1927-31-7Relevant articles and documents
Nucleoside diphosphate kinase and the activation of antiviral phosphonate analogs of nucleotides: Binding mode and phosphorylation of tenofovir derivatives
Koch, Kerstin,Chen, Yuxing,Feng, Joy Y.,Borroto-Esoda, Katyna,Deville-Bonne, Dominique,Janin, Joel,Morera, Solange
, p. 776 - 792 (2009)
Tenofovir is an acyclic phosphonate analog of deoxyadenylate used in AIDS and hepatitis B therapy. We find that tenofovir diphosphate, its active form, can be produced by human nucleoside diphosphate kinase (NDPK), but with low efficiency, and that creati
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Keir,Smellie
, p. 405,409 (1959)
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Class II ribonucleotide reductases catalyze carbon-cobalt bond reformation on every turnover
Licht, Stuart S.,Lawrence, Christopher C.,Stubbe, JoAnne
, p. 7463 - 7468 (1999)
Ribonucleoside triphosphate reductase (RTPR) from Lactobacillus leichmannii catalyzes the reduction of nucleotides to deoxynucleotides with concomitant oxidation of two cysteines within the active site to a disulfide. RTPR requires adenosylcobalamin (AdoCbl) as a cofactor and as a radical chain initiator. Catalysis is initiated by homolysis of the carbon-cobalt bond of AdoCbl to yield cob(II)alamin, 5'-deoxyadenosine, and a protein-based thiyl radical. The turnover numbers for ATP with its allosteric effector dGTP, and for CTP with its allosteric effector dATP, are both 2 s-1. The rate- limiting step for turnover in the steady state is re-reduction of the oxidized form of the protein, a conformational change, or both. Under conditions where [RTPR] >> [AdoCbl], the rates of ATP and CTP reduction do not vary linearly with [AdoCbl] but instead exhibit saturation behavior with turnover numbers of 10 s-1 (ATP) and 8.5 s-1 (CTP). This result suggests that dissociation of AdoCbl, which requires carbon-cobalt bond reformation, follows nucleotide reduction, but precedes the rate-limiting step in catalysis. A presteady-state analysis of the ATP reduction (using rapid chemical quench methods) in the presence of [5'-3H]-AdoCbl reveals formation of product dATP at a k(obs) of 55 ± 10 s-1 and tritium washout from [5'- 3H]-AdoCbl at 0.6 s-1. The rate of washout is approximately equivalent to the rate of washout of 3H in the absence of substrate. Measurement of the ratio of 3H2O:dATP over time reveals that washout of 3H occurs at the end of each turnover. Production of 3H2O requires reformation of the carbon- cobalt bond. These steady-state and presteady-state data suggest that carbon- cobalt bond reformation and dissociation of AdoCbl into solution accompany each turnover and that the radical chain length of the RTPR-catalyzed nucleotide reduction is approximately one.
P(V) Reagents for the Scalable Synthesis of Natural and Modified Nucleoside Triphosphates
Liao, Jen-Yu,Bala, Saikat,Ngor, Arlene K.,Yik, Eric J.,Chaput, John C.
supporting information, p. 13286 - 13289 (2019/09/04)
Natural and modified nucleoside triphosphates impact nearly every major aspect of healthcare research from DNA sequencing to drug discovery. However, a scalable synthetic route to these molecules has long been hindered by the need for purification by high performance liquid chromatography (HPLC). Here, we describe a fundamentally different approach that uses a novel P(V) pyrene pyrophosphate reagent to generate derivatives that are purified by silica gel chromatography and converted to the desired compounds on scales vastly exceeding those achievable by HPLC. The power of this approach is demonstrated through the synthesis of a broad range of natural and unnatural nucleoside triphosphates (dNTPs and xNTPs) using protocols that are efficient, inexpensive, and operationally straightforward.
REVERSIBLY PROTECTED NUCLEOTIDE REAGENTS WITH HIGH THERMAL STABILITY
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Page/Page column 22, (2018/07/29)
The present invention provides for stable nucleotide reagents used for nucleic acid amplification by PCR and RT-PCR (Reverse Transcriptase-PCR) that comprises modified nucleoside polyphosphates. The present invention also provides for methods for using the modified nucleoside polyphosphates for detecting the presence or absence of a target nucleic acid sequence in a sample in an amplification reaction.
Nucleotide promiscuity of 3-phosphoglycerate kinase is in focus: Implications for the design of better anti-HIV analogues
Varga, Andrea,Chaloin, Laurent,Sagi, Gyula,Sendula, Robert,Graczer, Eva,Liliom, Karoly,Zavodszky, Peter,Lionne, Corinne,Vas, Maria
experimental part, p. 1863 - 1873 (2012/04/17)
The wide specificity of 3-phosphoglycerate kinase (PGK) towards its nucleotide substrate is a property that allows contribution of this enzyme to the effective phosphorylation (i.e. activation) of nucleotide-based pro-drugs against HIV. Here, the structural basis of the nucleotide-PGK interaction is characterised in comparison to other kinases, namely pyruvate kinase (PK) and creatine kinase (CK), by enzyme kinetic analysis and structural modelling (docking) studies. The results provided evidence for favouring the purine vs. pyrimidine base containing nucleotides for PGK rather than for PK or CK. This is due to the exceptional ability of PGK in forming the hydrophobic contacts of the nucleotide rings that assures the appropriate positioning of the connected phosphate-chain for catalysis. As for the d-/l-configurations of the nucleotides, the l-forms (both purine and pyrimidine) are well accepted by PGK rather than either by PK or CK. Here again the dominance of the hydrophobic interactions of the l-form of pyrimidines with PGK is underlined in comparison with those of PK or CK. Furthermore, for the l-forms, the absence of the ribose OH-groups with PGK is better tolerated for the purine than for the pyrimidine containing compounds. On the other hand, the positioning of the phosphate-chain is an even more important term for PGK in the case of both purines and pyrimidines with an l-configuration, as deduced from the present kinetic studies with various nucleotide-site mutants of PGK. These characteristics of the kinase-nucleotide interactions can provide a guideline for designing new drugs.
