M.R. Atkinson

Bio: M.R. Atkinson is an academic researcher from Flinders University. The author has contributed to research in topics: Adenine nucleotide & Nucleotide. The author has an hindex of 8, co-authored 11 publications receiving 595 citations.

Nucleotide biosynthesis from preformed purines in mammalian cells: regulatory mechanisms and biological significance.

Abstract: Publisher Summary This chapter discusses that all cells need a balanced supply of nucleotides as precursors of DNA, RNA, and the nucleotide coenzymes involved in group transfer and bioenergetic processes. The study of purine nucleotide biosynthesis does not reveal the ultimate control points of the normal cell's economy, but clarifies the picture already emerging of a highly efficient production line using regulation of enzyme activity by metabolites to ensure adequate provision of essential building blocks, with minimum waste of energy or of nutrients. The chapter deals with the catalytic arid regulatory properties of purine-utilization enzymes and includes a comparison of natural and artificial regulators. Except in the special case of nucleotidases, nucleoside phosphorylases and aminopurine hydrolases, the enzymes that make purine fragments available by degradation of DNA, RNA, and nucleotide coenzymes are not discussed here, and the reader is referred to recent, reviews on nucleases. It discusses the availability of purines and purine nucleosides with particular reference to the availability of these compounds in mammalian plasma for utilization by specialized cells. The function of purine-utilization enzymes in the conversion of purine and purine nucleoside antimetabolites into active nucleotide derivatives is discussed, as is the significance of this activation in immunosuppressive and cancer chemotherapy. Recent studies on defects in function or regulation of purine utilization and de novo pathways are also discussed.

Deoxyribonucleic acid synthesis in mammalian nuclei. Incorporation of deoxyribonucleotides and chain-terminating nucleotide analogues.

Abstract: The properties of a nuclear preparation from rat liver and thymus are described. (1) Nearest-neighbour analysis after incorporation of 32P-labelled nucleotide residues from dATP, dCTP, dGTP, dTTP and arabinofuranosyl analogues of CTP and ATP shows template-dependent DNA synthesis. (2) Where primer termini are limiting, incorporation of arabinofuranosyl analogues of AMP and CMP residues proceeds to a limit indicating that both of these analogues are DNA chain terminators. (3) No large differences have been found between the priming potentialities or the intrinsic DNA polymerase activities of nuclei from resting or regenerating liver and the relationship of this DNA synthesis in vitro to DNA replication or repair in vivo is briefly discussed.

DNA sequencing with chain-terminating inhibitors

Abstract: A new method for determining nucleotide sequences in DNA is described. It is similar to the “plus and minus” method [Sanger, F. & Coulson, A. R. (1975) J. Mol. Biol. 94, 441-448] but makes use of the 2′,3′-dideoxy and arabinonucleoside analogues of the normal deoxynucleoside triphosphates, which act as specific chain-terminating inhibitors of DNA polymerase. The technique has been applied to the DNA of bacteriophage ϕX174 and is more rapid and more accurate than either the plus or the minus method.

Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation

Abstract: In near-physiological concentrations, glucocorticoid hormones cause the death of several types of normal and neoplastic lymphoid cell, but the mechanisms involved are unknown. One of the earliest structural changes in the dying cell is widespread chromatin condensation, of the type characteristic of apoptosis, the mode of death frequently observed where cell deletion seems to be 'programmed'. It is shown here that this morphological change is closely associated with excision of nucleosome chains from nuclear chromatin, apparently through activation of an intracellular, but non-lysosomal, endonuclease.

Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity.

Abstract: Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs such as 6-mercaptopurine. Erythrocyte (RBC) TPMT activity was measured in blood samples from 298 randomly selected subjects. Of the subjects, 88.6% were included in a subgroup with high enzyme activity (13.50 ± 1.86 U, mean ± SD), 11.1% were included in a subgroup with intermediate activity (7.20 ± 1.08 U), and 0.3% had undetectable activity. This distribution conforms to Hardy-Weinberg predictions for the autosomal codominant inheritance of a pair of alleles for low and high TPMT activity, TPMTL and TPMTH, with gene frequencies of .059 and .941, respectively. If RBC TPMT activity is inherited in an autosomal codominant fashion, then subjects homozygous for TPMTH would have high enzyme activity, subjects heterozygous for the two alleles would have intermediate activity, and subjects homozygous for TPMTL would have undetectable activity. The segregation of RBC TPMT activity among 215 first-degree relatives in 50 randomly selected families and among 35 members of two kindreds and one family selected because they included probands with undetectable RBC enzyme activity were also compatible with the autosomal codominant inheritance of RBC TPMT. For example, in eight matings between subjects with intermediate activity (presumed genotype TPMTL TPMTH) and subjects with high activity (presumed genotype TPMTH TPMTH), 47% (8/17) of the offspring had intermediate activity. This value is very similar to the 50% figure expected on the basis of autosomal codominant inheritance (χ2[1] = .059). Further experiments are required to determine whether this genetic polymorphism for an important drug metabolizing enzyme may represent one factor in individual variations in sensitivity to thiopurines.