Silvia Marín

Universitat de Barcelona

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Marta Cascante

Universitat de Barcelona

Pedro de Atauri

Universitat de Barcelona

Vitaly A. Selivanov

Universitat de Barcelona

Josep J. Centelles

Universitat de Barcelona

Rafael P. Mellado

Centro Nacional de Biotecnología

Jorge A. R. Salvador

University of Coimbra

Carles Foguet

Universitat de Barcelona

Timothy M. Thomson

Institut de Biologia Molecular de Barcelona

Sonia Gullón

Centro Nacional de Biotecnología

László G. Boros

Vrije Universiteit Amsterdam

Cooperative Institutions

Universitat de Barcelona

173

Instituto de Salud Carlos III

Consorci Institut D'Investigacions Biomediques August Pi I Sunyer

Consejo Superior de Investigaciones Científicas

Centro de Investigación Biomédica en Red

Hospital Clínic de Barcelona

Universitat Autònoma de Barcelona

Universidad Autónoma de Madrid

Hospital Sant Joan de Déu Barcelona

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

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Four thiol-oxidoreductases involved in the formation of disulphide bonds in the Streptomyces lividans TK21 secretory proteins

Microbial Cell Factories (2019)

Sonia Gullón Silvia Marín Rafael P. Mellado

Bacterial secretory proteins often require the formation of disulphide bonds outside the cell to acquire an active conformation. Thiol-disulphide oxidoreductases are enzymes that catalyse the formation of disulphide bonds. The bacterium Streptomyces lividans is a well-known host for the efficient secretion of overproduced homologous and heterologous secretory proteins of industrial application. Therefore, the correct conformation of these extracellular proteins is of great importance when engineering that overproduction.We have identified four acting thiol-disulphide oxidoreductases (TDORs) in S. lividans TK21, mutants in all TDOR candidates affect the secretion and activity of the Sec-dependent alpha-amylase, which contains several disulphide bonds, but the effect was more drastic in the case of the Sli-DsbA deficient strain. Thus, the four TDOR are required to obtain active alpha-amylase. Additionally, only mutations in Sli-DsbA and Sli-DsbB affect the secretion and activity of the Tat-dependent agarase, which does not form a disulphide bond, when it is overproduced. This suggests a possible role of the oxidised Sli-DsbA as a chaperone in the production of active agarase.Enzymes involved in the production of the extracellular mature active proteins are not fully characterised yet in Streptomyces lividans. Our results suggest that the role of thiol-disulphide oxidoreductases must be considered when engineering Streptomyces strains for the overproduction of homologous or heterologous secretory proteins of industrial application, irrespective of their secretion route, in order to obtain active, correctly folded proteins.

Overproduction

DsbA

Heterologous

Secretory protein

Thiol

Heterologous expression

Protein superfamily

10.1186/s12934-019-1175-0

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Citations (2)

Epigenetic loss of the endoplasmic reticulum–associated degradation inhibitor SVIP induces cancer cell metabolic reprogramming

JCI Insight (2019)

Pere Llinàs‐Arias Margalida Rosselló-Tortella Paula López-Serra Montserrat Pérez-Salvia Fernando Setién

The endoplasmic reticulum (ER) of cancer cells needs to adapt to the enhanced proteotoxic stress associated with the accumulation of unfolded, misfolded, and transformation-associated proteins. One way by which tumors thrive in the context of ER stress is by promoting ER-associated degradation (ERAD), although the mechanisms are poorly understood. Here, we show that the small p97/VCP-interacting protein (SVIP), an endogenous inhibitor of ERAD, undergoes DNA hypermethylation–associated silencing in tumorigenesis to achieve this goal. SVIP exhibits tumor suppressor features and its recovery is associated with increased ER stress and growth inhibition. Proteomic and metabolomic analyses show that cancer cells with epigenetic loss of SVIP are depleted in mitochondrial enzymes and oxidative respiration activity. This phenotype is reverted upon SVIP restoration. The dependence of SVIP-hypermethylated cancer cells on aerobic glycolysis and glucose was also associated with sensitivity to an inhibitor of the glucose transporter GLUT1. This could be relevant to the management of tumors carrying SVIP epigenetic loss, because these occur in high-risk patients who manifest poor clinical outcomes. Overall, our study provides insights into how epigenetics helps deal with ER stress and how SVIP epigenetic loss in cancer may be amenable to therapies that target glucose transporters.

