Time-Structure of the Yeast Metabolism In vivo

Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 736)

Abstract

All previous studies on the yeast metabolome have yielded a plethora of information on the components, function and organisation of low molecular mass and macromolecular components involved in the cellular metabolic network. Here we emphasise that an understanding of the global dynamics of the metabolome in vivo requires elucidation of the temporal dynamics of metabolic processes on many time-scales. We illustrate this using the 40 min oscillation in respiratory activity displayed in auto-synchronous continuously grown cultures of Saccharomyces cerevisiae, where respiration cycles between a phase of increased respiration (oxidative phase) and decreased respiration (reductive phase). Thereby an ultradian clock, i.e. a timekeeping device that runs through many cycles during one day, is involved in the co-ordination of the vast majority of events and processes in yeast. Through continuous online measurements, we first show that mitochondrial and redox physiology are intertwined to produce the temporal landscape on which cellular events occur. Next we look at the higher order processes of DNA duplication and mitochondrial structure to reveal that both events are choreographed during the respiratory cycles. Furthermore, spectral analysis using the discrete Fourier transformation of high-resolution (10 Hz) time-series of NAD(P)H confirms the existence of higher frequency components of biological origin and that these follow a scale-free architecture even in stable oscillating modes. A different signal-processing approach using discrete wavelet transformations (DWT) indicates that there is a significant contribution to the overall signal from ∼ 5, ∼ 10 and ∼ 20-minutes cycles and the amplitudes of these cycles are phase-dependent. Further investigation (derivative of Gaussian continuous wavelet transformation) reveals that the observed 20-minutes cycles are actually confined to the reductive phase and consist of two ∼ 15-minutes cycles. Moreover, the 5 and 10-minutes cycles are restricted to the oxidative phase of the cycle. The mitochondrial origin of these signals was confirmed by pulse-injection of the cytochrome c oxidase inhibitor H2S. We next discuss how these multi-oscillatory states can impinge on the apparently complex reactome (represented as a phase diagram of 1,650 chemical species that show oscillatory behaviour). We conclude that biological processes can be considerably more comprehensible when dynamic in vivo time-structure is taken into account.

Keywords

Cadmium Glutathione Cysteine Respiration Coherence 

Notes

Acknowledgements

We thank Rainer Machné for helpful discussions. DL and DBM are grateful to the Royal Society and the Japan Society for the Promotion of Science for supporting this work. KS, DBM and MT are supported in part by funds from Yamagata Prefectural Government and Tsuruoka-city. MT and DBM are also supported by a Japan partnering award (Japan Science and Technology agency and the Biotechnology and Biological Sciences Research Council, UK).

