Metabolic defence against oxidative stress: the road less travelled so far

Lemire, Joe; Alhasawi, Azhar; Appanna, Varun P.; Tharmalingam, Sujeenthar

doi:10.1111/jam.13509

Cited by 114 publications

(86 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An increased NADH/NAD + ratio (1) triggers ROS production (2) by NADH dehydrogenase Nuo activity (52, 53). The corresponding cell response to oxidative stress is rerouting the carbon flux through the TCA cycle into the glyoxylate shunt (3) to reduce NADH formation (56–58) and scavenging of reactive oxygen species by glyoxylate (56, 59). Limited ATP provision from oxidative phosphorylation might be mitigated by upregulation of the ADI pathway ( 4 ) (65, 66).…”

Section: Discussionmentioning

confidence: 99%

The metabolic response ofPseudomonas taiwanensisto NADH dehydrogenase deficiency

Nies

Dinger

Chen

et al. 2019

Preprint

View full text Add to dashboard Cite

30Obligate aerobic organisms rely on a functional electron transport chain for energy 31 generation and NADH oxidation. Because of this essential requirement, the genes of 32 this pathway are likely constitutively and highly expressed to avoid a cofactor imbalance 33 and energy shortage under fluctuating environmental conditions. 34We here investigated the essentiality of the three NADH dehydrogenases of the 35 respiratory chain of the obligate aerobe Pseudomonas taiwanensis VLB120 and the 36 impact of the knockouts of corresponding genes on its physiology and metabolism. 37While a mutant lacking all three NADH dehydrogenases seemed to be nonviable, the 38 generated single or double knockout strains displayed none or only a marginal 39 phenotype. Only the mutant deficient in both type 2 dehydrogenases showed a clear 40 phenotype with biphasic growth behavior and strongly reduced growth rate in the 41 second phase. In-depth analyses of the metabolism of the generated mutants including 42 quantitative physiological experiments, transcript analysis, proteomics and enzyme 43 activity assays revealed distinct responses to type II and type I dehydrogenase 44deletions. An overall high metabolic flexibility enables P. taiwanensis to cope with the 45 introduced genetic perturbations and maintain stable phenotypes by rerouting of 46 metabolic fluxes. 47 This metabolic adaptability has implications for biotechnological applications. While the 48 phenotypic robustness is favorable in large-scale applications with inhomogeneous 49 conditions, versatile redirecting of carbon fluxes upon genetic interventions can frustrate 50 metabolic engineering efforts. 51 52 Importance 53While Pseudomonas has the capability for high metabolic activity and the provision of 54 reduced redox cofactors important for biocatalytic applications, exploitation of this 55 3 characteristic might be hindered by high, constitutive activity of and consequently 56 competition with the NADH dehydrogenases of the respiratory chain. The in-depth 57 analysis of NADH dehydrogenase mutants of Pseudomonas taiwanensis VLB120 58 presented here, provides insight into the phenotypic and metabolic response of this 59 strain to these redox metabolism perturbations. The observed great metabolic flexibility 60 needs to be taken into account for rational engineering of this promising 61 biotechnological workhorse towards a host with controlled and efficient supply of redox 62 cofactors for product synthesis. 63 64 65Many industrially relevant molecules, e. g., ethanol, butanediol or isoprene, are more 66 reduced than the industrially-used sugars glucose and sucrose or alternative, upcoming 67 carbon sources such as xylose or glycerol (1-3). The microbial production of those 68 favored compounds hence is inherently redox limited, i.e. by the supply of reduced 69 redox cofactors, generally NADH or NADPH. This bottleneck has been overcome in 70 some cases, e.g., 1,4 butanediol and 1,3-propanediol production in Escherichia coli (4, 71 5) or L-lysine synthesis in Corynebacter...

show abstract

Section: Discussionmentioning

confidence: 99%

The metabolic response ofPseudomonas taiwanensisto NADH dehydrogenase deficiency

Nies

Dinger

Chen

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…O 2 Á − , which can cause damage to the cell by indiscriminately oxidizing macromolecules such as DNA or proteins (Imlay, 2013). Pseudomonas species use several (and often, concomitant) mechanisms to detoxify ROS (Kim and Park, 2014): (i) increasing the formation of specific ROS detoxifying enzymes (Lu and Holmgren, 2014), (ii) controlling other physiological aspects related to ROS production, such as iron homeostasis (Lemire et al, 2017) and (iii) rewiring central carbon metabolism to favour reducing power homeostasis (Nikel and Chavarría, 2016). Our results indicate that Crc modulates all three aspects in P. aeruginosa at different levels.…”

