Guanine alteration

When the receptor interacts with its associated G protein, the conformation of the guanine-nucleotide-binding site is altered. The subunits then dissociate, and a phosphatidylinositol-specific phospholipase C (PI-PLC) is activated [5]. The subsequent hydrolysis of phosphatidylinositol bisphosphate then produces inositol triphosphate (IP3) and diacylglycerol (DAG), which are known to be secondary messengers. For example, the water soluble IP3 is released into the cell where its ultimate targets are the calcium storage organelles from which Ca2+ is released [3]. The presence of DAG in cells is known to activate the cellular enzyme protein kinase C (PKC) [6, 7], which phosphorylates a number of cellular... 

Cisplatin (Platinol) is an inorganic coordination complex with a broad range of antitumor activity. It is especially useful in the treatment of testicular and ovarian cancer. It binds to DNA at nucleophilic sites, such as the N7 and 06 of guanine, producing alterations in DNA structure and inhibition of DNA synthesis. Adjacent guanine residues on the same DNA strand are preferentially cross-linked. This platinating activity is analogous... 

Alkylating agents can alter certain bases of DNA For example, the highly reactive chemical dimethylsul-fate (Fig. 8—35b) can methylate a guanine to yield O6-methylguanine, which cannot base-pair with cytosine. 

Because the chemical shifts of the nonexchangeable nucleobase proton signals are sensitive to (de)protonations of the aromatic structure, the absence of certain protonation shifts, or alterations in the expected pKa values, can give valuable information about the sites where platinum is bound. So, in N7-platinated guanine, no N7 protonation shift around pH 2 is observed, whereas the pKa of the N1 protonation decreases from 9.5 to 8.5 (54). 

Another source of modified bases in both DNA and RNA is spontaneous or "accidental" alteration. Nucleic acids encounter many highly reactive and mutagenic materials including hydroxyl radicals, formed from 02, and are able to convert guanine rings into 7,8-dihydro-8-oxoguanine.362 Other reactive and carcinogenic compounds can form adducts with nucleic acid bases.363 See Eq. 5-18 and also Chapter 27. 

Grishina, G., and Berlot, C. H. (1998). Mutations at the domain interface of GOT impair receptor-mediated activation by altering receptor and guanine nucleotide binding. / Biol. Chem. 273, 15053-15060. 

DNA isolated from cells (Kessel et al., 2002) and tissues and urine of animals (Vijayaraghavan et al., 2001 Yamanaka et al., 2001) treated with arsenic show lesions induced by oxidative stress. These lesions include 8-oxo-2 -deoxyguanosine and 8-hydroxy-2 -deoxyguanosine. These DNA lesions may lead to base-pair substitutions (guanine to thymidine and adenine to cytosine) during DNA synthesis, which could lead to altered gene products. 

The absence of protonation shifts proves platination at this site, i.e. when a metal ion is coordinated at e.g. N7 of guanine, protonation cannot occur anymore at this site, resulting in the absence of a protonation pK at about pH 2. An illustration of such a pH dependent chemical shift pattern of nucleobase protons is given in Fig. 11a, b. Metal binding can also alter pKa s of sites where no metal is bound, e.g. the decrease of the pKa at Nl. 

Perturbation of the lanthanide singlet excited state, in which quenching by electron- or charge-transfer processes may be altered by the binding of analytes to the metal centre. For example the W-alkylphenanthridinium unit in 11.32 binds selectively to the electron-rich guanine-cytosine... 

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