Eduardo Salido

Hospital Universitario de Canarias

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Armando Torres

The Royal Melbourne Hospital

ÁL

Ángel L. Pey

Universidad de Granada

Domingo Hernández

Hospital Universitario de Canarias

Larry J. Shapiro

Delray Medical Center

José Manuel González‐Posada

Hospital Universitario de Canarias

Vı́ctor de Lorenzo

Centro Nacional de Biotecnología

Esteban Porrini

Universidad de La Laguna

Noel Mesa‐Torres

Universidad de Granada

Enrique Quintero

Hospital Universitario de Canarias

Vicente Medina‐Arana

Hospital Universitario de Canarias

Cooperative Institutions

Hospital Universitario de Canarias

259

Universidad de La Laguna

183

Instituto de Salud Carlos III

129

Consejo Superior de Investigaciones Científicas

Centro de Investigación Biomédica en Red

Inserm

Universidad Autónoma de Madrid

Hospital Universitario Virgen de la Arrixaca

Centre for Biomedical Network Research on Rare Diseases

Universidad de Navarra

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Naturally-Occurring Rare Mutations Cause Mild to Catastrophic Effects in the Multifunctional and Cancer-Associated NQO1 Protein

Journal of Personalized Medicine (2020)

Juan Luis Pacheco‐García Mario Cano‐Muñoz Isabel Sánchez-Ramos Eduardo Salido Ángel L. Pey

The functional and pathological implications of the enormous genetic diversity of the human genome are mostly unknown, primarily due to our unability to predict pathogenicity in a high-throughput manner. In this work, we characterized the phenotypic consequences of eight naturally-occurring missense variants on the multifunctional and disease-associated NQO1 protein using biophysical and structural analyses on several protein traits. Mutations found in both exome-sequencing initiatives and in cancer cell lines cause mild to catastrophic effects on NQO1 stability and function. Importantly, some mutations perturb functional features located structurally far from the mutated site. These effects are well rationalized by considering the nature of the mutation, its location in protein structure and the local stability of its environment. Using a set of 22 experimentally characterized mutations in NQO1, we generated experimental scores for pathogenicity that correlate reasonably well with bioinformatic scores derived from a set of commonly used algorithms, although the latter fail to semiquantitatively predict the phenotypic alterations caused by a significant fraction of mutations individually. These results provide insight into the propagation of mutational effects on multifunctional proteins, the implementation of

Loss function

Exome

10.3390/jpm10040207

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Citations (9)

Exploiting the passenger ACO1-deficiency arising from 9p21 deletions to kill T-cell lymphoblastic neoplasia cells

Carcinogenesis (2019)

Laura González-Sánchez María Cobos-Fernández Pilar López‐Nieva María Villa‐Morales Kostas Stamatakis

Precursor T-cell lymphoblastic neoplasms are aggressive malignancies in need for more effective and specific therapeutic treatments. A significant fraction of these neoplasms harbor deletions on the locus 9p21, targeting the tumor suppressor CDKN2A but also deleting the aconitase 1 (ACO1) gene, a neighboring housekeeping gene involved in cytoplasm and mitochondrial metabolism. Here we show that reducing the aconitase activity with fluorocitrate decreases the viability of T-cell lymphoblastic neoplasia cells in correlation to the differential aconitase expression. The consequences of the treatment were evidenced in vitro using T-cell lymphoblastic neoplasia cell lines exhibiting 9p21 deletions and variable levels of ACO1 expression or activity. Similar results were observed in melanoma cell lines, suggesting a true potential for fluorocitrate in different cancer types. Notably, ectopic expression of ACO1 alleviated the susceptibility of cell lines to fluorocitrate and, conversely, knockdown experiments increased susceptibility of resistant cell lines. These findings were confirmed in vivo on athymic nude mice by using tumor xenografts derived from two T-cell lines with different levels of ACO1. Taken together, our results indicate that the non-targeted ACO1 deficiency induced by common deletions exerts a collateral cellular lethality that can be used as a novel therapeutic strategy in the treatment of several types of cancer.

