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Intracellular Flows and Fluctuations
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mathematical models are now gaining in importance for descriptions of biological processes. In this thesis, such models have been used to identify and analyze principles that govern bacterial protein synthesis under amino acid limitation. New techniques, that are generally applicable for analysis of intrinsic fluctuations in systems of chemical reactions, are also presented.

It is shown how multi-substrate reactions, such as protein synthesis, may display zero order kinetics below saturation, because an increase in one substrate pool is compensated by a decrease in another, so that the overall flow is unchanged. Under those conditions, metabolite pools display hyper sensitivity and large fluctuations, unless metabolite synthesis is carefully regulated. It is demonstrated that flow coupling in protein synthesis has consequences for transcriptional control of amino acid biosynthetic operons, accuracy of mRNA translation and the stringent response.

Flow coupling also determines the choices of synonymous codons in a number of cases. The reason is that tRNA isoacceptors, cognate to the same amino acid, often read different codons and become deacylated to very different degrees when their amino acid is limiting for protein synthesis. This was demonstrated theoretically and used to successfully predict the choices of control codons in ribosome mediated transcriptional attenuation and codon bias in stress response genes.

New tools for the analysis of internal fluctuations have been forged, most importantly, an efficient Monte Carlo algorithm for simulation of the Markov-process corresponding to the reaction-diffusion master equation. The algorithm makes it feasible to analyze stochastic kinetics in spatially extended systems. It was used to demonstrate that bi-stable chemical systems can display spontaneous domain separation also in three spatial dimensions. This analysis reveals geometrical constraints on biochemical memory circuits built from bistable systems. Further, biochemical applications of the Fokker-Planck equation and the Linear Noise Approximation have been explored.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 63
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 988
Keywords [en]
Molecular biology, mesoscopic, reaction-diffusion, protein synthesis, amino acid, flow, fluctuations
Keywords [sv]
Molekylärbiologi
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biotechnology
Identifiers
URN: urn:nbn:se:uu:diva-4291ISBN: 91-554-5988-9 (print)OAI: oai:DiVA.org:uu-4291DiVA, id: diva2:164746
Public defence
2004-06-03, Room B41, Uppsala Biomedical Centre, Husarg. 3, Uppsala, 10:00 (English)
Opponent
Supervisors
Available from: 2004-05-13 Created: 2004-05-13 Last updated: 2010-01-14Bibliographically approved
List of papers
1. Selective charging of tRNA isoacceptors explains patterns of codon usage
Open this publication in new window or tab >>Selective charging of tRNA isoacceptors explains patterns of codon usage
2003 In: Science, Vol. 300, no 5626, p. 1718-1722Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91869 (URN)
Available from: 2004-05-13 Created: 2004-05-13Bibliographically approved
2. Comparison of repressor and transcriptional attenuator systems for control of amino acid biosynthetic operons
Open this publication in new window or tab >>Comparison of repressor and transcriptional attenuator systems for control of amino acid biosynthetic operons
2001 In: Journal of Molecular Biology, Vol. 313, p. 941-954Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91870 (URN)
Available from: 2004-05-13 Created: 2004-05-13Bibliographically approved
3. Near-critical phenomena in intracellular metabolite pools
Open this publication in new window or tab >>Near-critical phenomena in intracellular metabolite pools
2003 In: Biophysical Journal, Vol. 84, p. 154-170Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91871 (URN)
Available from: 2004-05-13 Created: 2004-05-13Bibliographically approved
4. Fast evaluation of fluctuations in biochemical networks with the linear noise approximation
Open this publication in new window or tab >>Fast evaluation of fluctuations in biochemical networks with the linear noise approximation
2003 In: Genome Research, Vol. 13, p. 2475-2484Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91872 (URN)
Available from: 2004-05-13 Created: 2004-05-13Bibliographically approved
5. The bacterial toxin RelE displays codon specific cleavage of mRNAs in the ribosomal A-site
Open this publication in new window or tab >>The bacterial toxin RelE displays codon specific cleavage of mRNAs in the ribosomal A-site
Show others...
2003 In: Cell, Vol. 112, p. 131-140Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91873 (URN)
Available from: 2004-05-13 Created: 2004-05-13Bibliographically approved
6. Mesoscopic reaction-diffusion in intracellular signaling
Open this publication in new window or tab >>Mesoscopic reaction-diffusion in intracellular signaling
2003 In: Proceedings of SPIE -- Volume 5110: Fluctuations and Noise in Biological, Biophysical, and Biomedical Systems, 2003, p. 114-124Chapter in book (Other academic) Published
Identifiers
urn:nbn:se:uu:diva-91874 (URN)0-8194-4970-9 (ISBN)
Available from: 2004-05-13 Created: 2004-05-13Bibliographically approved
7. Problems of high dimension in molecular biology
Open this publication in new window or tab >>Problems of high dimension in molecular biology
2003 (English)In: Proc. 19th GAMM Seminar Leipzig on High-dimensional problems: Numerical treatment and applications, Leipzig, Germany: Max Planck Institute for Mathematics in the Sciences , 2003, p. 21-30Conference paper, Published paper (Refereed)
Place, publisher, year, edition, pages
Leipzig, Germany: Max Planck Institute for Mathematics in the Sciences, 2003
National Category
Biochemistry and Molecular Biology Computational Mathematics
Identifiers
urn:nbn:se:uu:diva-91875 (URN)
Available from: 2004-05-13 Created: 2004-05-13 Last updated: 2011-11-26Bibliographically approved
8. Systems Biology is Taking
Open this publication in new window or tab >>Systems Biology is Taking
Show others...
2003 In: Genome Research, Vol. 13, p. 2377-2380Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91876 (URN)
Available from: 2004-05-13 Created: 2004-05-13Bibliographically approved
9. Stochastic reaction-diffusion kinetics separates bi-stable biological systems into spatial domains of opposite phases
Open this publication in new window or tab >>Stochastic reaction-diffusion kinetics separates bi-stable biological systems into spatial domains of opposite phases
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-91877 (URN)
Available from: 2004-05-13 Created: 2004-05-13Bibliographically approved
10. Near-critical behavior of aminoacyl-tRNA pools at rate limiting supply of several types of amino acids in E. coli.
Open this publication in new window or tab >>Near-critical behavior of aminoacyl-tRNA pools at rate limiting supply of several types of amino acids in E. coli.
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91878 (URN)
Available from: 2004-05-13 Created: 2004-05-13 Last updated: 2010-01-13Bibliographically approved

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