized from D-ribose, employing stereoselective hydroxymethylation, regioselective oxidation, and regio- and chemoselective hydroboration as key steps. 相似文献
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《Nucleosides, nucleotides & nucleic acids》2013,32(5-8):589-592
Abstract Halogenated analogues of neplanocin A were synthesized from the key intermediate 1, among which fluoro-neplanocin A was found to be novel mechanism-based irreversible inhibitor of S-Adenosylhomocysteine hydrolase. 相似文献
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The biochemical lesion in two cysteine auxotrophs of Tetrahymena thermophila has been established as a defect in S-adenosylhomocysteine hydrolase, an enzyme of the transsulfuration pathway. As a result, these mutants require cysteine (or cystathionine or homocysteine) for growth in a denned medium. Cell-free extracts of the mutants contained < 5% of the level of the enzyme seen in the wild type. One of the mutant strains accumulated intracellular levels of S-adenosylhomocysteine as high as 1380 üM, a level 200 times normal. When both mutant strains were maintained in defined medium without cysteine, growth occurred after a long lag; this phenomenon was termed “adaptation.” Adaptation was a) reversed by passage through rich medium, b) was not a recovery of S-adenosylhomocysteine hydrolase, and c) was probably linked to induction of an alternate pathway for cysteine biosynthesis, involving a lysosomal S-adenosylhomocysteine nucleosidase activity. 相似文献
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Jack D. Anderson Roger J. Bontems Stewart Geary Howard B. Cottam Steven B. Larson Steven S. Matsumoto 《Nucleosides, nucleotides & nucleic acids》2013,32(7):1201-1216
Abstract Tubercidin (7-deazaadenosine, 1a) and several 6-chlorotuber-cidin derivatives were synthesized including 4-amino-6-chloro-7-β-D-ribofuranosylpyrrolo[2,3-d]pyrimidine-3′,5′-cycyclic phosphate 9. Isolation of a side product found in the glycosylation step of the reaction sequence proved to be the N-1 ribosyl-attached isomer as shown by X-ray diffraction analysis. All derivatives were tested for in vitro antiviral and antitumor activity. 相似文献
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《Nucleosides, nucleotides & nucleic acids》2013,32(5-8):783-785
Abstract Conjugated diene 5–7 and enyne 8 analogs derived from adenosine and uridine were synthesized employing Pd-catalyzed cross-coupling reactions. 相似文献
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Chong-Sheng Yuan Siming Liu Stanislaw F. Wnuk Moms J. Robins Ronald T. Borchardt 《Nucleosides, nucleotides & nucleic acids》2013,32(3-5):439-447
Abstract Crucial to the rational design of inhibitors of S-adenosyl-L-homocysteine (AdoHcy) hydrolase was the elucidation of its mechanism of catalysis by Palmer and Abeles (J. Biol. Chem. 254, 1217–1226, 1979). This mechanism involves an NAD+-dependent oxidation (oxidative activity) of the 3′-hydroxyl group of AdoHcy followed by elimination of homocysteine (Hcy) to form 4′,5′-didehydro-3′-keto-Ado. Addition of water at the 5′-position (hydrolytic activity) of this tightly bound intermediate followed by an NADH-dependent reduction results in the formation of adenosine (Ado). Many inhibitors of this enzyme have been shown to serve as substrates [e.g., 9-(trans-2-trans-3-dihydroxycyclopent-4-en-1-yl)adenine, DHCeA)] for the oxidative activity of AdoHcy hydrolase, affording the 3′-keto-derivative (e.g., 3′-keto-DHCeA), which is tightly bound to the enzyme, and converting the enzyme from its active form (NAD+) to its inactive form (NADH) (Type I mechanism-based inhibitors; Wolfe and Borchardt, J. Med. Chem. 34, 1521–1530, 1991). More recently, substrates [e.g., (E)-5.,6′-didehydro-6′-deoxy-6′-fluorohomoadenosine, EDDFHA] for the hydrolytic activity of AdoHcy hydrolase have been identified by our laboratories. Identification of hydrolytic substrates affords a new strategy for the design of more potent and more specific inhibitors of AdoHcy hydrolase. 相似文献
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A novel method is described for the synthesis of pyrimidine nucleosides. 1-β-d-Gluco-pyranosyl-, 1-β-d-xylopyranosyl-, and 1-β-d-ribopyranosyl-uracils were prepared in good yields by the condensation of uracil with 1-O-trichloroacetyl-2,3,4,6:tetra-O-acetyl-α-d-glucopyranose, 1-O-trichloroacety1-2,3,4-tri-O-acetyl-α-d-xylopyranose, and 1 - O - trichloroacetyl-2,3-4-tri-O-acetyl-α-d-ribopyranose, respectively. Glucosyl- and xylosyluracils were prepared under the reaction conditions similar to those used in the Hilbert-Johnson method, whereas the synthesis of ribosyluracil was carried out by the fusion procedure of the reactants. 相似文献
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Akira Kamimura Koji Mitsugi Shinji Okumura 《Bioscience, biotechnology, and biochemistry》2013,77(9):2063-2072
Synthesis of nucleosides by the pentosyl transfer reaction in Ps. trifolii (IAM-1555) was studied. The ribosyl transfer reaction between purine or pyrimidine bases and their nucleosides as an acceptor and a donor, respectively, was observed in the presence or absence of inorganic phosphate, and the participations of nucleoside phosphorylase in the former and nucleoside N-ribosyltransferase in the latter were suggested. This transribosylation to the base in the latter was observed to proceed stoichiometrically between pH 6 and 9.5, but the apparent optimal pH in the former was observed at around 10.5. Effects of cultural condition of bacterium, reaction temperature and metallic ions on this reaction and acceptor-and donor-specificities were studied in detail. 相似文献
