Metabolic Photofragmentation Kinetics for a Minimal Protocell: Rate-Limiting Factors, Efficiency, and Implications for Evolution

2008 ◽  
Vol 14 (2) ◽  
pp. 189-201 ◽  
Author(s):  
Chad Knutson ◽  
Gil Benkö ◽  
Tristan Rocheleau ◽  
Fouzi Mouffouk ◽  
Jerzy Maselko ◽  
...  
Keyword(s):  
Kinetic Equations ◽  
Building Blocks ◽  
Reaction Rates ◽  
Limiting Factors ◽  
Metabolic System ◽  
Evolutionary Selection ◽  
Gene Replication ◽  
Analytical Approximations ◽  
Rate Limiting ◽  
Analytical Expressions

A key requirement of an autonomous self-replicating molecular machine, a protocell, is the ability to digest resources and turn them into building blocks. Thus a protocell needs a set of metabolic processes fueled by external free energy in the form of available chemical redox potential or light. We introduce and investigate a minimal photodriven metabolic system, which is based on photofragmentation of resource molecules catalyzed by genetic molecules. We represent and analyze the full metabolic set of reaction-kinetic equations and, through a set of approximations, simplify the reaction kinetics so that analytical expressions can be obtained for the building block production. The analytical approximations are compared with the full equation set and with corresponding experimental results to the extent they are available. It should be noted, however, that the proposed metabolic system has not been experimentally implemented, so this investigation is conducted to obtain a deeper understanding of its dynamics and perhaps to anticipate its limitations. We demonstrate that this type of minimal photodriven metabolic scheme is typically rate-limited by the front-end photoexcitation process, while its yield is determined by the genetic catalysis. We further predict that gene-catalyzed metabolic reactions can undergo evolutionary selection only for certain combinations of the involved reaction rates due to their intricate interactions. We finally discuss how the expected range of metabolic rates likely affects other key protocellular processes such as container growth and division as well as gene replication.

scholarly journals Rapid Elimination of Blood Alcohol Using Erythrocytes: Mathematical Modeling and In Vitro Study

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Yuliya G. Alexandrovich ◽  
Elena A. Kosenko ◽  
Elena I. Sinauridze ◽  
Sergey I. Obydennyi ◽  
Igor I. Kireev ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Ethanol Oxidation ◽  
Alcohol Intoxication ◽  
Limiting Factors ◽  
Blood Alcohol ◽  
Cell Recovery ◽  
Optimal Method ◽  
Metabolic System ◽  
Rate Limiting

Erythrocytes (RBCs) loaded with alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALD) can metabolize plasma ethanol and acetaldehyde but with low efficiency. We investigated the rate-limiting factors in ethanol oxidation by these enzymes loaded into RBCs. Mathematical modeling and in vitro experiments on human RBCs loaded simultaneously with ADH and ALD (by hypoosmotic dialysis) were performed. The simulation showed that the rate of nicotinamide-adenine dinucleotide (NAD+) generation in RBC glycolysis, but not the activities of the loaded enzymes, is the rate-limiting step in external ethanol oxidation. The rate of oxidation could be increased if RBCs are supplemented by NAD+ and pyruvate. Our experimental data verified this theoretical conclusion. RBCs loaded with the complete system of ADH, ALD, NAD+, and pyruvate metabolized ethanol 20–40 times faster than reported in previous studies. The one-step procedure of hypoosmotic dialysis is the optimal method to encapsulate ADH and ALD in RBCs after cell recovery, encapsulation yield, osmotic resistance, and RBC-indexes. Consequently, transfusion of the RBCs loaded with the complete metabolic system, including ADH, ALD, pyruvate, and NAD+ in the patients with alcohol intoxication, may be a promising method for rapid detoxification of blood alcohol based on metabolism.

scholarly journals A first-takes-all model of centriole copy number control

2020 ◽  
Author(s):  
Marco António Dias Louro ◽  
Mónica Bettencourt-Dias ◽  
Jorge Carneiro
Keyword(s):  
Cell Cycle ◽  
Copy Number Variation ◽  
Cell Population ◽  
Copy Number ◽  
Building Blocks ◽  
Limiting Factors ◽  
Copy Number Control ◽  
Wide Range ◽  
Number Variation ◽  
Rate Limiting

