Variance-corrected Michaelis-Menten equation predicts transient rates of single-enzyme reactions and response times in bacterial gene-regulation

Pulkkinen, Otto; Metzler, Ralf

doi:10.1038/srep17820

Cited by 26 publications

(20 citation statements)

References 61 publications

(98 reference statements)

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“…Another important biophysical application concerns the search process of certain DNA binding proteins and enzymes for their specific binding site on the genome. In the facilitated diffusion picture mentioned above, the binding to the DNA from the bulk is the first step in the final target localisation [44]. The intermittent bulk dynamics determines the mixing behaviour and thus the efficiency of decorrelations by the three-dimensional steps of the search dynamics [3,4].…”

Section: Binding Of Proteins To Dnamentioning

confidence: 99%

Effects of the target aspect ratio and intrinsic reactivity onto diffusive search in bounded domains

2017

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We study the mean first passage time (MFPT) to a reaction event on a specific site in a cylindrical geometry-characteristic, for instance, for bacterial cells, with a concentric inner cylinder representing the nuclear region of the bacterial cell. A similar problem emerges in the description of a diffusive search by a transcription factor protein for a specific binding region on a single strand of DNA. We develop a unified theoretical approach to study the underlying boundary value problem which is based on a self-consistent approximation of the mixed boundary condition. Our approach permits us to derive explicit, novel, closed-form expressions for the MFPT valid for a generic setting with an arbitrary relation between the system parameters. We analyse this general result in the asymptotic limits appropriate for the above-mentioned biophysical problems. Our investigation reveals the crucial role of the target aspect ratio and of the intrinsic reactivity of the binding region, which were disregarded in previous studies. Theoretical predictions are confirmed by numerical simulations.

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Section: Binding Of Proteins To Dnamentioning

confidence: 99%

Effects of the target aspect ratio and intrinsic reactivity onto diffusive search in bounded domains

2017

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“…The frequency of the 3D search can be examined by the kinetic association and dissociation constants of p53 to nontarget DNA (11,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Accordingly, the efficiency and accuracy in the target search of p53 as well as of other DNA-binding proteins is achieved based on the interplay of distinct elementary processes that can be examined by various approaches (32)(33)(34)(35).…”

Section: Introductionmentioning

confidence: 99%

One-Dimensional Search Dynamics of Tumor Suppressor p53 Regulated by a Disordered C-Terminal Domain

Murata

Itoh

Mano

et al. 2017

Biophysical Journal

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Tumor suppressor p53 slides along DNA and finds its target sequence in drastically different and changing cellular conditions. To elucidate how p53 maintains efficient target search at different concentrations of divalent cations such as Ca and Mg, we prepared two mutants of p53, each possessing one of its two DNA-binding domains, the CoreTet mutant having the structured core domain plus the tetramerization (Tet) domain, and the TetCT mutant having Tet plus the disordered C-terminal domain. We investigated their equilibrium and kinetic dissociation from DNA and search dynamics along DNA at various [Mg]. Although binding of CoreTet to DNA becomes markedly weaker at higher [Mg], binding of TetCT depends slightly on [Mg]. Single-molecule fluorescence measurements revealed that the one-dimensional diffusion of CoreTet along DNA consists of fast and slow search modes, the ratio of which depends strongly on [Mg]. In contrast, diffusion of TetCT consisted of only the fast mode. The disordered C-terminal domain can associate with DNA irrespective of [Mg], and can maintain an equilibrium balance of the two search modes and the p53 search distance. These results suggest that p53 modulates the quaternary structure of the complex between p53 and DNA under different [Mg] and that it maintains the target search along DNA.

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“…Even for cells with the same copy number of a specific enzyme, the metabolite product could be synthesized at a different rate due to stochastic enzyme turnover. However, in the regime of high gene expression, the case most applicable to an engineered system, the ensemble enzyme turnover rate matches the simple Michaelis–Menten kinetics due to the law of large numbers, meaning there are negligible effects on metabolite heterogeneity arising from stochastic enzyme turnover . Additionally, when considering time‐scales of seconds or longer, heterogeneity in single enzyme turnover is negligible …”

Section: Metabolite Heterogeneitymentioning

confidence: 96%

Engineering Microbial Metabolite Dynamics and Heterogeneity

Schmitz

Hartline

Zhang

2017

Biotechnology Journal

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As yields for biological chemical production in microorganisms approach their theoretical maximum, metabolic engineering requires new tools, and approaches for improvements beyond what traditional strategies can achieve. Engineering metabolite dynamics and metabolite heterogeneity is necessary to achieve further improvements in product titers, productivities, and yields. Metabolite dynamics, the ensemble change in metabolite concentration over time, arise from the need for microbes to adapt their metabolism in response to the extracellular environment and are important for controlling growth and productivity in industrial fermentations. Metabolite heterogeneity, the cell-to-cell variation in a metabolite concentration in an isoclonal population, has a significant impact on ensemble productivity. Recent advances in single cell analysis enable a more complete understanding of the processes driving metabolite heterogeneity and reveal metabolic engineering targets. The authors present an overview of the mechanistic origins of metabolite dynamics and heterogeneity, why they are important, their potential effects in chemical production processes, and tools and strategies for engineering metabolite dynamics and heterogeneity. The authors emphasize that the ability to control metabolite dynamics and heterogeneity will bring new avenues of engineering to increase productivity of microbial strains.

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Variance-corrected Michaelis-Menten equation predicts transient rates of single-enzyme reactions and response times in bacterial gene-regulation

Cited by 26 publications

References 61 publications

Effects of the target aspect ratio and intrinsic reactivity onto diffusive search in bounded domains

Effects of the target aspect ratio and intrinsic reactivity onto diffusive search in bounded domains

One-Dimensional Search Dynamics of Tumor Suppressor p53 Regulated by a Disordered C-Terminal Domain

Engineering Microbial Metabolite Dynamics and Heterogeneity

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