References

  1. 1.
    Aon MA et al (2008) The scale free network organization of yeast and heart systems biology. PLoS One 3:e3624PubMedCrossRefGoogle Scholar
  2. 2.
    Aon MA, Cortassa S, Lemar KM, Hayes AJ, Lloyd D (2007) Single and cell population respiratory oscillations in yeast: a 2-photon scanning laser microscopy study. FEBS Lett 581: 8–14PubMedCrossRefGoogle Scholar
  3. 3.
    Murray DB, Beckmann M, Kitano H (2007) Regulation of yeast oscillatory dynamics. Proc Natl Acad Sci USA 104:2241–2246PubMedCrossRefGoogle Scholar
  4. 4.
    Murray DB, Lloyd D (2007) A tuneable attractor underlies yeast respiratory dynamics. Bio Systems 90:287–294PubMedCrossRefGoogle Scholar
  5. 5.
    Jacquet M, Renault G, Lallet S, De Mey J, Goldbeter A (2003) Oscillatory nucleocytoplasmic shuttling of the general stress response transcriptional activators Msn2 and Msn4 in Saccharomyces cerevisiae. J Cell Biol 161:497–505PubMedCrossRefGoogle Scholar
  6. 6.
    Shedden K, Cooper S (2002) Analysis of cell-cycle gene expression in Saccharomyces cerevisiae using microarrays and multiple synchronization methods. Nucleic Acids Res 30:2920–2929PubMedCrossRefGoogle Scholar
  7. 7.
    Arreguin de Lorencez M, Käppeli O (1987) Regulation of gluconeogenic enzymes during the cell cycle of Saccharomyces cerevisiae growing in a chemostat. J Gen Microbiol 133: 2517–2522PubMedGoogle Scholar
  8. 8.
    Wiemken A, Matile P, Moor H (1970) Vacuolar dynamics in synchronously budding yeast. Arch Mikrobiol 70:89–103PubMedCrossRefGoogle Scholar
  9. 9.
    Dawson PS, Westlake DW (1975) Changes in pattern of respiration and glucose utilisation in Candida utilis during the cell cycle: some variations with growth rate. Can J Microbiol 21:1013–1019PubMedCrossRefGoogle Scholar
  10. 10.
    Creanor J (1978) Oxygen uptake during the cell cycle of the fission yeast Schizosaccharomyces pombe. J Cell Sci 33:399–411PubMedGoogle Scholar
  11. 11.
    Creanor J (1978) Carbon dioxide evolution during the cell cycle of the fission yeast Schizosaccharomyces pombe. J Cell Sci 33:385–397PubMedGoogle Scholar
  12. 12.
    Lloyd D, Poole RK, Edwards SW (1982) The cell division cycle: temporal organization control of cellular growth and reproduction. Academic, LondonGoogle Scholar
  13. 13.
    Goodwin BC (1965) Oscillatory behavior in enzymatic control processes. Adv Enzyme Regul 3:425–437PubMedCrossRefGoogle Scholar
  14. 14.
    Lloyd D, Rossi EL (2008) Ultradian rhythms from molecules to mind: a new vision of life. Springer, New YorkCrossRefGoogle Scholar
  15. 15.
    Lloyd D, Rossi EL (1992) Ultradian rhythms in life processes: an inquiry into fundamental principles of chronobiology and psychobiology. Springer-Verlag Berlin and Heidelberg GmbH & Co. KGoogle Scholar
  16. 16.
    von Meyenburg HK (1968) The budding cycle of Saccharomyces cerevisiae. Pathol Microbiol 31:117–127Google Scholar
  17. 17.
    von Meyenburg HK (1969) Energetics of the budding cycle of Saccharomyces cerevisiae during glucose limited aerobic growth. Arch Microbiol 66:289–303CrossRefGoogle Scholar
  18. 18.
    Münch T, Sonnleitner B, Fiechter A (1992) [Repeat] The decisive role of the Saccharomyces cerevisiae cell cycle behaviour for dynamic growth characterization. J Biotechnol 22: 329–351PubMedCrossRefGoogle Scholar
  19. 19.
    Sonnleitner B (1991) Dynamics of yeast metabolism and regulation. Bioprocess Eng 6: 187–193CrossRefGoogle Scholar
  20. 20.
