DERA is the human deoxyribose phosphate aldolase and is involved in stress response

Salleron, Lisa; Magistrelli, Giovanni; Mary, Camille; Fischer, Nicolas; Bairoch, Amos Marc; Lane, Lydie

doi:10.1016/j.bbamcr.2014.09.007

Cited by 30 publications

(24 citation statements)

References 74 publications

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“…This included the enzyme deoxyribose‐phosphate aldolase (DERA, Tb927.7.5680). In HeLa cells, DERA is important for stress granule formation and interacts with the Y‐box binding protein YB‐1 (Salleron et al ., ). YB‐1 participates in a wide variety of DNA/RNA‐dependent events, including regulation of mRNA stability and translation.…”

Section: Resultsmentioning

confidence: 97%

Gene expression regulatory networks in Trypanosoma brucei: insights into the role of the mRNA‐binding proteome

Lueong

Merce

Fischer

et al. 2016

Molecular Microbiology

113

206

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Control of gene expression at the post-transcriptional level is essential in all organisms, and RNA-binding proteins play critical roles from mRNA synthesis to decay. To fully understand this process, it is necessary to identify the complete set of RNA-binding proteins and the functional consequences of the protein-mRNA interactions. Here, we provide an overview of the proteins that bind to mRNAs and their functions in the pathogenic bloodstream form of Trypanosoma brucei. We describe the production of a small collection of open-reading frames encoding proteins potentially involved in mRNA metabolism. With this ORFeome collection, we used tethering to screen for proteins that play a role in post-transcriptional control. A yeast two-hybrid screen showed that several of the discovered repressors interact with components of the CAF1/NOT1 deadenylation complex. To identify the RNA-binding proteins, we obtained the mRNA-bound proteome. We identified 155 high-confidence candidates, including many not previously annotated as RNA-binding proteins. Twenty seven of these proteins affected reporter expression in the tethering screen. Our study provides novel insights into the potential trypanosome mRNPs composition, architecture and function.

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Section: Resultsmentioning

confidence: 97%

Gene expression regulatory networks in Trypanosoma brucei: insights into the role of the mRNA‐binding proteome

Lueong

Merce

Fischer

et al. 2016

Molecular Microbiology

113

206

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“…Salmonella typhimurium , Klebsiella pneumoniae , Vibrio cholerae , and others ( Figure S12 ), show a high sequence identity (81% for V. cholerae and >94% identity for the others presented) with ec DERA, unlike human DERA with only 38% identity. 98 All of these pathogens (except V. cholerae ) have an identical C-terminal tail sequence. Since DERA plays a crucial role in microbial survival by participating in nucleotide catabolism and providing key metabolic intermediates such as acetaldehyde and G3P, it is considered to be a promising drug target against human pathogens.…”

Section: Discussionmentioning

confidence: 99%

Conformational Sampling of the Intrinsically Disordered C-Terminal Tail of DERA Is Important for Enzyme Catalysis

et al. 2018

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2-Deoxyribose-5-phosphate aldolase (DERA) catalyzes the reversible conversion of acetaldehyde and glyceraldehyde-3-phosphate into deoxyribose-5-phosphate. DERA is used as a biocatalyst for the synthesis of drugs such as statins and is a promising pharmaceutical target due to its involvement in nucleotide catabolism. Despite previous biochemical studies suggesting the catalytic importance of the C-terminal tyrosine residue found in several bacterial DERAs, the structural and functional basis of its participation in catalysis remains elusive because the electron density for the last eight to nine residues (i.e., the C-terminal tail) is absent in all available crystal structures. Using a combination of NMR spectroscopy and molecular dynamics simulations, we conclusively show that the rarely studied C-terminal tail of E. coli DERA (ecDERA) is intrinsically disordered and exists in equilibrium between open and catalytically relevant closed states, where the C-terminal tyrosine (Y259) enters the active site. Nuclear Overhauser effect distance restraints, obtained due to the presence of a substantial closed state population, were used to derive the solution-state structure of the ecDERA closed state. Real-time NMR hydrogen/deuterium exchange experiments reveal that Y259 is required for efficiency of the proton abstraction step of the catalytic reaction. Phosphate titration experiments show that, in addition to the phosphate-binding residues located near the active site, as observed in the available crystal structures, ecDERA contains previously unknown auxiliary phosphate-binding residues on the C-terminal tail which could facilitate in orienting Y259 in an optimal position for catalysis. Thus, we present significant insights into the structural and mechanistic importance of the ecDERA C-terminal tail and illustrate the role of conformational sampling in enzyme catalysis.

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“…The abundance of this purine nucleoside increased by an average of 4-fold after the incubation with hepatic EVs. Interestingly, purine nucleosides can be used by mammalian cells as an energy source to replenish ATP; there is growing evidence indicating that they exert a protective effect during stress conditions 23 24 25 26 . The proposed mechanism involves the pentose phosphate pathway and glycolysis; the sugar moieties of the nucleosides are converted to the molecules that can be used as an energy source.…”

Section: Discussionmentioning

confidence: 99%

Hepatocyte-secreted extracellular vesicles modify blood metabolome and endothelial function by an arginase-dependent mechanism

Royo

Moreno

Mleczko

et al. 2017

Sci Rep

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Hepatocytes release extracellular vesicles (EVs) loaded with signaling molecules and enzymes into the bloodstream. Although the importance of EVs in the intercellular communication is already recognized, the metabolic impact of the enzymes carried by these vesicles is still unclear. We evaluated the global effect of the enzymatic activities of EVs by performing untargeted metabolomic profiling of serum samples after their exposure to EVs. This approach revealed a significant change in the abundance of 94 serum metabolic signals. Our study shows that these vesicles modify the concentration of metabolites of different chemical nature including metabolites related to arginine metabolism, which regulates vascular function. To assess the functional relevance of this finding, we examined the levels of arginase-1 protein and its activity in the hepatic EVs carrying the exosomal markers CD81 and CD63. Remarkably, the arginase activity was also detected in EVs isolated from the serum in vivo, and this vesicular activity significantly increased under liver-damaging conditions. Finally, we demonstrated that EVs secreted by hepatocytes inhibited the acetylcholine-induced relaxation in isolated pulmonary arteries, via an arginase-dependent mechanism. In summary, our study demonstrates that the hepatocyte-released EVs are metabolically active, affecting a number of serum metabolites involved in oxidative stress metabolism and the endothelial function.

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DERA is the human deoxyribose phosphate aldolase and is involved in stress response

Cited by 30 publications

References 74 publications

Gene expression regulatory networks in Trypanosoma brucei: insights into the role of the mRNA‐binding proteome

Gene expression regulatory networks in Trypanosoma brucei: insights into the role of the mRNA‐binding proteome

Conformational Sampling of the Intrinsically Disordered C-Terminal Tail of DERA Is Important for Enzyme Catalysis

Hepatocyte-secreted extracellular vesicles modify blood metabolome and endothelial function by an arginase-dependent mechanism

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