Mechanism of inhibition of DNA (cytosine C5)-methyltransferases by oligodeoxyribonucleotides containing 5,6-dihydro-5-azacytosine 1 1Edited by R. Huber

Sheikhnejad, Gholamreza; Brank, Adam S.; Christman, Judith K.; Goddard, A.; Álvarez, Estela; Ford, Harry; Márquez, Víctor E.; Marasco, Canio J.; Sufrin, Janice R.; O’Gara, Margaret; Cheng, Xiaodong

doi:10.1006/jmbi.1998.2426

Cited by 72 publications

(85 citation statements)

References 41 publications

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“…For M.HhaI, the single tryptophan residue (Trp 41 ), located in the AdoMet binding pocket (9), facilitates detection of the enzyme⅐AdoMet complex via steady state native fluorescence experiments. In agreement with the crystal structures, the native fluorescence upon excitation at 280 nm has an emission maximum of 358 nm, indicative of a solvent-exposed tryptophan residue (32).…”

Section: Steady State Parameters and Kinetic Mechanism For Singlesitementioning

confidence: 99%

“…The nucleoside flipping process has been observed via 2-aminopurine fluorescence in M.EcoRI (6, 37), M.TaqI, and M.HhaI (16), and uracil-DNA glycosylase (38). Crystal structures are available of M.HhaI bound to AdoMet (9, 39); covalently bound to DNA (5); noncovalently bound to unmethylated, fully methylated (19), and hemimethylated DNA (20); and both nucleoside analog-containing (40,41) and base pair mismatch-containing DNA (42). M.HhaI represents a rich structural paradigm for DNA-modifying enzymes, yet many mechanistic issues remain unresolved.…”

Section: Measurement Of Equilibrium Dissociation Constants-mentioning

confidence: 99%

“…The larger cavity volume seen in the unmethylated DNA complex (left) results from the absence of the methyl moiety and the lack of compensatory repacking of the proximal structural elements. 41 and Phe 18 (red) are visible through the calculated molecular surface of the enzyme. The extrahelical cytosine of the ternary complex is shown (blue).…”

Section: Functional Dissection Of Hhai Dna Methyltransferasementioning

confidence: 99%

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Reconciling Structure and Function in HhaI DNA Cytosine-C-5 Methyltransferase

Lindstrom

Flynn

Reich

2000

Journal of Biological Chemistry

127

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Pre-steady state partitioning analysis of the HhaI DNA methyltransferase directly demonstrates the catalytic competence of the enzyme⅐DNA complex and the lack of catalytic competence of the enzyme⅐S-adenosyl-L-methionine (AdoMet) complex. The enzyme⅐AdoMet complex does form, albeit with a 50-fold decrease in affinity compared with the ternary enzyme⅐AdoMet⅐DNA complex. These findings reconcile the distinct binding orientations previously observed within the binary enzyme⅐AdoMet and ternary enzyme⅐S-adenosyl-Lhomocysteine⅐DNA crystal structures. The affinity of the enzyme for DNA is increased 900-fold in the presence of its cofactor, and the preference for hemimethylated DNA is increased to 12-fold over unmethylated DNA. We suggest that this preference is partially due to the energetic cost of retaining a cavity in place of the 5-methyl moiety in the ternary complex with the unmethylated DNA, as revealed by the corresponding crystal structures. The hemi-and unmethylated substrates alter the fates and lifetimes of discrete enzyme⅐substrate intermediates during the catalytic cycle. Hemimethylated substrates partition toward product formation versus dissociation significantly more than unmethylated substrates. The mammalian DNA cytosine-C-5 methyltransferase Dnmt1 shows an even more pronounced partitioning toward product formation.

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Section: Steady State Parameters and Kinetic Mechanism For Singlesitementioning

confidence: 99%

Section: Measurement Of Equilibrium Dissociation Constants-mentioning

confidence: 99%

Section: Functional Dissection Of Hhai Dna Methyltransferasementioning

confidence: 99%

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Reconciling Structure and Function in HhaI DNA Cytosine-C-5 Methyltransferase

Lindstrom

Flynn

Reich

2000

Journal of Biological Chemistry

127

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“…As analogsofHPMP-cytosine [8,9 ], they both have extinctf unctions anda nti-virus potential. As AC and DAC are unstable in water, further solutions are put forward, that is, saturation of the 5,6-double bond, which leads to 5,6-dihydro-5-azacytidine (DHAC)a nd 2'-deoxy-5,6-dihydro-5-azacytidine (DHDAC), formerone could inhibit RNA synthesis [10], while the later exhibits unique anti-HIV potential [11]. Beside their mainly applications in medical chemistry, they have shown distinctive lanthanides/actinides separation efficacy.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of isobutyl 3-(4-amino-2-oxo-1,3,5-triazin-1(2H)-yl) propanoate, C10H16N4O3

