Nucleoside cofactors

Adenosine. Adenosine [58-61-7] (Ado), (29), a purine nucleoside, is an intracellular constituent acting as both an enzyme cofactor... 

The molyhdopterin cofactor, as found in different enzymes, may be present either as the nucleoside monophosphate or in the dinucleotide form. In some cases the molybdenum atom binds one single cofactor molecule, while in others, two pterin cofactors coordinate the metal. Molyhdopterin cytosine dinucleotide (MCD) is found in AORs from sulfate reducers, and molyhdopterin adenine dinucleotide and molyb-dopterin hypoxanthine dinucleotide were reported for other enzymes (205). The first structural evidence for binding of the dithiolene group of the pterin tricyclic system to molybdenum was shown for the AOR from Pyrococcus furiosus and D. gigas (199). In the latter, one molyb-dopterin cytosine dinucleotide (MCD) is used for molybdenum ligation. Two molecules of MGD are present in the formate dehydrogenase and nitrate reductase. 

Those nucleosides found in the nucleic acids DNA and RNA involve the joining of ribose of deoxyribose to a purine or a pyrimidine base. One such nucleoside is adenosine, in which a nitrogen of adenine is linked to carbon 1 of the pentose, ribose. In this form it is a component of RNA but as a phosphory-lated derivative of adenosine (e.g. ATP), which is a high energy compound, it fulfils an important role in metabolism. The dinucleotides NAD and NADP are two cofactors necessary for many enzymic transformations and these also contain /V-glycosides of ribose phosphate. Other important nucleosides are found... 

The vast majority of research focused on selenium in biology (primarily in the fields of molecular biology, cell biology, and biochemistry) over the past 20 years has centered on identification and characterization of specific selenoproteins, or proteins that contain selenium in the form of selenocysteine. In addition, studies to determine the unique machinery necessary for incorporation of a nonstandard amino acid (L-selenocysteine) during translation also have been central to our understanding of how cells can utilize this metalloid. This process has been studied in bacterial models (primarily Escherichia colt) and more recently in mammals in vitro cell culture and animal models). In this work, we will review the biosynthesis of selenoproteins in bacterial systems, and only briefly review what is currently known about parallel pathways in mammals, since a comprehensive review in this area has been recently published. Moreover, we summarize the global picture of the nonspecific and specific use of selenium from a broader perspective, one that includes lesser known pathways for selenium utilization into modified nucleosides in tRNA and a labile selenium cofactor. We also review recent research on newly identified mammalian selenoproteins and discuss their role in mammalian cell biology. 

The DNA-mediated effects of fluropyrimidines can be modulated by a number of agents, such as leucovorin (LV), levamisole, and interferon-alpha (IFN-alpha). LV prolongs TS inhibition by increasing the availability of the reduced folate cofactor necessary for formation of the inactive TS-FdUMP complex (21) (Fig. 4). Studies show alpha-interferon can potentiate 5-FU-mediated cyotoxicity, but the mechanisms are not yet defined (22,23). Another approach to modulate the activity of fluoropyrimidines is the use of the nucleoside transport inhibitor dipyridamole. Dipyridamole probably permits... 

CoA, the coenzyme A derivative of acetoacetate, reduces its reactivity as a substrate for /3-ketoacyl-CoA transferase (an enzyme of lipid metabolism) by a factor of 106. Although this requirement for adenosine has not been investigated in detail, it must involve the binding energy between enzyme and substrate (or cofactor) that is used both in catalysis and in stabilizing the initial enzyme-substrate complex (Chapter 6). In the case of /3-ketoacyl-CoA transferase, the nucleotide moiety of coenzyme A appears to be a binding handle that helps to pull the substrate (acetoacetyl-CoA) into the active site. Similar roles may be found for the nucleoside portion of other nucleotide cofactors. 

Adenosine. A purine nucleoside found in DNA, RNA, and many cofactors. 

En/ymes catalyze a broad spectrum of reactions. They often require such coen/yincs as the nicotinamides NADPH and NADH or a nucleoside triphosphate like ATP together with cofactors, usually metal ions. Hydrolases, including PLE, are exceptions in this regard. They complete their tasks without the need for coenzymes. Enzyme-catalyzed asymmetric syntheses can be conducted either with cell-free enzymes or with microbial systems (i.e., enzymes included within cells).14... 

Fig. 22. Schematic presentation of the enzymatic synthesis of UDP-GalNH2 (33) including cofactor regeneration systems. A nucleoside monophosphate kinase (EC 2.7.7.4), B sucrose synthase (EC 2.4.1.13), C gal-l-P uridyltransferase (EC 2.7.7.12), D phosphoglucomutase (EC 2.7.5.1), E glucose-6-P dehydrogenase (EC 1.1.1.49), F lactate dehydrogenase (EC 1.1.1.27), G pyruvate kinase (EC 2.7.1.40) [319]...

PURPOSE AND RATIONALE During the last 10 years many uptake transporters as well as efflux transporters have been discovered in the GI and especially in the small intestine. They allow uptake of ions, amino acids, peptides, nucleic acids, sugars, organic acids, vitamins, cofactors and nucleosides. On the other hand, efflux transporters ensure protection of the organism from unwanted pathogen or compound delivery. Subsequently, cellular systems have been used to study uptake in mechanistic studies in more detail. Additionally inhibition studies provide hints on potential drag-drug interactions. 

In addition, many examples of binding systems were investigated by stopped-flow fluorescence spectroscopy, such as the binding of calmodulin to calcineuiin, the binding of guanine to calf spleen purine nucleoside phosphorylase, the nucleotide cofactor binding to the Escherichia coli PriA Helicase, etc. 

A swap of the methyl carbon with nitrogen in aza-AdoMet leads to sinefungin (see Fig. 2g)—a natural nucleoside antibiotic found in Streptomyces griseolus. Such reverse chemistry additionally enhances the chemical stability of cofactor. Because of the positive charge of the protonated amine and correct chirahty at the carbon center, sinefungin has an extremely high inhibitory potential for AdoMet-dependent methyltransferases. 

There are a large number of nucleoside analogues which undergo conversion to the triphosphate stage before they act as enzyme inhibitors. As such, they may inhibit, in addition to the polymerases, various enzymes which utilize the corresponding normal nucleoside triphosphate (e.g., ATP) as cofactor. Thus, both 9-(3-D-xylofuranosyladenine29 (23) and 9-0-D-arabinofuranosyl-... 

Nucleoside Pyrophosphates. - 2.2.1 Nucleoside Diphosphate Analogues. The enzymatic regeneration of 3 -phosphoadenosine-5 -phosphosulfate (76) catalysed by the rat liver sulfotransferase IV enzyme has been reported to provide useful quantities of the cofactor for enzyme kinetic experiments. The first thio-nucleotide analogues of adenosine 5 -phosphosulfate (77a) and of 3 -phosphoadenosine 5 -phosphosulfate (77b) have been synthesised in enantio-merically pure forms. Using these novel analogues, the sulfuryl transfer reaction to adenosine 5 -triphosphate was shown to proceed with inversion of configuration at the a-phosphorus. ... 

Reverse transcription and nuclear translocation of the preintegration complex are thought to be limiting steps in retroviral transduction, especially in terminally differentiated postmitotic cells. Proviral DNA synthesis of all retroviruses depends strongly on cellular conditions, and low nucleoside pools or absence of cellular cofactors may explain the incomplete reverse transcription in quiescent or stationary cells (56, 65-70). 

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