In this thesis, quantum chemistry, in particular the B3LYP density functional method, is used to investigate a number of methyl transfer enzymes. Quantum chemical methodology is today a very important tool in the elucidation of properties and reaction mechanisms of enzyme active sites. The enzymes considered in this thesis are the S-adenosyl L-methionine-dependent enzymes glycine N-methyltransf...

Temozolomide is an alkylating agent used in the treatment of gliomas and, more recently, aggressive pituitary adenomas and carcinomas. Temozolomide methylates DNA and, thereby, has antitumor effects. O6-methylguanine-DNA methyltransferase, a DNA repair enzyme, removes the alkylating adducts that are induced by temozolomide, thereby counteracting its effects. A Medline search for all of the avai...

BACKGROUND DNA methylation is the addition of a methyl group to the 5 position of cytosine. It is an epigenetic process with several effects, including chromatin structure modulation, transcriptional repression and the suppression of transposable elements. In malignancy, methylation patterns change, resulting in global hypomethylation with regional hypermethylation. This can lead to genetic ins...

Glycine N-methyltransferase (GNMT) affects genetic stability by (a) regulating the ratio of S-adenosylmethionine to S-adenosylhomocystine and (b) binding to folate. Based on the identification of GNMT as a 4 S polyaromatic hydrocarbon-binding protein, we used liver cancer cell lines that expressed GNMT either transiently or stably in cDNA transfections to analyze the role of GNMT in the benzo(a...

Molecular dynamics (MD) simulations of HhaI DNA methyltransferase and statistical coupling analysis (SCA) data on the DNA cytosine methyltransferase family were combined to identify residues that are coupled by coevolution and motion. The highest ranking correlated pairs from the data matrix product (SCA.MD) are colocalized and form stabilizing interactions; the anticorrelated pairs are separat...

Protozoan parasites are among the most devastating infectious agents of humans responsible for a variety of diseases including amebiasis, which is one of the three most common causes of death from parasitic disease. The agent of amebiasis is the amoeba parasite Entamoeba histolytica that exists under two stages: the infective cyst found in food or water and the invasive trophozoite living in th...

Inheritance of epigenetic information encoded by cytosine DNA methylation patterns is crucial for mammalian cell survival, in large part through the activity of the maintenance DNA methyltransferase (DNMT1). Here, we show that SET7, a known histone methyltransferase, is involved in the regulation of protein stability of DNMT1. SET7 colocalizes and directly interacts with DNMT1 and specifically ...

DNA methylation is found throughout all domains of life, yet the extent and function differ among eukaryotes. Strains plant pathogenic fungus Zymoseptoria tritici appeared to lack cytosine (5mC) because gene amplification followed by Repeat-Induced Point mutation (RIP) resulted in inactivation dim2 methyltransferase gene. 5mC is, however, present closely related sister species. We demonstrate t...

DNA base flipping, which was first observed for the C5-cytosine DNA methyltransferase M. Hha I, results in a complete removal of the stacking interactions between the target base and its neighbouring bases. We have investigated whether duplex oligodeoxynucleotides containing the fluorescent base analogue 2-aminopurine can be used to sense DNA base flipping. Using M. Hha I as a paradigm for a ba...

The pathogenesis of atherosclerosis has been partly acknowledged to result from aberrant epigenetic mechanisms. Accordingly, low folate levels are considered to be a contributing factor to promoting vascular disease because of deregulation of DNA methylation. We hypothesized that increasing the levels of folic acid may act via an epigenetic gene silencing mechanism to ameliorate atherosclerosis...