- Identification of a cyclic nucleotide as a cryptic intermediate in molybdenum cofactor biosynthesis
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The molybdenum cofactor (Moco) is a redox cofactor found in all kingdoms of life, and its biosynthesis is essential for survival of many organisms, including humans. The first step of Moco biosynthesis is a unique transformation of guanosine 5′-triphosphate (GTP) into cyclic pyranopterin monophosphate (cPMP). In bacteria, MoaA and MoaC catalyze this transformation, although the specific functions of these enzymes were not fully understood. Here, we report the first isolation and structural characterization of a product of MoaA. This molecule was isolated under anaerobic conditions from a solution of MoaA incubated with GTP, S-adenosyl-l-methionine, and sodium dithionite in the absence of MoaC. Structural characterization by chemical derivatization, MS, and NMR spectroscopy suggested the structure of this molecule to be (8S)-3′,8-cyclo-7,8-dihydroguanosine 5′-triphosphate (3′,8-cH2GTP). The isolated 3′,8-cH2GTP was converted to cPMP by MoaC or its human homologue, MOCS1B, with high specificities (Km 2GTP. These observations, in combination with some mechanistic studies of MoaA, unambiguously demonstrate that MoaA catalyzes a unique radical C-C bond formation reaction and that, in contrast to previous proposals, MoaC plays a major role in the complex rearrangement to generate the pyranopterin ring.
- Hover, Bradley M.,Loksztejn, Anna,Ribeiro, Anthony A.,Yokoyama, Kenichi
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p. 7019 - 7032
(2013/06/05)
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- Reaction between 7,8-dihydropterins and hydrogen peroxide under physiological conditions
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In vitiligo, a common skin disorder that produces white patches of depigmentation, 7,8-dihydropterins accumulate in the presence of high concentration of H2O2. In this work, we present a study of the reaction between 7,8-dihydropterins and H2O2. The rate of the reaction, as well as the products formed, strongly depend on the chemical structure of the substituents. Electron-donor groups as substituents are the most reactive derivatives and undergo oxidation of the pterin moiety. The corresponding bimolecular rate constants at 37 °C in neutral aqueous solutions are reported. The biological implications of the results obtained are also discussed.
- Laura Dántola,Schuler, Tobias M.,Paula Denofrio,Vignoni, Mariana,Capparelli, Alberto L.,Lorente, Carolina,Thomas, Andrés H.
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p. 8692 - 8699
(2008/12/21)
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- Stability of 7,8-dihydropterins in air-equilibrated aqueous solutions
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6-Substituted 7,8-dihydropterins (=2-amino-7,8-dihydropteridin-4(1H)-ones) are heterocyclic compounds that occur in a wide range of living systems and participate in relevant biological functions. In airequilibrated aqueous solutions, these compounds react with dissolved O2 (autooxidation). The rates of these reactions as well as the products formed strongly depend on the chemical structure of the substituents. 7,8-Dihydro-6-methylpterin and 7,8-dihydro-6,7-dimethylpterin that bear electron-donor groups as substituents are the most reactive derivatives and undergo oxidation of the pterin moiety to yield the corresponding oxidized derivatives (6-methylpterin and 6,7-dimethylpterin, resp.). The oxidations of 7,8-dihydrobiopterin, 7,8-dihydroneopterin, and 7,8-dihydrofolic acid are slower, and they yield 7,8-dihydroxanthopterin as the main product. 7,8-Dihydroxanthopterin, 6-formyl-7,8-dihydropterin, and sepiapterin are rather stable, and their consumption in air-equilibrated solutions is negligible for several days. The pseudo-first-order rate constants of the reactions between these compounds and O2 at 25° and 40° are reported. The biological implications of the results obtained are also discussed.
- Dantola, M. Laura,Vignoni, Mariana,Capparelli, Alberto L.,Lorente, Carolina,Thomas, Andres H.