AbstractHow cells control the numbers of its subcellular components is a fundamental question in biology. Given that biosynthetic processes are fundamentally stochastic it is utterly puzzling that some structures display no copy number variation within a cell population. Centriole biogenesis, with each centriole being duplicated once and only once per cell cycle, stands out due to its remarkable fidelity. This is a highly controlled process, which depends on low-abundance rate-limiting factors. How can exactly one centriole copy be produced given the natural variation in the concentration of these key players? Hitherto, tentative explanations of this control evoked lateral inhibition-or phase separation-like mechanisms emerging from the dynamics of these rate-limiting factors, but how centriole number is regulated remains unclear. Here, we propose a novel solution to centriole copy number control based on the assembly of a centriolar scaffold, the cartwheel. We hypothesise that once the first cartwheel is formed it continues to elongate by stacking the intermediate cartwheel building blocks that would otherwise form supernumerary structures. Using probability theory and computer simulations, we show that this mechanism may ensure formation of one and only one cartwheel over a wide range of parameter values at physiologically relevant conditions. By comparison to alternative models, we conclude that the key signatures of this novel mechanism are an increasing assembly time with cartwheel numbers and that stochasticity in cartwheel building blocks should be converted into variation in cartwheel numbers or length, both of which can be tested experimentally.Author summaryCentriole duplication stands out as a biosynthetic process of exquisite fidelity in the noisy world of the cell. Each centriole duplicates exactly once per cell cycle, such that the number of centrioles per cell shows no variance across cells, in contrast with most cellular components that show broadly distributed copy numbers. We propose a new solution to the number control problem. We show that elongation of the first cartwheel, a core centriolar structure, may sequester the building blocks necessary to assemble supernumerary centrioles. As a corollary, the variation in regulatory kinases and cartwheel components across the cell population is predicted to translate into cartwheel length variation instead of copy number variation, which is an intriguing overlooked possibility.

scholarly journals A first-takes-all model of centriole copy number control based on cartwheel elongation

2021 ◽  
Vol 17 (5) ◽  
pp. e1008359
Author(s):  
Marco António Dias Louro ◽  
Mónica Bettencourt-Dias ◽  
Jorge Carneiro
Keyword(s):  
Copy Number ◽  
Building Blocks ◽  
Limiting Factors ◽  
Copy Number Control ◽  
Wide Range ◽  
Mother Centriole ◽  
Number Variation ◽  
A Cell ◽  
Parameter Values ◽  
Rate Limiting

How cells control the numbers of its subcellular components is a fundamental question in biology. Given that biosynthetic processes are fundamentally stochastic it is utterly puzzling that some structures display no copy number variation within a cell population. Centriole biogenesis, with each centriole being duplicated once and only once per cell cycle, stands out due to its remarkable fidelity. This is a highly controlled process, which depends on low-abundance rate-limiting factors. How can exactly one centriole copy be produced given the variation in the concentration of these key factors? Hitherto, tentative explanations of this control evoked lateral inhibition- or phase separation-like mechanisms emerging from the dynamics of these rate-limiting factors but how strict centriole number is regulated remains unsolved. Here, a novel solution to centriole copy number control is proposed based on the assembly of a centriolar scaffold, the cartwheel. We assume that cartwheel building blocks accumulate around the mother centriole at supercritical concentrations, sufficient to assemble one or more cartwheels. Our key postulate is that once the first cartwheel is formed it continues to elongate by stacking the intermediate building blocks that would otherwise form supernumerary cartwheels. Using stochastic models and simulations, we show that this mechanism may ensure formation of one and only one cartwheel robustly over a wide range of parameter values. By comparison to alternative models, we conclude that the distinctive signatures of this novel mechanism are an increasing assembly time with cartwheel numbers and the translation of stochasticity in building block concentrations into variation in cartwheel numbers or length.

Probing the Substrate Promiscuity of Isopentenyl Phosphate Kinase as a Platform for Hemiterpene Analogue Production

2019 ◽  
Author(s):  
Sean Lund ◽  
Taylor Courtney ◽  
Gavin Williams
Keyword(s):  
Synthetic Biology ◽  
Building Blocks ◽  
Isoprenoid Biosynthesis ◽  
Thermoplasma Acidophilum ◽  
Substrate Promiscuity ◽  
Enzymatic Pathways ◽  
First Time ◽  
Rate Limiting ◽  
Alcohol Dependent ◽  
Isopentenyl Phosphate

Isoprenoids are a large class of natural products with wide-ranging applications. Synthetic biology approaches to the manufacture of isoprenoids and their new-to-nature derivatives are limited due to the provision in Nature of just two hemiterpene building blocks for isoprenoid biosynthesis. To address this limitation, artificial chemo-enzymatic pathways such as the alcohol-dependent hemiterpene pathway (ADH) serve to leverage consecutive kinases to convert exogenous alcohols to pyrophosphates that could be coupled to downstream isoprenoid biosynthesis. To be successful, each kinase in this pathway should be permissive of a broad range of substrates. For the first time, we have probed the promiscuity of the second enzyme in the ADH pathway, isopentenyl phosphate kinase from Thermoplasma acidophilum, towards a broad range of acceptor monophosphates. Subsequently, we evaluate the suitability of this enzyme to provide non-natural pyrophosphates and provide a critical first step in characterizing the rate limiting steps in the artificial ADH pathway.<br>