10.1093/carcin/bgz185

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The Role of Protein Denaturation Energetics and Molecular Chaperones in the Aggregation and Mistargeting of Mutants Causing Primary Hyperoxaluria Type I

PLoS ONE (2013)

Noel Mesa‐Torres Israel Fabelo-Rosa Débora Riverol Cristina Yunta Armando Albert

Primary hyperoxaluria type I (PH1) is a conformational disease which result in the loss of alanine:glyoxylate aminotransferase (AGT) function. The study of AGT has important implications for protein folding and trafficking because PH1 mutants may cause protein aggregation and mitochondrial mistargeting. We herein describe a multidisciplinary study aimed to understand the molecular basis of protein aggregation and mistargeting in PH1 by studying twelve AGT variants. Expression studies in cell cultures reveal strong protein folding defects in PH1 causing mutants leading to enhanced aggregation, and in two cases, mitochondrial mistargeting. Immunoprecipitation studies in a cell-free system reveal that most mutants enhance the interactions with Hsc70 chaperones along their folding process, while in vitro binding experiments show no changes in the interaction of folded AGT dimers with the peroxisomal receptor Pex5p. Thermal denaturation studies by calorimetry support that PH1 causing mutants often kinetically destabilize the folded apo-protein through significant changes in the denaturation free energy barrier, whereas coenzyme binding overcomes this destabilization. Modeling of the mutations on a 1.9 Å crystal structure suggests that PH1 causing mutants perturb locally the native structure. Our work support that a misbalance between denaturation energetics and interactions with chaperones underlie aggregation and mistargeting in PH1, suggesting that native state stabilizers and protein homeostasis modulators are potential drugs to restore the complex and delicate balance of AGT protein homeostasis in PH1.

Denaturation (fissile materials)

Chaperone (clinical)

10.1371/journal.pone.0071963

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Citations (55)

Constitutive no synthase isoforms accounts for gastric mucosal nitric oxide overproduction in uremic rats

Gastroenterology (1995)

Rats Barrios M Fern indez Eduardo Salido I Bosch E Ouintero

Overproduction

Uremic Toxins

10.1016/0016-5085(95)23746-1

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Epigenomic and transcriptional profiling identifies impaired glyoxylate detoxification in NAFLD as a risk factor for hyperoxaluria

Cell Reports (2021)

Kathrin Gianmoena Nina Gasparoni Adelina Jashari Philipp Gabrys Katharina Grgas

Epigenetic modifications (e.g. DNA methylation) in NAFLD and their contribution to disease progression and extrahepatic complications are poorly explored. Here, we use an integrated epigenome and transcriptome analysis of mouse NAFLD hepatocytes and identify alterations in glyoxylate metabolism, a pathway relevant in kidney damage via oxalate release-a harmful waste product and kidney stone-promoting factor. Downregulation and hypermethylation of alanine-glyoxylate aminotransferase (Agxt), which detoxifies glyoxylate, preventing excessive oxalate accumulation, is accompanied by increased oxalate formation after metabolism of the precursor hydroxyproline. Viral-mediated Agxt transfer or inhibiting hydroxyproline catabolism rescues excessive oxalate release. In human steatotic hepatocytes, AGXT is also downregulated and hypermethylated, and in NAFLD adolescents, steatosis severity correlates with urinary oxalate excretion. Thus, this work identifies a reduced capacity of the steatotic liver to detoxify glyoxylate, triggering elevated oxalate, and provides a mechanistic explanation for the increased risk of kidney stones and chronic kidney disease in NAFLD patients.

Epigenome

10.1016/j.celrep.2021.109526

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Citations (39)

Hematopoietic Prostaglandin D Synthase Suppresses Intestinal Adenomas inApcMin/+ Mice

Cancer Research (2007)

Jae Man Park Yoshihide Kanaoka Naomi Eguchi Kosuke Aritake Sava Grujic

Abstract Aspirin and other nonsteroidal anti-inflammatory drugs prevent some cases of colon cancer by inhibiting prostaglandin (PG) synthesis. PGE2 promotes colon neoplasia, as shown by knockout mouse studies on enzymes and receptors in the PG cascade. A few experiments 20 to 30 years ago suggested that PGD2 may suppress tumors, but a role for biosynthetic enzymes for PGD2 in tumor development has not been studied. We report here that disruption of the gene for hematopoietic PGD synthase in ApcMin/+ mice led to ∼50% more intestinal adenomas compared with controls. Tumor size was not affected. By immunohistochemistry, we detected hematopoietic PGD synthase mainly in macrophages and monocytes of the gut mucosa. The mean number of tumors did not increase with knockout of the gene for the lipocalin type of the enzyme, which is not produced in the intestine. On the other hand, ApcMin/+ mice with transgenic human hematopoietic PGD synthase tended to have 80% fewer intestinal adenomas. The transgene produced high mRNA levels (375-fold over endogenous). There was a suggestion of higher urinary excretion of 11β-PGF2α and a lower excretion of a PGE2 metabolite in transgenic mice, but differences (30–40%) were not statistically significant. The results support an interpretation that hematopoietic PGD synthase controls an inhibitory effect on intestinal tumors. Further studies will be needed to prove possible mechanisms, such as routing of PG production away from protumorigenic PGE2 or inhibition of the nuclear factor-κB cascade by PGD2 metabolites. [Cancer Res 2007;67(3):881–9]