    Satroutdinov AD, Kuriyama H, Kobayashi H (1992) Oscillatory metabolism of Saccharomyces cerevisiae in continuous culture. FEMS Microbiol Lett 77:261–267PubMedCrossRefGoogle Scholar
  21. 21.
    Klevecz RR, Bolen J, Forrest G, Murray DB (2004) A genomewide oscillation in transcription gates DNA replication and cell cycle. Proc Natl Acad Sci USA 101:1200–1205PubMedCrossRefGoogle Scholar
  22. 22.
    Lloyd D, Murray DB (2006) The temporal architecture of eukaryotic growth. FEBS Lett 580:2830–2835PubMedCrossRefGoogle Scholar
  23. 23.
    Murray DB, Engelen FA, Keulers M, Kuriyama H, Lloyd D (1998) NO + , but not NO. , inhibits respiratory oscillations in ethanol-grown chemostat cultures of Saccharomyces cerevisiae. FEBS Lett 431:297–299Google Scholar
  24. 24.
    Li CM, Klevecz RR (2006) A rapid genome-scale response of the transcriptional oscillator to perturbation reveals a period-doubling path to phenotypic change. Proc Natl Acad Sci USA 103:16254–16259PubMedCrossRefGoogle Scholar
  25. 25.
    Tu BP et al (2007) Cyclic changes in metabolic state during the life of a yeast cell. Proc Natl Acad Sci USA 104:16886–16891PubMedCrossRefGoogle Scholar
  26. 26.
    Tu BP, Kudlicki A, Rowicka M, McKnight SL (2005) Logic of the yeast metabolic cycle: temporal compartmentalization of cellular processes. Science 310:1152–1158PubMedCrossRefGoogle Scholar
  27. 27.
    Murray DB, Haynes K, Tomita M (2011) Redox regulation in respiring Saccharomyces cerevisiae. Biochim Biophys Acta http://www.ncbi.nlm.nih.gov/pubmed/21549177
  28. 28.
    Locher G, Sonnleitner B, Fiechter A (1992) On-line measurement in biotechnology: exploitation, objectives and benefits. J Biotechnol 25:55–73PubMedCrossRefGoogle Scholar
  29. 29.
    Herrgård MJ et al (2008) A consensus yeast metabolic network reconstruction obtained from a community approach to systems biology. Nat Biotechnol 26:1155–1160PubMedCrossRefGoogle Scholar
  30. 30.
    Lloyd D, Murray DB (2005) Ultradian metronome: timekeeper for orchestration of cellular coherence. Trends Biochem Sci 30:373–377PubMedCrossRefGoogle Scholar
  31. 31.
    Murray DB, Engelen F, Lloyd D, Kuriyama H (1999) Involvement of glutathione in the regulation of respiratory oscillation during a continuous culture of Saccharomyces cerevisiae. Microbiol 145(Pt 10):2739–2745Google Scholar
  32. 32.
    Lo K, Hahne F, Brinkman RR, Gottardo R (2009) flowClust: a Bioconductor package for automated gating of flow cytometry data. BMC Bioinform 10:145CrossRefGoogle Scholar
  33. 33.
    Chance B, Cohen P, Jobsis F, Schoener B (1962) Intracellular oxidation-reduction states in vivo. Science 137:499–508PubMedCrossRefGoogle Scholar
  34. 34.
    Chance B, Thorell B (1959) Fluorescence measurements of mitochondrial pyridine nucleotide in aerobiosis and anaerobiosis. Nature 184:931–934PubMedCrossRefGoogle Scholar
  35. 35.
    Carmona R, Hwang W-L, Torresani B (1998) Practical time-frequency analysis, volume 9: gabor and wavelet transforms, with an implementation in s (wavelet analysis and its applications). Academic Press, San DiegoGoogle Scholar
  36. 36.
    Du P, Kibbe WA, Lin SM (2006) Improved peak detection in mass spectrum by incorporating continuous wavelet transform-based pattern matching. Bioinformatics 22:2059–2065PubMedCrossRefGoogle Scholar
  37. 37.
    Funahashi A, Tanimura N, Morohashi M, Kitano H (2003) CellDesigner: a process diagram editor for gene-regulatory and biochemical networks. BioSilico 1:159–162CrossRefGoogle Scholar
  38. 38.
