scholarly journals Holistic bioengineering: rewiring central metabolism for enhanced bioproduction

2017 ◽  
Vol 474 (23) ◽  
pp. 3935-3950 ◽  
Author(s):  
Selçuk Aslan ◽  
Elad Noor ◽  
Arren Bar-Even
Keyword(s):  
Metabolic Network ◽  
Metabolic Pathways ◽  
Tricarboxylic Acid Cycle ◽  
Holistic Approach ◽  
Living Organism ◽  
Tricarboxylic Acid ◽  
High Availability ◽  
Biosynthesis Pathway ◽  
Central Metabolism ◽  
Host Organism

What does it take to convert a living organism into a truly productive biofactory? Apart from optimizing biosynthesis pathways as standalone units, a successful bioengineering approach must bend the endogenous metabolic network of the host, and especially its central metabolism, to support the bioproduction process. In practice, this usually involves three complementary strategies which include tuning-down or abolishing competing metabolic pathways, increasing the availability of precursors of the desired biosynthesis pathway, and ensuring high availability of energetic resources such as ATP and NADPH. In this review, we explore these strategies, focusing on key metabolic pathways and processes, such as glycolysis, anaplerosis, the TCA (tricarboxylic acid) cycle, and NADPH production. We show that only a holistic approach for bioengineering — considering the metabolic network of the host organism as a whole, rather than focusing on the production pathway alone — can truly mold microorganisms into efficient biofactories.

scholarly journals Oxidative Stress Evokes a Metabolic Adaptation That Favors Increased NADPH Synthesis and Decreased NADH Production in Pseudomonas fluorescens

2007 ◽  
Vol 189 (18) ◽  
pp. 6665-6675 ◽  
Author(s):  
Ranji Singh ◽  
Ryan J. Mailloux ◽  
Simone Puiseux-Dao ◽  
Vasu D. Appanna
Keyword(s):  
Oxidative Stress ◽  
Metabolic Pathways ◽  
Metabolic Networks ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Metabolic Adaptation ◽  
Atp Production ◽  
Oxidative Challenge ◽  
Glucose 6 Phosphate Dehydrogenase ◽  
Oxidative Insult

ABSTRACT The fate of all aerobic organisms is dependent on the varying intracellular concentrations of NADH and NADPH. The former is the primary ingredient that fuels ATP production via oxidative phosphorylation, while the latter helps maintain the reductive environment necessary for this process and other cellular activities. In this study we demonstrate a metabolic network promoting NADPH production and limiting NADH synthesis as a consequence of an oxidative insult. The activity and expression of glucose-6-phosphate dehydrogenase, malic enzyme, and NADP+-isocitrate dehydrogenase, the main generators of NADPH, were markedly increased during oxidative challenge. On the other hand, numerous tricarboxylic acid cycle enzymes that supply the bulk of intracellular NADH were significantly downregulated. These metabolic pathways were further modulated by NAD+ kinase (NADK) and NADP+ phosphatase (NADPase), enzymes known to regulate the levels of NAD+ and NADP+. While in menadione-challenged cells, the former enzyme was upregulated, the phosphatase activity was markedly increased in control cells. Thus, NADK and NADPase play a pivotal role in controlling the cross talk between metabolic networks that produce NADH and NADPH and are integral components of the mechanism involved in fending off oxidative stress.

scholarly journals The Tricarboxylic Acid Cycle, an Ancient Metabolic Network with a Novel Twist

PLoS ONE ◽  
2007 ◽  
Vol 2 (8) ◽  
pp. e690 ◽  
Author(s):  
Ryan J. Mailloux ◽  
Robin Bériault ◽  
Joseph Lemire ◽  
Ranji Singh ◽  
Daniel R. Chénier ◽  
...  
Keyword(s):  
Metabolic Network ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Acid Cycle

scholarly journals Abiotic and biotic processes that drive carboxylation and decarboxylation reactions

