Dinucleotide dimers

The dinucleotide dimers were synthesised in moderate yields and showed good cellular uptake and anti-HIV activity. ... 

Azacyclobutane dimers 28 were obtained (84H67, 84H1363) in high yields by irradiation of some pyrimidine 6-azapyrimidine dinucleotide analogs 27. They are unstable in aqueous solution and decomposed back to 27 (Scheme 8). 

The conformations of L-adenylyl-(3 5 )-L-adenosine (28) and L-adenylyl-(2 -> 5 )-L-adenosine (29), as deduced from circular dichroic spectra, are different from the corresponding DD-dinucleotides. < The n.m.r. and u.v. absorption spectra of (28) and (29) are the same as the DD-dimers and their chromatographic and electrophoretic properties appear identical. While (28) and (29) are resistant to enzymic hydrolysis they form complexes with polyU. 

The reason for this phase effect is the apparent necessity for the proximity and proper orientation of two monomer molecules before dimer formation can take place (the mechanistic significance of this will be discussed later). Thus dinucleotides such as TpT form dimers even in solution, and the yield of dimers in polynucleotides and nucleic acids is even higher. 

A photodimer of thymine could have one of four isomeric structures 10-13. Although, as described below, a number of dimeric products result from photolysis of thymidine, thymidine dinucleotide, and other thymine-containing materials, a single dimer appears to be the... 

Only a confused picture is revealed by these essentially qualitative studies. Many questions are left unanswered. The probable formation of uracil hydrate in cytosine photolysis has not been reported and the question of dimer formation, either in solution or in ice, is still unresolved. There are thus large gaps in our knowledge about the photolysis of cytosine and cytidine. Much more detailed work has been carried out on cytidylic acid and on dinucleotides of cytosine (Sect. XI-C). 

Dinucleotides (see Glossary), even TpT, are affected by ultraviolet light in solution.7 The products are both dimers and hydrates (except... 

Dimer yields in aqueous solution of the dinucleotides are usually lower than in the frozen solution of the bases. Hydrates of either or both components of the dinucleotide can be formed. The multiplicity of products possible makes these photolyses of unique kinetic complexity. 

The probable structures of the dimers and hydrates are illustrated below for a uracil derivative. The constraints imposed upon the orientation of the pyrimidine residues in the dinucleotide should restrict the number of geometrical isomers possible, relative to the number of possibilities for a derivative containing only a single pyrimidine residue. 

When Nm is the concentration of monomeric dinucleotide (pTpT), Nd is the concentration of dinucleotide with dimerized thymine residues, and Nm0 is the total concentration of dinucleotide, it can be shown that the concentration of Nm at a particular dose, D, of ultraviolet light is given by eq. (8). 

Weinblum and Johns43 also have shown that hydrolysis of the two dimeric dinucleotide products, D1 and Dz, leads to the isolation of two forms of thymine dimer which were assigned tentatively to structures 10 and 11. 

Most recent work has been concerned with UpU (16b, R = OH).t This substance forms three dimeric dinucleotides and three hydrates (U pU, UpU, and U pUp) which are so similar in properties that they can be lumped together.11,72 The interrelationships are shown in Figure 12, where H = U pU + UpU + U pU. These products can also be... 

The cross sections for formation of the two dimers are similar, but not identical, with those for the formation of two of the dimers from UpU, and the wavelength dependencies are similar. Hydrate formation occurs more rapidly in d-UpU than in UpU. The marked quantitative and qualitative differences in the photochemistry of these two closely similar dinucleotides, along with the additional difference in results observed with poly U, to be discussed below, make it clear that the factors influencing the course of the photolysis of polynucleotides are not well known. It must be pointed out that the structures of the various... 

In either case, polyuridylic acid or polythymidylic acid, the rate of dimer formation will not be that calculated for an assemblage of independent sites, as in a solution of mononucleotide or dinucleotide, given by eq. (11). The sites are not independent but are in a connected sequence along a one-dimensional chain, and the rate of dimer formation will begin to deviate from the rate law of eq. (11) as soon as the location of unreacted sites becomes an important factor, certainly when... 

Thus it is important to consider not just thymine dimer but pyrimidine dimers in general as a photochemical lesion,10 and it is obvious that the careful study of the photochemical products is just beginning. Work of the depth and detail which has been carried out on the dinucleotides, UpU72 and CpC,74 and which is beginning to be done on polyuridylic acid, has not yet really been attempted on DNA or... 

In 1989, BH4 was found to be a cofactor for nitric oxide synthase (NOS) [ 126, 127]. BH4 is also involved in dimerization of NOS, as NOS is catalytically active in a homodimer structure. Three isoforms of NOS exist neuronal NOS (NOS 1), inducible NOS (NOS 2) and endothelial NOS (NOS 3). BH4 is essential for all NOS isoforms. The NOS isoforms share approximately 50-60% sequence homology. Each NOS polypeptide is comprised of oxygenase and reductase domains. An N-terminal oxygenase domain contains iron protoporphyrin IX (heme), BH4 and an arginine binding site, and a C-terminal reductase domain contains flavin mononucleotide (FMN), and a reduced nicotin-amide adenine dinucleotide phosphate (NADPH) binding site. 

The purified E. coli protein has a molecular weight of 49 kD. It does not require any divalent cation for activity. It contains two different noncovalently bound chromophores that absorb light. One chromophore is flavin adenine dinucleotide (FADH- or FADH2). The other is 5,10-methenyltetrahydrofolyl polyglutamate (MTHF). The absorption of light by the chromophores is essential for the enzymatic reversal of the pyrimidine dimer back to the original pyrimidine monomers. However,... 

In bacteria, flavin adenine dinucleotide (FAD) is the prosthetic group of the photolyases that catalyze reductive repair of light-induced pyrimidine dimers in DNA. Riboflavin is the light-emitting molecule in some bioluminescent fungi and bacteria, and is the precursor for synthesis of the dimethylbenzimidazole ring of vitamin B12 (Section 10.7.3). 

A pulse of 2-10 Mev electrons from a linear accelerator, passed through aqueous solutions of pyridinium ions leads rapidly to substantial concentrations of pyridinyl radicals , including those derived from the coenzyme, nicotinamide adenine dinucleotide . The pyridinyl radicals disproportionate, are protonated or dimerize. The reducing agent is a solvated electron or the COj" radical anion (Eq. 4) . 

Photodissociation of dimer coupled to current measurement of electrochemical oxidation of the pyridinyl radical to the pyridinium ion has been described in Section 3.1.3. Oxidation of the l-methyl-3-carbamidopyridinyl and NAD (nicotinamide adenine dinucleotide radical) after dissociation of the dimers has been reported the agents being either oxygen or OH radical. Reasonable mechanisms for the latter are either electron transfer or radical combination, followed by dissociation to Py+ and OH. 

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