Phage T4 has provided countless contributions to the paradigms of genetics and biochemistry. Its complete genome sequence of 168,903 bp encodes about 300 gene products. T4 biology and its genomic sequence provide the best-understood model for modern functional genomics and proteomics. Variations on gene expression, including overlapping genes, internal translation initiation, spliced genes, translational bypassing, and RNA processing, alert us to the caveats of purely computational methods. The T4 transcriptional pattern reflects its dependence on the host RNA polymerase and the use of phage-encoded proteins that sequentially modify RNA polymerase; transcriptional activator proteins, a phage sigma factor, anti-sigma, and sigma decoy proteins also act to specify early, middle, and late promoter recognition. Posttranscriptional controls by T4 provide excellent systems for the study of RNA-dependent processes, particularly at the structural level. The redundancy of DNA replication and recombination systems of T4 reveals how phage and other genomes are stably replicated and repaired in different environments, providing insight into genome evolution and adaptations to new hosts and growth environments. Moreover, genomic sequence analysis has provided new insights into tail fiber variation, lysis, gene duplications, and membrane localization of proteins, while high-resolution structural determination of the "cell-puncturing device," combined with the three-dimensional image reconstruction of the baseplate, has revealed the mechanism of penetration during infection. Despite these advances, nearly 130 potential T4 genes remain uncharacterized. Current phage-sequencing initiatives are now revealing the similarities and differences among members of the T4 family, including those that infect bacteria other than Escherichia coli. T4 functional genomics will aid in the interpretation of these newly sequenced T4-related genomes and in broadening our understanding of the complex evolution and ecology of phages-the most abundant and among the most ancient biological entities on Earth.

Bacteriophage T4 Genome

SUMMARY Precise coupling of spatially separated intracellular ATP-producing and
ATP-consuming processes is fundamental to the bioenergetics of living
organisms, ensuring a fail-safe operation of the energetic system over a broad
range of cellular functional activities. Here, we provide an overview of the
role of spatially arranged enzymatic networks, catalyzed by creatine kinase,
adenylate kinase, carbonic anhydrase and glycolytic enzymes, in efficient
high-energy phosphoryl transfer and signal communication in the cell. Studies
of transgenic creatine kinase and adenylate kinase deficient mice, along with
pharmacological targeting of individual enzymes, have revealed the importance
of near-equilibrium reactions in the dissipation of metabolite gradients and
communication of energetic signals to distinct intracellular compartments,
including the cell nucleus and membrane metabolic sensors. Enzymatic
capacities, isoform distribution and the dynamics of net phosphoryl flux
through the integrated phosphotransfer systems tightly correlate with cellular
functions, indicating a critical role of such networks in efficient energy
transfer and distribution, thereby securing the cellular economy and energetic
homeostasis under stress.

/pdf/phosphotransfer-networks-and-cellular-energetics-2qtrgsqpzr.pdf

Phosphotransfer networks and cellular energetics.

Biochemical experiments over the past 40 years have shown that nucleoside diphosphate(NDP) kinase activity, which catalyzes phosphoryl transfer from a nucleoside triphosphate toa nucleoside diphosphate, is ubiquitously found in organisms from bacteria to human. Overthe past 10 years, eight human genes of the nm23/NDP kinase family have been discoveredthat can be separated into two groups based on analysis of their sequences. In addition tocatalysis, which may not be exhibited by all isoforms, evidence for regulatory roles has comerecently from the discovery of the genes nm23 and awd, which encode NDP kinases and areinvolved in tumor metastasis and Drosophila development, respectively. Current work showsthat the human NDP kinase genes are differentially expressed in tissues and that their productsare targeted to different subcellular locations. This suggests that Nm23/NDP kinases possessdifferent, but specific, functions within the cell, depending on their localization. The roles ofNDP kinases in metabolic pathways and nucleic acid synthesis are discussed.

The human Nm23/nucleoside diphosphate kinases.