Prostaglandin D2

10.1158/0008-5472.can-05-3767

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Citations (58)

New salicylic acid derivatives, double inhibitors of glycolate oxidase and lactate dehydrogenase, as effective agents decreasing oxalate production

European Journal of Medicinal Chemistry (2022)

María Dolores Moya-Garzón Barbara Rodriguez-Rodriguez Cristina Martín-Higueras Francisco Franco-Montalbán Miguel X. Fernandes

The synthesis and biological evaluation of double glycolate oxidase/lactate dehydrogenase inhibitors containing a salicylic acid moiety is described. The target compounds are obtained in an easily scalable two-step synthetic procedure. These compounds showed low micromolar IC50 values against the two key enzymes in the metabolism of glyoxylate. Mechanistically they behave as noncompetitive inhibitors against both enzymes and this fact is supported by docking studies. The biological evaluation also includes in vitro and in vivo assays in hyperoxaluric mice. The compounds are active against the three types of primary hyperoxalurias. Also, possible causes of adverse effects, such as cyclooxygenase inhibition or renal toxicity, have been studied and discarded. Altogether, this makes this chemotype with drug-like structure a good candidate for the treatment of primary hyperoxalurias.

Docking (animal)

10.1016/j.ejmech.2022.114396

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Citations (14)

Lactate dehydrogenase A inhibitors with a 2,8-dioxabicyclo[3.3.1]nonane scaffold: A contribution to molecular therapies for primary hyperoxalurias

Bioorganic Chemistry (2022)

Alfonso Alejo‐Armijo Cristina Cuadrado Joaquı́n Altarejos Miguel X. Fernandes Eduardo Salido

Primary hyperoxaluria

10.1016/j.bioorg.2022.106127

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Citations (15)

TNF +250 polymorphism and hyperdynamic state in cardiac surgery with extracorporeal circulation

Interactive Cardiovascular and Thoracic Surgery (2008)

J Iribarren Fernando Martínez‐Sagasti Juan José Jiménez M Brouard Eduardo Salido

We have investigated genetic and clinical factors associated with hyperdynamic state (HS) after heart surgery with extracorporeal circulation (ECC). We performed a prospective cohort study of consecutive patients who underwent elective heart surgery with ECC. HS was defined as hyperthermia (>38 °C), cardiac index (CI) >3.5 l/min/m2 and systemic vascular resistance index (SVRI) <1600 dynes·s/cm5·m2. The study included demographic variables, gene polymorphisms A/G of tumor necrosis factor-beta (TNFβ+250), G/A-1082 of interleukin-10 (IL-10), polymorphism of interleukin-1 receptor antagonist (IL-1ra), comorbidity, type of surgery, serum levels of interleukin-6 (IL-6), and postoperative course. We used Pearson χ2 or Fisher exact test, and Student t-test for univariate analysis, with forward stepwise logistic regression for multivariate adjustment. Eighty patients were studied, of whom 22 (27.5%) developed HS. The presence of allele G of TNFβ+250 polymorphism was associated with an increased incidence of HS (68% vs. 37%; P=0.011). In the multivariate analysis, a longer duration of ECC, and the presence of the G allele, were associated with the development of HS. The G allele of TNFβ+250 polymorphism, and prolonged extracorporeal circuit times, may favor the development of a hyperdynamic state after heart surgery with ECC.

Extracorporeal circulation

Cardiac index

Univariate analysis

10.1510/icvts.2008.177501

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Citations (4)

Restored glyoxylate metabolism after AGXT gene correction and direct reprogramming of primary hyperoxaluria type 1 fibroblasts

iScience (2024)

Virginia Nieto-Romero Aida García-Torralba Andrea Molinos-Vicente Francisco Moya Sandra Rodríguez

Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder characterized by oxalate overproduction in the liver, resulting in renal damage. It is caused by mutations in the

Primary hyperoxaluria

Overproduction

Reprogramming

10.1016/j.isci.2024.109530

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Citations (4)