Genetic Evidence for a Link Between Glycolysis and DNA Replication

Janniere, Laurent; Canceill, Danielle; Suski, Catherine; Kanga, Sophie; Dalmais, Bérengère; Lestini, Roxane; Monnier, Anne-Francoise; Chapuis, Jérôme; Bolotin, Alexander; Титок, М. А.; Chatelier, Emmanuelle Le; Ehrlich, S. Dusko

doi:10.1371/journal.pone.0000447

Cited by 73 publications

(111 citation statements)

References 92 publications

(96 reference statements)

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“…Glucose makes important contributions to anabolic processes in all organs of the body providing needed intermediates for cellular proliferation including NADPH, nucleotides for DNA replication (45), and intermediates for fatty acid synthesis (46,47) all largely by way of the pentose phosphate pathway (PPP). In animal experiments, estimates of the amount of glucose entering the PPP in the mature brain have been variable but generally low (reviewed in ref.…”

Section: Discussionmentioning

confidence: 99%

Regional aerobic glycolysis in the human brain

Vaishnavi¹,

Vlassenko²,

Rundle³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

609

620

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Aerobic glycolysis is defined as glucose utilization in excess of that used for oxidative phosphorylation despite sufficient oxygen to completely metabolize glucose to carbon dioxide and water. Aerobic glycolysis is present in the normal human brain at rest and increases locally during increased neuronal activity; yet its many biological functions have received scant attention because of a prevailing energy-centric focus on the role of glucose as substrate for oxidative phosphorylation. As an initial step in redressing this neglect, we measured the regional distribution of aerobic glycolysis with positron emission tomography in 33 neurologically normal young adults at rest. We show that the distribution of aerobic glycolysis in the brain is differentially present in previously well-described functional areas. In particular, aerobic glycolysis is significantly elevated in medial and lateral parietal and prefrontal cortices. In contrast, the cerebellum and medial temporal lobes have levels of aerobic glycolysis significantly below the brain mean. The levels of aerobic glycolysis are not strictly related to the levels of brain energy metabolism. For example, sensory cortices exhibit high metabolic rates for glucose and oxygen consumption but low rates of aerobic glycolysis. These striking regional variations in aerobic glycolysis in the normal human brain provide an opportunity to explore how brain systems differentially use the diverse cell biology of glucose in support of their functional specializations in health and disease. W hen glucose metabolism exceeds that used for oxidative phosphorylation despite sufficient oxygen to metabolize glucose to carbon dioxide and water, it has traditionally been referred to as aerobic glycolysis. Aerobic glycolysis has a long history in cancer cell biology, where the phenomenon was first noted by Otto Warburg (1), for whom it is often referred to as the "Warburg effect." Since Warburg's early work (2), much research has focused on the reasons for aerobic glycolysis mainly in cancer cells (3-5). Topics have included, but are not limited to, the role of aerobic glycolysis in biosynthesis, the maintenance of cellular redox states, the regulation of apoptosis and the provision of ATP for membrane pumps and protein phosphorylation. Little attention has been paid to the normal brain in this regard, despite the well documented presence of aerobic glycolysis (6-8; noteworthy recent exception in ref. 9).From a whole-brain perspective, aerobic glycolysis may account for ∼10-12% of the glucose used in the adult human (6-8). This percentage varies in interesting ways. In the newborn, it represents more than 30% of the glucose metabolized (10). In the adult, aerobic glycolysis varies diurnally from a low in the morning of ∼11% to nearly 20% in the evening (7). In none of these observations do we have any information on the regional distribution of aerobic glycolysis in the brain or its role in cell biology.The only information presently on regional brain aerobic glycolysis relates to task...

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Section: Discussionmentioning

confidence: 99%

Regional aerobic glycolysis in the human brain

Vaishnavi¹,

Vlassenko²,

Rundle³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

609

620

View full text Add to dashboard Cite

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“…It is tempting to speculate that these essential enzymes have cellular functions in addition to just providing the cell with the proper metabolic intermediates. Indeed, glycolytic enzymes of E. coli and B. subtilis are involved in mRNA processing and DNA replication, respectively (2,22). It will thus be an important task to identify the essential, secondary functions of the glycerol facilitator and of glycerol kinase.…”

Section: Discussionmentioning

confidence: 99%

Glycerol Metabolism Is Important for Cytotoxicity of Mycoplasma pneumoniae

Hames¹,

Halbedel²,

Hoppert³

et al. 2009

J Bacteriol

120

174

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Glycerol is one of the few carbon sources that can be utilized by Mycoplasma pneumoniae. Glycerol metabolism involves uptake by facilitated diffusion, phosphorylation, and the oxidation of glycerol 3-phosphate to dihydroxyacetone phosphate, a glycolytic intermediate. We have analyzed the expression of the genes involved in glycerol metabolism and observed constitutive expression irrespective of the presence of glycerol or preferred carbon sources. Similarly, the enzymatic activity of glycerol kinase is not modulated by HPr-dependent phosphorylation. This lack of regulation is unique among the bacteria for which glycerol metabolism has been studied so far. Two types of enzymes catalyze the oxidation of glycerol 3-phosphate: oxidases and dehydrogenases. Here, we demonstrate that the enzyme encoded by the M. pneumoniae glpD gene is a glycerol 3-phosphate oxidase that forms hydrogen peroxide rather than NADH 2 . The formation of hydrogen peroxide by GlpD is crucial for cytotoxic effects of M. pneumoniae. A glpD mutant exhibited a significantly reduced formation of hydrogen peroxide and a severely reduced cytotoxicity. Attempts to isolate mutants affected in the genes of glycerol metabolism revealed that only the glpD gene, encoding the glycerol 3-phosphate oxidase, is dispensable. In contrast, the glpF and glpK genes, encoding the glycerol facilitator and the glycerol kinase, respectively, are essential in M. pneumoniae. Thus, the enzymes of glycerol metabolism are crucial for the pathogenicity of M. pneumoniae but also for other essential, yet-to-be-identified functions in the M. pneumoniae cell.Mycoplasma pneumoniae causes infections of the upper and lower respiratory tracts. These bacteria are responsible for a large fraction of community-acquired pneumonias. Although usually harmless for adult patients, M. pneumoniae may cause severe disease in children or elderly people. In addition, M. pneumoniae is involved in extrapulmonary complications such as pediatric encephalitis and erythema multiforme (for reviews, see references 15, 21, and 34).M. pneumoniae and its relatives, the Mollicutes, are all characterized by the lack of a cell wall and a very close adaptation to a life within a eukaryotic host. This close adaptation is reflected by degenerative genome evolution that resulted in an extreme genome reduction. As a result, the Mollicutes are the organisms that are capable of independent life with the smallest known genome. M. pneumoniae has a genome of 816 kb and encodes only 688 proteins (18). This genome reduction is taken even further in the close relative Mycoplasma genitalium, which has only 482 protein-coding genes (18). Thus, the analysis of the Mollicutes allows us to study a minimal form of natural life. This question has recently attracted much interest and resulted in the determination of the essential gene sets of M. pneumoniae, M. genitalium, and, more recently, Mycoplasma pulmonis (6,20). In M. genitalium, with the most reduced genomes, only 100 out of the 482 protein-coding genes are dispensable, ...

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“…Although replication fork speed can vary significantly Odsbu et al 2009;Stokke et al 2012), it is not known whether the speed of each individual replication fork is regulated. In Bacillus subtilis, it has been found that replication elongation can be regulated by ppGpp (Wang et al 2007) and metabolic enzymes (Janniere et al 2007). …”

Section: Coordination Of Regulation For Oric and Dnaamentioning

confidence: 99%