    Kitano H, Funahashi A, Matsuoka Y, Oda K (2005) Using process diagrams for the graphical representation of biological networks. Nat Biotechnol 23:961–966PubMedCrossRefGoogle Scholar
  39. 39.
    Murray DB, Roller S, Kuriyama H, Lloyd D (2001) Clock control of ultradian respiratory oscillation found during yeast continuous culture. J Bacteriol 183:7253–7259PubMedCrossRefGoogle Scholar
  40. 40.
    Sohn H, Kuriyama H (2001) Ultradian metabolic oscillation of Saccharomyces cerevisiae during aerobic continuous culture: hydrogen sulphide, a population synchronizer, is produced by sulphite reductase. Yeast 18:125–135PubMedCrossRefGoogle Scholar
  41. 41.
    Lloyd D, Salgado LE, Turner MP, Suller MT, Murray DB (2002) Cycles of mitochondrial energization driven by the ultradian clock in a continuous culture of Saccharomyces cerevisiae. Microbiology 148:3715–3724PubMedGoogle Scholar
  42. 42.
    Sohn HY, Murray DB, Kuriyama H (2000) Ultradian oscillation of Saccharomyces cerevisiae during aerobic continuous culture: hydrogen sulphide mediates population synchrony. Yeast 16:1185–1190PubMedCrossRefGoogle Scholar
  43. 43.
    Sohn H, Kuriyama H (2001) The role of amino acids in the regulation of hydrogen sulfide production during ultradian respiratory oscillation of Saccharomyces cerevisiae. Arch Microbiol 176:69–78PubMedCrossRefGoogle Scholar
  44. 44.
    Kwak WJ, Kwon GS, Jin I, Kuriyama H, Sohn HY (2003) Involvement of oxidative stress in the regulation of H2S production during ultradian metabolic oscillation of Saccharomyces cerevisiae. FEMS Microbiol Lett 219:99–104PubMedCrossRefGoogle Scholar
  45. 45.
    Sohn H-Y, Kum E-J, Kwon G-S, Jin I, Kuriyama H (2005) Regulation of branched-chain, and sulfur-containing amino acid metabolism by glutathione during ultradian metabolic oscillation of Saccharomyces cerevisiae. J Microbiol 43:375–380PubMedGoogle Scholar
  46. 46.
    Keulers M, Satroutdinov AD, Suzuki T, Kuriyama H (1996) Synchronization affector of autonomous short-period-sustained oscillation of Saccharomyces cerevisiae. Yeast 12: 673–682PubMedCrossRefGoogle Scholar
  47. 47.
    Sohn H-Y et al. (2005) GLR1 plays an essential role in the homeodynamics of glutathione and the regulation of H2S production during respiratory oscillation of Saccharomyces cerevisiae. Biosci Biotechnol Biochem 69:2450–2454CrossRefGoogle Scholar
  48. 48.
    Murray DB, Klevecz RR, Lloyd D (2003) Generation and maintenance of synchrony in Saccharomyces cerevisiae continuous culture. Exp Cell Res 287:10–15PubMedCrossRefGoogle Scholar
  49. 49.
    Keulers M, Suzuki T, Satroutdinov AD, Kuriyama H (1996) Autonomous metabolic oscillation in continuous culture of Saccharomyces cerevisiae grown on ethanol. FEMS Microbiol Lett 142:253–258PubMedCrossRefGoogle Scholar
  50. 50.
    Aubin JE (1979) Autofluorescence of viable cultured mammalian cells. J Histochem Cytochem 27:36–43PubMedCrossRefGoogle Scholar
  51. 51.
    Elsey DJ, Fowkes RC, Baxter GF (2010) Regulation of cardiovascular cell function by hydrogen sulfide (H(2)S). Cell Biochem Funct 28:95–106PubMedCrossRefGoogle Scholar
  52. 52.
    Gadalla MM, Snyder SH (2010) Hydrogen sulfide as a gasotransmitter. J Neurochem 113: 14–26PubMedCrossRefGoogle Scholar
  53. 53.
    Wang M-J, Cai W-J, Zhu Y-C (2010) Mechanisms of angiogenesis: role of hydrogen sulphide. Clin Exp Pharmacol Physiol 37:764–771PubMedCrossRefGoogle Scholar
  54. 54.
    Lloyd D (2006) Hydrogen sulfide: clandestine microbial messenger? Trends Microbiol 14:456–462PubMedCrossRefGoogle Scholar
  55. 55.