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A new procedure which involves 1-trichloroacetyl sugars as the starting material has been developed for the synthesis of purine nucleosides. 7-β-d-Glucopyranosyl-, 7-β-d-xylopyranosyl-, 7-β-d-ribopyranosyl-theophylline, 9-(tetra-O-acetyl-β-d-glucopyranosyl)-2,6,8-trichloropurine and 9-β-d-glucopyranosyl adenine were prepared in good yields by the reaction in fusion of purine bases with 1-trichloroacetyl sugars, using zinc chloride, p-toluenesulfonic acid, or ethyl polyphosphate as catalyst. 9-d-Ribofuranosyl adenine was also prepared by the same procedures, although the anomeric configuration of the compound is not yet definite. The effect of catalysts on the yields of purine nucleosides is discussed. 相似文献
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为了在原核细胞中表达青岛文昌鱼Branchiostoma belcheri tsingtaunese S-腺苷高半胱氨酸水解酶(S-adeno-sylhomocysteine hydrolase,SAHH),采取构建文昌鱼SAHH基因的原核表达重组质粒pGEX-6P-1-SAHH的方法,转化入大肠杆菌JMl09感受态细胞中,IPTG诱导蛋白表达,并进行分离纯化.结果经SDS-PAGE分析,重组质粒在JM109中表达并纯化得到的融合蛋白大约为70 kDa,成功构建了文昌鱼SAHH基因原核表达载体,且重组载体表达出融合蛋白,分离纯化得到目的蛋白. 相似文献
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《Journal of enzyme inhibition and medicinal chemistry》2013,28(3):159-167
AbstractThe ability of some substrate-analogues to inhibit or to inactivate S-adenosylhomocysteine hydrolase (SAHase) purified from bovine pancreas was investigated. Our results confirm that 3-deazaarysteromicin (DZAry) is a more potent competitive inhibitor than 3-deazaadenosine (DZA), while nebularine (purine riboside), contrary to previous reports, showed an uncompetitive inhibition. Moreover, 2-chloroadenosine and 2′-deoxyadenosine were found to be irreversible inactivators of SAHase with increasing potency, respectively. Ki values found for these drugs were of the same order of magnitude as those reported for SAHases from other mammalian tissues. The SAHase substrate-analogues studied are believed to act as antineoplastic and/or antiviral agents. It is conceivable to postulate that their therapeutic effects could be, at least in part, attributable to inhibition or even to inactivation of SAHase which, in turn, causes a reduction in S-adenosylmethionine-dependent methylation reactions. 相似文献
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Erik De Clerq 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):625-634
Abstract Various carbocyclic analogues of adenosine, including aristeromycin (carbocyclic adenosine), carbocyclic 3-deazaadenosine, neplanocin A, 3-deazaneplanocin A, the 5′-nor derivatives of aristeromycin, carbocylic 3-deazaadenosine, neplanocin A and 3-deazaneplanocin A, and the 2-halo (i.e., 2-fluoro) and 6′-R-alkyl (i.e., 6′-R-methyl) derivatives of neplanocin A have been recognized as potent inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase. This enzyme plays a key role in methylation reactions depending on S-adenosylmethionine (AdoMet) as methyl donor. AdoHcy hydrolase inhibitors have been shown to exert broad-spectrum antiviral activity against pox-, paramyxo-, rhabdo-, filo-, bunya-, arena-, and reoviruses. They also interfere with the replication of human immunodeficiency virus through inhibition of the Tat transactivation process. 相似文献
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J. H. Arango A. Geer J. Rodriguez P. E. Young P. Scheiner 《Nucleosides, nucleotides & nucleic acids》2013,32(7):773-784
Abstract Cis and trans-1-(4-hydroxy-2-cyclohexenyl)- and 1-(2-hydroxy-5-cyclohexenyl) thymines were obtained by stereospecific routes. Oxidation of the 1, 4-products afforded 1-(4-oxo-2-cyclohexenyl)thymine, the carbocyclic analog of a reportedly antiviral ketopyranosyl nucleoside. Exclusive 1, 6-conjugate addition occurred with heterocyclic bases and methyl 1, 3-cyclohexadiene-1-carboxylate. Reduction of the thymine adduct gave 1-(4-hydroxymethyl1-3-cyclohexenyl)thymine. Michael-type addition provided a direct route to 3-oxocycloalkyl nucleosides, and lactone nucleosides resulted from addition of bases to α-methylene-γ-butyrolactone. Anti-HIV screening revealed no activity for the new compounds. 相似文献
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《Nucleosides, nucleotides & nucleic acids》2013,32(5-8):747-749
Abstract A selective metalation at the 6-CH3 over C-8 of 6-methylpurine derivative 6 was observed with softer counter cation (Na+ or K+) of the base, while the harder Li+ showed no selectivity. In the presence of N-fluorobenzenesulfonamide (NFSI), this property was utilized for the synthesis of 6-fluoromethylpurine derivatives 4 and 5 as potential toxins for suicide gene therapy. 相似文献
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Abdalla E. A. Hassan Reham A. I. Abou-elkair John A. Montgomery John A. Secrist III 《Nucleosides, nucleotides & nucleic acids》2013,32(7):1123-1134
Abstract Efficient methods for the synthesis of 6-methylpurine (3), 9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-methylpurine (8), and 6-methyl-9-β-D-ribofuranosylpurine (5) are described. Methodology involving the (Ph3P)4Pd catalyzed cross-coupling reaction of CH3ZnBr with several different 6-chloropurine derivatives is described in high yield. This methodology now provides a facile and high-yielding synthesis of 8, which is needed in significant amounts for studies in cancer gene therapy. 相似文献