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body text
p. 411 - 425
(2009/02/07)
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- 2-Pivalamido-3H-pyrimidin-4-one derivatives: Convenient pivalamide hydrolysis using Fe(NO3)3 in MeOH
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A simple methodology for pivalamide (trimethylacetamide, pivaloylamino) hydrolysis has been discovered using Fe(NO3)3 in MeOH at room temperature. The pivalamido group of 2-pivalamido-3H-pyrimidin-4-ones or fused 2-pivalamido-3H-pyrimidin-4-ones such as 2-pivalamido-3H-quinazolin-4-ones and 2-pivalamido-3H-pteridines have been hydrolysed under these conditions to afford the corresponding amine.
- Bavetsias,Henderson,McDonald
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p. 5643 - 5644
(2007/10/03)
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- A prototype solid phase synthesis of pteridines and related heterocyclic compounds
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The development of a versatile solid phase synthesis of bicyclic polyaza heterocycles including pteridines, purines, and deazapurines is described. The strategy comprises the linking of a pre-formed pyrimidine through a thioether at the 2 or 4 position to a polystyrene resin, the cyclisation of the second ring, and the direct or oxidative cleavage of the product from the resin by nucleophilic substitution. This provides not only for substituent variation in the second ring, but also for variation at the site of cleavage. Limitations in the scope of the methodology are set by the intrinsic reactivity of pyrimidinyl 2- or 4-thioethers which, whilst undergoing ready nitration at C5, are surprisingly difficult to alkylate and acylate.
- Gibson, Colin L.,La Rosa, Salvatore,Suckling, Colin J.
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p. 1909 - 1918
(2007/10/03)
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- A traceless solid-phase synthesis of pteridines
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The linking of pyrimidines to polystyrene supports via either a 2- or 4-thioether provides access to pteridines through solid-phase synthesis. Oxidative cleavage (dimethyldioxirane) followed by nucleophilic substitution by amines, azide, or water completes a traceless synthesis of pteridines.
- Gibson, Colin L.,La Rosa, Salvatore,Suckling, Colin J.
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p. 1267 - 1270
(2007/10/03)
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- Antiamnesic use of pteridine derivatives
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Pteridines of general formula (I): STR1 in which Y and Z, which can be identical or different, are hydrogen, OH or NH2, and X1 and X2, which can be identical or different, are hydrogen, OH, C1 -C4 alkyl, phenyl, hydroxymethyl or carboxyl, for the preparation of pharmaceutical compositions for treating cognitive pathologies characterized by memory and vigilance disturbances, such as senile dementia of Alzheimer type, multiinfarctual dementia, metabolic encephalopathies, Korsakoff's syndrome, and the consequences of the abuse of certain therapies such as anxiolytic and neuroleptic.
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- HYDROGENATION OF SILYLATED PTERIDINES IN BENZENE SOLUTION
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Hydrogenation of pteridines in benzene solution was investigated by solubilising them either as their trimethylsilyl or their 4-benzyloxy derivatives.Using a platinum catalyst, 6,7-dimethyl-4-trimethylsiloxy-2-trimethylsilylaminopteridine (2) could be converted to cis-6,7-dimethyl-5,6,7,8-tetrahydropterin (3), provided that the 4-siloxy group was first selectively cleaved by water.The same silylated pteridine, (2), in anhydrous benzene with either Rh(DIOP)Cl or (1+)*ClO4(1-), underwent a novel de-silylation reaction to give 6,7-dimethylpterin, (1), with no reducation of the pyrazine ring.
- Boyle, Peter H.,Kelly, Mary F.
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p. 5179 - 5188
(2007/10/02)
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- SYNTHESIS OF QUINONOID 6-METHYL AND 6,7-DIMETHYLDIHYDROPTERINS
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Quinonoid 6-methyl and 6,7-dimethylpterins were synthesized by the chemical oxidation.Some of their properties are described.
- Matsuura, Sadao,Sugimoto, Takashi,Murata, Shizuaki
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p. 4003 - 4004
(2007/10/02)
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