    Smith MCA, Sumner ER, Avery SV (2007) Glutathione and Gts1p drive beneficial variability in the cadmium resistances of individual yeast cells. Mol Microbiol 66:699–712PubMedCrossRefGoogle Scholar
  56. 56.
    Walker JS (2008) Beyond wavelets. In: Walker, JS (ed.) A primer on wavelets and their scientific applications. Chapman and Hall, London, pp 223–254CrossRefGoogle Scholar
  57. 57.
    Wek RC, Jackson BM, Hinnebusch AG (1989) Juxtaposition of domains homologous to protein kinases and histidyl-tRNA synthetases in GCN2 protein suggests a mechanism for coupling GCN4 expression to amino acid availability. Proc Natl Acad Sci USA 86:4579–4583PubMedCrossRefGoogle Scholar
  58. 58.
    Dever TE et al (1992) Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Cell 68:585–596PubMedCrossRefGoogle Scholar
  59. 59.
    Natarajan K et al (2001) Transcriptional profiling shows that Gcn4p is a master regulator of gene expression during amino acid starvation in yeast. Mol Cell Biol 21:4347–4368PubMedCrossRefGoogle Scholar
  60. 60.
    Boczko EM et al (2005) Structure theorems and the dynamics of nitrogen catabolite repression in yeast. Proc Natl Acad Sci USA 102:5647–5652PubMedCrossRefGoogle Scholar
  61. 61.
    Albers E, Laizé V, Blomberg A, Hohmann S, Gustafsson L (2003) Ser3p (Yer081wp) and Ser33p (Yil074cp) are phosphoglycerate dehydrogenases in Saccharomyces cerevisiae. J Biol Chem 278:10264–10272PubMedCrossRefGoogle Scholar
  62. 62.
    Martens JA, Wu P-YJ, Winston F (2005) Regulation of an intergenic transcript controls adjacent gene transcription in Saccharomyces cerevisiae. Genes Dev 19:2695–26704PubMedCrossRefGoogle Scholar
  63. 63.
    Thebault P et al (2011) Transcription regulation by the noncoding RNA SRG1 requires Spt2-dependent chromatin deposition in the wake of RNA polymerase II. Mol Cell Biol 31: 1288–1300PubMedCrossRefGoogle Scholar
  64. 64.
    Dubrow R, Pizer LI (1977) Transient kinetic studies on the allosteric transition of phosphoglycerate dehydrogenase. J Biol Chem 252:1527–1538PubMedGoogle Scholar
  65. 65.
    Murray DB (2006) The respiratory oscillation in yeast phase definitions and periodicity. Nat Rev Mol Cell Biol 7:696–701CrossRefGoogle Scholar
  66. 66.
    Cohen R, Holland JP, Yokoi T, Holland MJ (1986) Identification of a regulatory region that mediates glucose-dependent induction of the Saccharomyces cerevisiae enolase gene ENO2. Mol Cell Biol 6:2287–2297PubMedGoogle Scholar
  67. 67.
    Etchegaray JP, Lee C, Wade PA, Reppert SM (2003) Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421:177–182PubMedCrossRefGoogle Scholar
  68. 68.
    Ptitsyn AA et al. (2006) Circadian clocks are resounding in peripheral tissues. PLoS Comput Biol 2:e16PubMedCrossRefGoogle Scholar
  69. 69.
    Yamada R, Ueda HR (2007) Microarrays: statistical methods for circadian rhythms. Meth Mol Biol 362:245–264CrossRefGoogle Scholar
  70. 70.
    Lloyd D, Murray DB (2000) Redox cycling of intracellular thiols: state variables for ultradian, cell division cycle and circadian cycles? In: Driessche TV, Guisset JL, Vries GMP-de (eds.) The redox state and circadian rhythms. Kluwer, Dordrecht, pp 85–94Google Scholar
  71. 71.
    O’Neill JS et al (2011) Circadian rhythms persist without transcription in a eukaryote. Nature 469:554–558PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Institute for Advanced BiosciencesKeio UniversityTsuruoka CityJapan
  2. 2.School of MedicineJohns Hopkins UniversityBaltimoreUSA
  3. 3.Microbiology, School of BiosciencesCardiff UniversityCardiffUK

Personalised recommendations