2020 ◽  
Vol 105 (5) ◽  
pp. 609-615
Author(s):  
Cody S. Sheik ◽  
H. James Cleaves ◽  
Kristin Johnson-Finn ◽  
Donato Giovannelli ◽  
Thomas L. Kieft ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Subduction Zones ◽  
Carbon Fixation ◽  
Prebiotic Chemistry ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Short Term ◽  
Planetary Evolution ◽  
Broad Overview

Abstract Carboxylation and decarboxylation are two fundamental classes of reactions that impact the cycling of carbon in and on Earth’s crust. These reactions play important roles in both long-term (primarily abiotic) and short-term (primarily biotic) carbon cycling. Long-term cycling is important in the subsurface and at subduction zones where organic carbon is decomposed and outgassed or recycled back to the mantle. Short-term reactions are driven by biology and have the ability to rapidly convert CO2 to biomass and vice versa. For instance, carboxylation is a critical reaction in primary production and metabolic pathways like photosynthesis in which sunlight provides energy to drive carbon fixation, whereas decarboxylation is a critical reaction in metabolic pathways like respiration and the tricarboxylic acid cycle. Early life and prebiotic chemistry on Earth likely relied heavily upon the abiotic synthesis of carboxylic acids. Over time, life has diversified (de)carboxylation reactions and incorporated them into many facets of cellular metabolism. Here we present a broad overview of the importance of carboxylation and decarboxylation reactions from both abiotic and biotic perspectives to highlight the importance of these reactions and compounds to planetary evolution.

scholarly journals Systems-Level Metabolic Flux Profiling Elucidates a Complete, Bifurcated Tricarboxylic Acid Cycle in Clostridium acetobutylicum

2010 ◽  
Vol 192 (17) ◽  
pp. 4452-4461 ◽  
Author(s):  
Daniel Amador-Noguez ◽  
Xiao-Jiang Feng ◽  
Jing Fan ◽  
Nathaniel Roquet ◽  
Herschel Rabitz ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Genome Annotation ◽  
Clostridium Acetobutylicum ◽  
Metabolic Flux ◽  
Tricarboxylic Acid Cycle ◽  
Anaerobic Bacteria ◽  
Tca Cycle ◽  
Tricarboxylic Acid ◽  
Fermentation Products

ABSTRACT Obligatory anaerobic bacteria are major contributors to the overall metabolism of soil and the human gut. The metabolic pathways of these bacteria remain, however, poorly understood. Using isotope tracers, mass spectrometry, and quantitative flux modeling, here we directly map the metabolic pathways of Clostridium acetobutylicum, a soil bacterium whose major fermentation products include the biofuels butanol and hydrogen. While genome annotation suggests the absence of most tricarboxylic acid (TCA) cycle enzymes, our results demonstrate that this bacterium has a complete, albeit bifurcated, TCA cycle; oxaloacetate flows to succinate both through citrate/α-ketoglutarate and via malate/fumarate. Our investigations also yielded insights into the pathways utilized for glucose catabolism and amino acid biosynthesis and revealed that the organism's one-carbon metabolism is distinct from that of model microbes, involving reversible pyruvate decarboxylation and the use of pyruvate as the one-carbon donor for biosynthetic reactions. This study represents the first in vivo characterization of the TCA cycle and central metabolism of C. acetobutylicum. Our results establish a role for the full TCA cycle in an obligatory anaerobic organism and demonstrate the importance of complementing genome annotation with isotope tracer studies for determining the metabolic pathways of diverse microbes.

scholarly journals Indole-3-acetic acid regulates the central metabolic pathways in Escherichia coli

Microbiology ◽  
2006 ◽  
Vol 152 (8) ◽  
pp. 2421-2431 ◽  
Author(s):  
C. Bianco ◽  
E. Imperlini ◽  
R. Calogero ◽  
B. Senatore ◽  
P. Pucci ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Metabolic Pathways ◽  
Tricarboxylic Acid Cycle ◽  
Tricarboxylic Acid ◽  
Mrna Levels ◽  
Glyoxylate Shunt ◽  
Acetyl Coa ◽  
Acid Cycle ◽  
E Coli ◽  
K 12

