Ribonucleotide Reductase

The subject of this book is the amazing enzyme ribonucleotide reductase (RNR), the enzyme responsible for the conversion of ribonucleotides to deoxyribonucleotides. The prerequisite for DNA-synthesis and DNA-repair in all living cells is the supply of the four deoxyribonucleotides. Such molecules result from the enzymatically difficult radical-induced reduction of ribonucleotides, a multistep chemical process catalyzed by RNR. RNR was the first enzyme in which the presence of an amino acid radical (a tyrosyl) in E. coli Class Ia RNR has been proven; since then several other biological amino acid radical species have been found on e.g. tryptophan, glycine, cysteine, lysine residues and on amino acid derived small cofactors like 2 tryptophanes in thryptophan-trypthanyl-radical or cysteine-tyrosyl-radical in other enzymes. As all known cellular life forms store their genetic information as DNA, RNR is likely to be found in all growing cells of every living organism, a fact that is confirmed by a rapidly increasing number of genomic screenings.

In addition to performing its prime function as a vehicle for scientific communications of varied colora­ tions, Molecular and Cellular Biochemistry is again focusing on two subjects which it treats in depth. One of these is a book issue dealing with the transglutaminase reaction. The other is this issue that deals with induction and modulation of enzymes. This is a very broad subject that calls for broader coverage than could be included in one book issue. However, I have elected to include only certain contributions that serve as general examples of the principles involved. There are six articles on enzyme regulation in hepatocyte culture. These include arginase and argino-succi­ nate synthetase, y-glutamyl transferase and plasminogen activitor. Other regulatory enzymes that are discussed are protein kinases, 2,3-bisphosphoglycerate synthetases, carbamoyl phosphate synthetase, heme oxygenase, cytochrome P-450, tyrosine hydroxylase, fatty acid synthetase, acetyl eoA carboxylase, among others. Also included is the regulation of several enzyme messengers RNAs. As in the past, subscribers to the journal will receive this double volume as a continuation of regular issues of the journal Molecular and Cellular Biochemistry. This double volume will also be available separately in the form of a book issue to interested readers through Martinus Nijhoff Publishers. v.A. Najjar Part I Molecular and Cellular Biochemistry 53;54,11-21 (1983). © 1983, Martinus 1\ ij hoff Publishers. Boston. Printed in The Netherlands.

Ribonucleotide reductase (RNR), a universal enzyme present in essentially all living cells and organisms, has a central role in DNA replication and repair by catalysing production of deoxyribonucleotides from the corresponding ribonucleotides. Three major classes of RNRs are known, differing in their cofactor requirements: class I RNRs (with subclasses Ia and Ib) carry a stable tyrosyl radical and are oxygen-dependent, class II RNRs require the vitamin B12 cofactor 5'-deoxyadenosylcobalamin and are oxygen-independent, and class III RNRs carry a stable glycyl radical and are oxygen-sensitive. Despite these differences, all classes have a similar reaction mechanism and the same highly specific catalytic core structure, indicating that they evolved from a common ancestor. Biochemical studies of RNRs from selected model organisms in combination with the vast number of deduced RNR sequences from publicly available complete genomic sequences show that whereas eukaryotes and their viruses with few exceptions contain only class Ia RNRs, all three major RNR classes are found among prokaryotes and bacteriophages and quite often one organism encodes more than one class of RNR. They are compiled in an open access database, called RNRdb for Ribonucleotide Reductase database that is available at http://rnrdb.molbio.su.se. RNRs are produced in a strictly controlled way depending upon growth phase and environmental cues. The authors describe a comprehensive summary of how the expression of RNR genes is regulated in several eubacterial organisms and in yeast. Due to RNR's importance for the realisation of DNA replication, it has been recognised as a possible target for antiproliferative therapy. The authors present a comprehensive summary of RNR-specific inhibitors that have reached clinical trials and/or are currently used in clinical therapy.

This book compiles detailed information concerning a dozen of the best known allosteric enzymes, and so allows the comparison of their regulatory mechanisms and the confrontation of these mechanisms with the theoretical models. Stimulating and unexpected ideas emerge from these comparisons and emphasize the importance of developing various methods of investigation such as crystallography, X-ray solution scattering, and the study of fast movements in proteins and site-directed mutagenesis. This book is addressed to students and researchers interested in structure-function relationship in proteins, enzymology and metabolic regulation. It is also a basis for teaching.

Microbial physiology, biochemistry and genetics allowed the formulation of concepts that turned out to be important in the study of higher organisms. In the first section, the principles of bacterial growth are given, as well as the description of the different layers that enclose the bacterial cytoplasm, and their role in obtaining nutrients from the outside media through different permeability mechanism described in detail. A chapter is devoted to allostery and is indispensable for the comprehension of many regulatory mechanisms described throughout the book. Another section analyses the mechanisms by which cells obtain the energy necessary for their growth, glycolysis, the pentose phosphate pathway, the tricarboxylic and the anaplerotic cycles. Two chapters are devoted to classes of microorganisms rarely dealt with in textbooks, namely the Archaea, mainly the methanogenic bacteria, and the methylotrophs. Eight chapters describe the principles of the regulations at the transcriptional level, with the necessary knowledge of the machineries of transcription and translation. The next fifteen chapters deal with the biosynthesis of the cell building blocks, amino acids, purine and pyrimidine nucleotides and deoxynucleotides, water-soluble vitamins and coenzymes, isoprene and tetrapyrrole derivatives and vitamin B12. The two last chapters are devoted to the study of protein-DNA interactions and to the evolution of biosynthetic pathways. The considerable advances made in the last thirty years in the field by the introduction of gene cloning and sequencing and by the exponential development of physical methods such as X-ray crystallography or nuclear magnetic resonance have helped presenting metabolism under a multidisciplinary attractive angle.

Volume 45 of Advances in Enzyme Regulation is the proceedings of the 45th International Synthesis in Normal and Neoplastic Tissues held at Indiana University School of Medicine Indianapolis, Indiana September 27-28, 2004. Volume 45 concentrates on subjects which have reached the stage of productive summarizaiton and critical evaluation in the light of extensive new results. This book also lives up to its goal of advancing a few steps ahead of the general front of mammalian enzymic and metabolic regulation studies. Latest information about mammalian enzymic and metabolic regulation studies Comprehensive lab resource and teaching companion International contributors from academia and industry