Wang

Xia

et al. 2014

Zeitschrift Für Kristallographie - New Crystal Structures

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Source of materialAllreactantare purchasedand used withoutfurther purification. In at ypical reaction 4-amino-1,3,5-triazin-2(1H)-one( 1.12 g, 10 mmol), isobutyl acrylate (2.2m l,15 mmol), and 0.06g boric acid (1 mmol)wereplacedintoaflask.Water (40 ml) was added andthe reaction mixture was stirred at 333 Kfor several hours. The progress of the reaction was monitored by thin-layer chromatography (TLC). The solvent was removed under reduced pressure.T hent he solidm aterial wasw ashedw ith ethyla cetate (40 ml) and the solution was filtered to afford the pure product. The purified product was dissolved in the mixture of ethyl alcohol and N,N-dimethylformamide (v/v =2/1).The resulting solution wasleft in air for afew days, yielding colourless crystals. Experimental detailsAllHatomswerepositionedgeometrically andallowed to ride on their parent atoms at distances of Csp 2 -H =0 .93 Åw ith U iso = 1.2U eq (parent atom), Csp 3 -H =0.97/0.98 Åwith U iso =1.5/1.2 U eq (parent atom)and N-H =0.86 Åwith U iso =1.2U eq (parent atom) [13,14]. DiscussionAmong various analogs of cytosine, the 5-azacytosine(5-azaC) analogs have attracted more attention than the normalcytosine or other analogs [1,2].For using as anti-cancer drugs, 5-azacytidine (AC)and 2'-deoxy-5-azacytidine (DAC), demonstrate their active in inhibition aflatoxin biosynthesis [3], the treatment of leukemia [4] and myelodysplastic syndrome (MDS) [5], acute myeloid leukemia (AML) [6], respectively.I na nti-viral range, HPMP-5-azaC,its cyclic formand ester prodrugs, all show remarkable activity againstvarious DNAviruses [7]. As analogsofHPMP-cytosine [8,9 ], they both have extinctf unctions anda nti-virus potential. As AC and DAC are unstable in water, further solutions are put forward, that is, saturation of the 5,6-double bond, which leads to 5,6-dihydro-5-azacytidine (DHAC)a nd 2'-deoxy-5,6-dihydro-5-azacytidine (DHDAC), formerone could inhibit RNA synthesis [10], while the later exhibits unique anti-HIV potential [11]. Beside their mainly applications in medical chemistry, they have shown distinctive lanthanides/actinides separation efficacy. Recently, report on the separation of uranium from multi-ion system has been discovered [12],broadening their scope to hazardous pollutants detection. Consequently, more effort and passion should be spend on the research of cytosine analogues. Herein we report the structure of isobutyl 3-(4-amino-2-oxo-1,3,5-triazin-1(2H)-yl)propanoate, also an cytosine analog. The bond lengths and angles in the title molecule (Fig.), are within normalranges. The N1-C1 and N1-C3 bond distances [1.4158(19) . Thepartial double bond character of the structure is presumed as aresult of the electron delocalization. Thedihedral angle formed by theheterocyclicringand theplane definedby N1/C4/C5 is 80.85°.The atoms C1, C2, C3, N1, N2 and N3 in the heterocyclic ring are slightly puckered, with an r.m.s. deviation of 0.093 Å. It should be noted that the hydrogen bonding interactions plays an important role in the crystal structure of the title comp...

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“…5-azacytidine (azacitidine, Vidaza) is a ribonucleotide analog, and 5-aza-2'-deoxycytidine (decitabine, Dacogen), is a deoxyribonucleotide analog. These analogs once incorporated into the DNA in place of cytosine, can covalently trap DNA methyltransferase leading to decrease in DNA methylation [9]. These mechanistic inhibitors of DNA methytransferase are currently approved for use in myelodysplastic syndrome [10,11], and have clinical activity in other malignancies [12].…”

Section: Introductionmentioning

confidence: 99%

2′-Deoxy-N4-[2-(4-nitrophenyl)ethoxycarbonyl]-5-azacytidine: A novel inhibitor of DNA methyltransferase that requires activation by human carboxylesterase 1

et al. 2008

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Abstract2'-Deoxy-N4-[2-(4-nitrophenyl) ethoxycarbonyl]-5-azacytidine (NPEOC-DAC), decitabine with a modification of the N4 position of the azacitidine ring can be used to inhibit DNA methyltransferase. This modification protects the azacitidine ring and can be cleaved by carboxylesterase to release decitabine. NPEOC-DAC was 23-fold less potent at low doses (<10 µM) than decitabine at inhibiting DNA methylation, and was also associated with a 3-day delay in its effect. However, at doses ≥ 10 µM NPEOC-DAC was more effective at inhibiting DNA methylation. Theses differences between decitabine and NPEOC-DAC are dependent on the cleavage of the carboxylester bond, and could be potentially exploited pharmacologically.

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Mechanism of inhibition of DNA (cytosine C5)-methyltransferases by oligodeoxyribonucleotides containing 5,6-dihydro-5-azacytosine 1 1Edited by R. Huber

Cited by 72 publications

References 41 publications

Reconciling Structure and Function in HhaI DNA Cytosine-C-5 Methyltransferase

Reconciling Structure and Function in HhaI DNA Cytosine-C-5 Methyltransferase

Crystal structure of isobutyl 3-(4-amino-2-oxo-1,3,5-triazin-1(2H)-yl) propanoate, C10H16N4O3

2′-Deoxy-N4-[2-(4-nitrophenyl)ethoxycarbonyl]-5-azacytidine: A novel inhibitor of DNA methyltransferase that requires activation by human carboxylesterase 1

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