Cytosine alteration

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. 

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. 

Mass, M.J. and Wang, L. (1997) Arsenic alters cytosine methylation patterns of the promoter of the tumor suppressor gene p53 in human lung cells a model for a mechanism of carcinogenesis. Mutation Research-Reviews in Mutation Research, 386(3), 263-77. 

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... 

To understand the biochemistry of mutagenesis, it is important to recall from Chapter 3 that DNA contains the nitrogenous bases adenine, guanine, cytosine, and thymine. The order in which these bases occur in DNA determines the nature and structure of newly produced ribonucleic acid (RNA), a substance produced as a step in the synthesis of new proteins and enzymes in cells. Exchange, addition, or deletion of any of the nitrogenous bases in DNA alters the nature of RNA produced and can change vital life processes, such as the synthesis of an important enzyme. This phenomenon, which can be caused by xenobiotic compounds, is a mutation that can be passed on to progeny, usually with detrimental results. 

There are two major mechanisms of epigenetic regulation, methylation of cytosines in the DNA sequence and modification of the histone proteins that the DNA is wrapped around. The co-ordination of both mechanisms results in dramatic changes in remodeling of chromatin and altered gene transcription. 

A plot of VQ against [S] for an allosteric enzyme gives a sigmoidal-shaped curve. Allosteric enzymes often have more than one active site which co-operatively bind substrate molecules, such that the binding of substrate at one active site induces a conformational change in the enzyme that alters the affinity of the other active sites for substrate. Allosteric enzymes are often multi-subunit proteins, with an active site on each subunit. In addition, allosteric enzymes may be controlled by effector molecules (activators or inhibitors) that bind to a site other than the active site and alter the rate of enzyme activity. Aspartate transcarbamoylase is an allosteric enzyme that catalyzes the committed step in pyrimidine biosynthesis. This enzyme consists of six catalytic subunits each with an active site and six regulatory subunits to which the allosteric effectors cytosine triphosphate (CTP) and ATP bind. Aspartate transcarbamoylase is feedback-inhibited by the end-product of the pathway, CTP, which acts as an allosteric inhibitor. In contrast, ATP an intermediate earlier in the pathway, acts as an allosteric activator. 

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