Section: Discussionmentioning

confidence: 99%

“…This scenario is particularly relevant in the case of opportunistic pathogens as P. aeruginosa, since an efficient response to oxidative stress is a pre-requisite to counteract the activity of macrophages during infection. A rearrangement of the entire metabolic architecture of Pseudomonas species takes place to curb an oxidative challenge, which could be summed up as the increase of metabolic activities that yield NADPH and the concomitant reduction of those that lead to NADH formation (Mailloux et al, 2011;Lemire et al, 2017). Several dehydrogenases of central carbon metabolism [e.g.…”

Section: Introductionmentioning

confidence: 99%

The global regulator Crc orchestrates the metabolic robustness underlying oxidative stress resistance in Pseudomonas aeruginosa

Corona

Martínez

Nikel

2018

Environmental Microbiology

View full text Add to dashboard Cite

Summary The remarkable metabolic versatility of bacteria of the genus Pseudomonas enable their survival across very diverse environmental conditions. P. aeruginosa, one of the most relevant opportunistic pathogens, is a prime example of this adaptability. The interplay between regulatory networks that mediate these metabolic and physiological features is just starting to be explored in detail. Carbon catabolite repression, governed by the Crc protein, controls the availability of several enzymes and transporters involved in the assimilation of secondary carbon sources. Yet, the regulation exerted by Crc on redox metabolism of P. aeruginosa (hence, on the overall physiology) had hitherto been unexplored. In this study, we address the intimate connection between carbon catabolite repression and metabolic robustness of P. aeruginosa PAO1. In particular, we explored the interplay between oxidative stress, metabolic rearrangements in central carbon metabolism and the cellular redox state. By adopting a combination of quantitative physiology experiments, multiomic analyses, transcriptional patterns of key genes, measurement of metabolic activities in vitro and direct quantification of redox balances both in the wild‐type strain and in an isogenic Δcrc derivative, we demonstrate that Crc orchestrates the overall response of P. aeruginosa to oxidative stress via reshaping of the core metabolic architecture in this bacterium.

show abstract

“…These results suggest that in the presence of O 2 .− both the frameworks are capable of oxidising Mn +2 to Mn +3 . It should be mentioned that the oxidative stress generated inside living cells are normally regulated by certain enzymes to keep cells disease free . The superoxide dismutase is such an enzyme that catalyses conversion of O 2 .− to H 2 O 2 .…”

Section: Resultsmentioning

confidence: 99%

Manganese‐Coordinated Tyrosine Bio Materials for the Sensing of Reactive Oxygen Species

Jena

2019

ChemistrySelect

View full text Add to dashboard Cite

Design of biosensor materials for the recognition of reactive oxygen species (ROS) inside living cells is necessary for the early diagnosis of cancer and other diseases induced by ROS. Here, the B3LYP−D3 dispersion‐corrected and Mo6 hybrid density functional theoretical methods and a polarized continuum model to account for the aqueous medium are used to propose models of manganese (Mn+2)‐coordinated tyrosine (Tyr) nano rods and porous bio materials to detect various ROS, such as .OH, .OOH, H2O2, .NO, ONOO−, and O2.−. It is found that the nano rods and porous polymers may sense the presence of different ROS by utilizing their edges and pores respectively. It is further revealed that due to stable binding and adsorption energies, entrapment of different ROS by the porous polymers would be sustained for longer time compared to the nano rods. However, the edges of nano rods are reactive and may initiate oxidation reactions by converting Mn+2 to Mn+3. It is thus expected that these bio materials would act as excellent ROS sensors.

show abstract

Metabolic defence against oxidative stress: the road less travelled so far

Cited by 114 publications

References 87 publications

The metabolic response ofPseudomonas taiwanensisto NADH dehydrogenase deficiency

The metabolic response ofPseudomonas taiwanensisto NADH dehydrogenase deficiency

The global regulator Crc orchestrates the metabolic robustness underlying oxidative stress resistance in Pseudomonas aeruginosa

Manganese‐Coordinated Tyrosine Bio Materials for the Sensing of Reactive Oxygen Species

Contact Info

Product

Resources

About