Kinetic model of hybridoma cultures for the identification of rate limiting factors and process optimisation

1996 ◽  
Vol 42 (2-3) ◽  
pp. 197-205
Author(s):  
A. Lourenço da Silva ◽  
A. Marc ◽  
J.M. Engasser ◽  
J.L. Goergen
Keyword(s):  
Kinetic Model ◽  
Limiting Factors ◽  
Process Optimisation ◽  
Rate Limiting

scholarly journals Structure–Function Relations of the First and Fourth Predicted Extracellular Linkers of the Type IIa Na+/Pi Cotransporter

2004 ◽  
Vol 124 (5) ◽  
pp. 475-488 ◽  
Author(s):  
Colin Ehnes ◽  
Ian C. Forster ◽  
Katja Kohler ◽  
Andrea Bacconi ◽  
Gerti Stange ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Reaction Rates ◽  
Transport Pathway ◽  
Extracellular Medium ◽  
Voltage Range ◽  
Substituted Cysteine Accessibility ◽  
Voltage Dependent ◽  
Opposite Behavior ◽  
Rate Limiting ◽  
Kinetics Of

The putative first intracellular and third extracellular linkers are known to play important roles in defining the transport properties of the type IIa Na+-coupled phosphate cotransporter (Kohler, K., I.C. Forster, G. Stange, J. Biber, and H. Murer. 2002b. J. Gen. Physiol. 120:693–705). To investigate whether other stretches that link predicted transmembrane domains are also involved, the substituted cysteine accessibility method (SCAM) was applied to sites in the predicted first and fourth extracellular linkers (ECL-1 and ECL-4). Mutants based on the wild-type (WT) backbone, with substituted novel cysteines, were expressed in Xenopus oocytes, and their function was assayed by isotope uptake and electrophysiology. Functionally important sites were identified in both linkers by exposing cells to membrane permeant and impermeant methanethiosulfonate (MTS) reagents. The cysteine modification reaction rates for sites in ECL-1 were faster than those in ECL-4, which suggested that the latter were less accessible from the extracellular medium. Generally, a finite cotransport activity remained at the end of the modification reaction. The change in activity was due to altered voltage-dependent kinetics of the Pi-dependent current. For example, cys substitution at Gly-134 in ECL-1 resulted in rate-limiting, voltage-independent cotransport activity for V ≤ −80 mV, whereas the WT exhibited a linear voltage dependency. After cys modification, this mutant displayed a supralinear voltage dependency in the same voltage range. The opposite behavior was documented for cys substitution at Met-533 in ECL-4. Modification of cysteines at two other sites in ECL-1 (Ile-136 and Phe-137) also resulted in supralinear voltage dependencies for hyperpolarizing potentials. Taken together, these findings suggest that ECL-1 and ECL-4 may not directly form part of the transport pathway, but specific sites in these linkers can interact directly or indirectly with parts of NaPi-IIa that undergo voltage-dependent conformational changes and thereby influence the voltage dependency of cotransport.

Is Cognitive Psychopathology Plausible? Illustrations from Memory Research

1996 ◽  
Vol 41 (7) ◽  
pp. S5-S13 ◽  
Author(s):  
Jean-Marie Danion ◽  
Herbert Weingartner ◽  
Leonard Singer
Keyword(s):  
Cognitive Remediation ◽  
Preliminary Evidence ◽  
Limiting Factors ◽  
Specific Rate ◽  
Memory Impairments ◽  
Central Processing ◽  
Elementary Computation ◽  
The One ◽  
Functional Mechanisms ◽  
Rate Limiting

Objective: To examine the strengths and weaknesses of cognitive psychopathology through the specific examples of the memory impairments associated with the administration of benzodiazepines, with schizophrenia, and with depression. Method: These examples are analyzed with reference to a model of memory based on the principle of division between specialized and central processing structures. A basic contention is that it is useful to consider 2 broad classes of processes—automatic, associative, or sensory/perceptual processes on the one hand and intentional, strategic, or reflective processes on the other hand—as being separate. Results: The functional mechanisms of the memory impairments associated with these conditions are beginning to be identified, and there is preliminary evidence that a deficit in an elementary computation may have dramatic consequences on highest cognitive functions. There is also evidence that certain memory impairments are linked to specific dysfunctional outcomes in everyday life. By showing that specific rate-limiting factors of cognitive performance can be identified and are amenable to cognitive interventions, existing data open the door for theoretically and empirically based cognitive remediation of mental disorders. Conclusion: The bulk of available evidence (albeit limited) makes the enterprise of cognitive psychopathology quite plausible and convincing.

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