The physiological changes induced by indoleacetic acid (IAA) treatment were investigated in the totally sequenced Escherichia coli K-12 MG1655. DNA macroarrays were used to measure the mRNA levels for all the 4290 E. coli protein-coding genes; 50 genes (1.1 %) exhibited significantly different expression profiles. In particular, genes involved in the tricarboxylic acid cycle, the glyoxylate shunt and amino acid biosynthesis (leucine, isoleucine, valine and proline) were up-regulated, whereas the fermentative adhE gene was down-regulated. To confirm the indications obtained from the macroarray analysis the activity of 34 enzymes involved in central metabolism was measured; this showed an activation of the tricarboxylic acid cycle and the glyoxylate shunt. The malic enzyme, involved in the production of pyruvate, and pyruvate dehydrogenase, required for the channelling of pyruvate into acetyl-CoA, were also induced in IAA-treated cells. Moreover, it was shown that the enhanced production of acetyl-CoA and the decrease of NADH/NAD+ ratio are connected with the molecular process of the IAA response. The results demonstrate that IAA treatment is a stimulus capable of inducing changes in gene expression, enzyme activity and metabolite level involved in central metabolic pathways in E. coli.

scholarly journals The LysR-Type Transcriptional Regulator BsrA (PA2121) Controls Vital Metabolic Pathways in Pseudomonas aeruginosa

mSystems ◽  
2021 ◽  
Author(s):  
Magdalena Modrzejewska ◽  
Adam Kawalek ◽  
Aneta Agnieszka Bartosik
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Regulatory Network ◽  
Metabolic Pathways ◽  
Tricarboxylic Acid Cycle ◽  
Transcriptional Regulator ◽  
Tricarboxylic Acid ◽  
Content Type ◽  
Acid Cycle

This study shows that BsrA, a LysR-type transcriptional regulator from Pseudomonas aeruginosa , previously identified as a repressor of biofilm synthesis, is part of an intricate global regulatory network. BsrA acts directly and/or indirectly as the repressor and/or activator of genes from vital metabolic pathways (e.g., pyruvate, acetate, and tricarboxylic acid cycle) and is involved in control of transport functions and the formation of surface appendages.

scholarly journals Metabolomic Study to Determine the Mechanism Underlying the Effects of Sagittaria sagittifolia Polysaccharide on Isoniazid- and Rifampicin-Induced Hepatotoxicity in Mice

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3087 ◽  
Author(s):  
Xiu-Hui Ke ◽  
Chun-Guo Wang ◽  
Wei-Zao Luo ◽  
Jing Wang ◽  
Bing Li ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Acid Metabolism ◽  
High Resolution Mass Spectrometry ◽  
Tricarboxylic Acid Cycle ◽  
Ultra Performance Liquid Chromatography ◽  
Tricarboxylic Acid ◽  
Protective Effects ◽  
Metabolomics Study ◽  
Sagittaria Sagittifolia ◽  
Metabolomic Study

In this study, a non-targeted metabolic profiling method based on ultra-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS) was used to characterize the plasma metabolic profile associated with the protective effects of the Sagittaria sagittifolia polysaccharide (SSP) on isoniazid (INH)—and rifampicin (RFP)-induced hepatotoxicity in mice. Fourteen potential biomarkers were identified from the plasma of SSP-treated mice. The protective effects of SSP on hepatotoxicity caused by the combination of INH and RFP (INH/RFP) were further elucidated by investigating the related metabolic pathways. INH/RFP was found to disrupt fatty acid metabolism, the tricarboxylic acid cycle, amino acid metabolism, taurine metabolism, and the ornithine cycle. The results of the metabolomics study showed that SSP provided protective effects against INH/RFP-induced liver injury by partially regulating perturbed metabolic pathways.

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