Most metabolic reactions are connected through either their utilization of nucleotides or their utilization of nucleotides or their regulation by these metabolites. In this review the biosynthetic pathways for pyrimidine and purine metabolism in lactic acid bacteria are described including the interconversion pathways, the formation of deoxyribonucleotides and the salvage pathways for use of exogenous precursors. The data for the enzymatic and the genetic regulation of these pathways are reviewed, as well as the gene organizations in different lactic acid bacteria. Mutant phenotypes and methods for manipulation of nucleotide pools are also discussed. Our aim is to provide an overview of the physiology and genetics of nucleotide metabolism and its regulation that will facilitate the interpretation of data arising from genetics, metabolomics, proteomics, and transcriptomics in lactic acid bacteria.

Nucleotide metabolism and its control in lactic acid bacteria

Membrane fluidity and the perception of environmental signals in cyanobacteria and plants.

This article summarizes research from our laboratory on two aspects of the biochemistry of nucleoside diphosphate kinase from Escherichia coli--first, its interactions with several T4 bacteriophage-coded enzymes, as part of a multienzyme complex for deoxyribonucleoside triphosphate biosynthesis. We identify some of the specific interactions and discuss whether the complex is linked physically or functionally with the T4 DNA replication machinery, or replisome. Second, we discuss phenotypes of an E. coli mutant strain carrying a targeted deletion of ndk, the structural gene for nucleoside diphosphate kinase. How do bacteria lacking this essential housekeeping enzyme synthesize nucleoside triphosphates? In view of the specific interactions of nucleoside diphosphate kinase with T4 enzymes of DNA metabolism, how does T4 multiply after infection of this host? Finally, the ndk disruption strain has highly biased nucleoside triphosphate pools, including elevations of the CTP and dCTP pools of 7- and 23-fold, respectively. Accompanied by these biased nucleotide pools is a strong mutator phenotype. What is the biochemical basis for the pool abnormalities and what are the mutagenic mechanisms? We conclude with brief references to related work in other laboratories.

Metabolic functions of microbial nucleoside diphosphate kinases.

T4 phage gene 32 protein as a candidate organizing factor for the deoxyribonucleoside triphosphate synthetase complex.

Publisher Summary This chapter discusses the functional link between intermediary metabolism and nucleic acid synthesis. Nucleoside diphosphokinase plays a pivotal role in metabolism, as it catalyzes the predominant reaction in synthesizing all but one of the eight common ribo- and deoxyribonucleoside triphosphates. The large DNA virus, on infection of E. coli , causes the rate of DNA synthesis to increase about 10-fold relative to the preinfection rate. This is necessary because of the large size of the genome and the rapid rate of reproduction of the virus. By use of affinity chromatography with an immobilized enzyme as the ligand, specific interactions between T4 dCMP hydroxymethylase and several replication proteins were demonstrated.

Nucleoside diphosphokinase : a functional link between intermediary metabolism and nucleic acid synthesis

The enzymatic machinery for DNA replication functions at a high rate and with extremely high accuracy. Typically, an Escherichia coli cell replicates its 4000-kilobase pair genome in 40 minutes, using two replication forks, each of which extends two chains. Thus, the rate of chain growth is about 800 nucleotides per second at 37°. The four deoxyribonucleoside triphosphates (dNTPs) must be provided efficiently at these few sites, in order to meet the demand. At the same time the four dNTPs must be maintained at balanced concentrations. An excess or deficiency of any one of the four leads to inaccurate DNA replication, thereby stimulating spontaneous mutagenesis. Evidence suggests that steady-state dNTP concentrations at replication sites are severalfold higher than intracellular concentrations, as estimated from dNTP pool measurements1. Thus, dNTP concentration gradients must be maintained in the face of enormous rates of dNTP pool turnover.

Enzyme interactions involving T4 phage-coded thymidylate synthase and deoxycytidylate hydroxymethylase.

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Papers

Metabolic functions of microbial nucleoside diphosphate kinases.

T4 phage gene 32 protein as a candidate organizing factor for the deoxyribonucleoside triphosphate synthetase complex.

Nucleoside diphosphokinase : a functional link between intermediary metabolism and nucleic acid synthesis

Enzyme interactions involving T4 phage-coded thymidylate synthase and deoxycytidylate hydroxymethylase.