Endoplasmic-reticulum-associated protein degradation

Reprogramming

10.1172/jci.insight.125888

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Citations (22)

Design, Synthesis, and Biological Evaluation of Novel Urea-Containing Carnosic Acid Derivatives with Anticancer Activity

International Journal of Molecular Sciences (2024)

Sara Moura Silvia Marín Ismael Rufino Rita C. Guedes Marta Cascante

A series of novel carnosic acid 1 derivatives incorporating urea moieties at the C-20 position was synthesized and evaluated for their antiproliferative activity against the HCT116 colorectal cancer cell line. Most derivatives demonstrated enhanced antiproliferative activity compared to that of carnosic acid 1. The most promising derivatives were tested in other colorectal cancer cell lines (SW480, SW620, and Caco-2), melanoma (A375), and pancreatic cancer (MiaPaca-2). Derivative 14 consistently demonstrated the highest activity across all tested cancer cell lines, showing selectivity for cancer cells over normal cells. Further investigation of the mechanism of action in SW480 cells revealed that compound 14 induced cell cycle arrest at the G0/G1 phase by downregulating CDK4 and CDK6. Molecular docking studies revealed that compound 14 established several interactions with key residues in the active site of CDK6. Additionally, compound 14 also reduced ROS production. In summary, our results strongly indicate that compound 14 has potential as a lead compound in the development of innovative anticancer drugs.

Carnosic acid

Cyclin-dependent kinase 6

Lead compound

10.3390/ijms252413332

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Alteraciones del metabolismo fosfocálcico

Anales de Pediatría Continuada (2009)

Silvia Marín Rubén Díaz

10.1016/s1696-2818(09)71117-5

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Citations (0)

Table S1 from Functional identification of a Streptomyces lividans FKBP-like protein involved in the folding of overproduced secreted proteins.

Figshare (2019)

Rebeca L. Vicente Silvia Marín Jósé R. Valverde Carmen Palomino Rafael P. Mellado

Proteins analysed by the Selected Reaction Monitoring experiment (SRM/MRM)

FKBP

Identification

Table (database)

Folding (DSP implementation)

10.6084/m9.figshare.9971627

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Effect of the herbicide glyphosate on glyphosate‐tolerant maize rhizobacterial communities: a comparison with pre‐emergency applied herbicide consisting of a combination of acetochlor and terbuthylazine

Environmental Microbiology (2010)

Jorge Barriuso Silvia Marín Rafael P. Mellado

Summary A comparison was made of the effect of glyphosate (Roundup ® Plus), a post‐emergency applied herbicide, and of Harness ® GTZ, a pre‐emergency applied herbicide, on the rhizobacterial communities of genetically modified NK603 glyphosate‐tolerant maize. The potential effect was monitored by direct amplification, cloning and sequencing of soil DNA encoding 16S rRNA, rhizobacterial DNA hybridization to commercially available genome‐wide microarrays from the soil bacterium Streptomyces coelicolor , and high‐throughput DNA pyrosequencing of the bacterial DNA coding for 16S rRNA hypervariable V6 region. The results obtained strongly suggest that both herbicides do in fact affect the maize rhizobacterial communities, glyphosate being, to a great extent, the environmentally less aggressive herbicide.

Pyrosequencing

10.1111/j.1462-2920.2009.02146.x

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Citations (64)

B-261 Comparing Selectivity of Core-Shell and Modified Fully Porous HPLC Columns to Optimize Separation of 3 Classes of 47 TDM Analytes

Clinical Chemistry (2024)

Sumona Huq Silvia Marín G Orquera-Aguirre

Abstract Background Therapeutic drug monitoring (TDM) research requires quantitation within narrow concentration ranges to distinguish between acceptable and toxic drug concentrations that could trigger potential adverse effects. In this communication a robust analytical LC-MS/MS method was developed for proper identification and measurement of a large TDM panel. This panel was comprised of three categories: 22 antidepressants, 14 antipsychotics and 11 anticonvulsants for a total of 47 analytes. A parallel comparison of two LC columns packed with modified fully porous and core-shell particles was conducted to determine the best columns and conditions for fast LC separation while achieving baseline resolution of critical isobaric compounds in each drug class. Methods In this study, a fully porous, thermally modified Luna Omega 3.0 μm Polar C18, 50x3 mm was compared against a core-shell Kinetex 2.6 μm Biphenyl 50x3.0 mm column. The Biphenyl column used 0.1 % formic acid in water and methanol as mobile phase A and B respectively for gradient elution. The Luna Omega column showed affinity for a buffered mobile phase. Therefore, 2 mM ammonium acetate in water and methanol were used as mobile phase A and B, respectively. Additionally, an Agilent 1290 Infinity series LC system was employed with a SCIEX 6500 QTRAP mass spectrometer and ESI for MS detection. Results The anticonvulsant panel represents analytes with a vast range of polarity and chemical properties featuring zwitterionic, weakly acidic, and neutral compounds. The preferential affinity of these compounds was highly noticeable when using the Luna Omega column and revealed the superiority of this fully porous column for baseline separation of the critical isobaric anticonvulsant analyte pair, Oxcarbazepine and Carbamazepine epoxide. In contrast, the unique selectivity of the core-shell particles renders longer retention and better separation of the isobaric compounds, Venlafaxine and amitriptyline, and Mirtazapine and N-desmethyldoxepin in the antidepressant panel. The Biphenyl column was also better for the separation of antipsychotics, where most of the analytes are basic and relatively more hydrophobic in nature. Furthermore, the fully porous column failed to differentiate between the isobaric antipsychotic analogs, Norclozapine and Olanzapine. The chromatographic run time for the above scenarios was 5 minutes, which includes a 1.5-minute column equilibration. Lastly, for the antidepressant panel, both columns showed successful separation of the two isobaric pairs, however, higher MS signal response and wider separation of the isobaric pairs was observed with the Biphenyl column. Conclusions The modified fully porous Luna Omega particle enhanced the selectivity and retention of polar and neutral analytes, making it suitable for analysis of the more challenging anticonvulsant panel. The high efficiency Kinetex Biphenyl column demonstrates better separation of antipsychotics and antidepressant panels with good resolution for the critical isobaric pairs.

10.1093/clinchem/hvae106.618

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The NADPH oxidase NOX4 regulates lipid metabolism, which contributes to its tumour suppressor actions in hepatocellular carcinoma

Journal of Hepatology (2020)

Irene Peñuelas‐Haro Esther Bertrán Eva Crosas‐Molist Fulvio Santacatterina Silvia Marín

NOX4

10.1016/s0168-8278(20)30708-x

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Exploratory and confirmatory analysis to investigate the presence of vaginal metabolome expression of microbial invasion of the amniotic cavity in women with preterm labor using high-performance liquid chromatography

American Journal of Obstetrics and Gynecology (2020)

Ibrahim H. Polat Silvia Marín José Ríos Marta Larroya Ana Belén Sánchez García

Metabolome

Exploratory analysis

10.1016/j.ajog.2020.07.040

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Citations (10)

TKTL1 Knockdown Impairs Hypoxia-Induced Glucose-6-phosphate Dehydrogenase and Glyceraldehyde-3-phosphate Dehydrogenase Overexpression

International Journal of Molecular Sciences (2022)

Inês Baptista Effrosyni Karakitsou Jean‐Baptiste Cazier Ulrich L. Günther Silvia Marín

Increased expression of transketolase (TKT) and its isoform transketolase-like-1 (TKTL1) has been related to the malignant leukemia phenotype through promoting an increase in the non-oxidative branch of the pentose phosphate pathway (PPP). Recently, it has also been described that TKTL1 can have a role in survival under hypoxic conditions and in the acquisition of radio resistance. However, TKTL1's role in triggering metabolic reprogramming under hypoxia in leukemia cells has never been characterized. Using THP-1 AML cells, and by combining metabolomics and transcriptomics techniques, we characterized the impact of TKTL1 knockdown on the metabolic reprogramming triggered by hypoxia. Results demonstrated that TKTL1 knockdown results in a decrease in TKT, glucose-6-phosphate dehydrogenase (G6PD) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activities and impairs the hypoxia-induced overexpression of G6PD and GAPDH, all having significant impacts on the redox capacity of NADPH- and NADH-related cells. Moreover, TKTL1 knockdown impedes hypoxia-induced transcription of genes encoding key enzymes and transporters involved in glucose, PPP and amino acid metabolism, rendering cells unable to switch to enhanced glycolysis under hypoxia. Altogether, our results show that TKTL1 plays a key role in the metabolic adaptation to hypoxia in THP-1 AML cells through modulation of G6PD and GAPDH activities, both regulating glucose/glutamine consumption and the transcriptomic overexpression of key players of PPP, glucose and amino acids metabolism.

Transketolase

Glyceraldehyde 3-phosphate dehydrogenase

10.3390/ijms23073574

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Citations (11)