Almudena Pino-Ángeles

Bicyclic Derivatives of l-Idonojirimycin as Pharmacological Chaperones for Neuronopathic Forms of Gaucher Disease

New human β-glucocerebrosidase (GCase) ligands with rigid 1,6-anhydro-β-L-idonojirimycin cores have been designed with the aid of molecular modeling. Efficient pharmacological chaperones for the L444P (trafficking-incompetent) mutant GCase enzyme associated with type 2 and 3 Gaucher disease (GD) were identified.

Structural features of mammalian histidine decarboxylase reveal the basis for specific inhibition

For a long time the structural and molecular features of mammalian histidine decarboxylase (EC 4.1.1.22), the enzyme that produces histamine, have evaded characterization. We overcome the experimental problems for the study of this enzyme by using a computer‐based modelling and simulation approach, and have now the conditions to use histidine decarboxylase as a target in histamine pharmacology. In this review, we present the recent (last 5 years) advances in the structure–function relationship of histidine decarboxylase and the strategy for the discovery of new drugs.

Histamine: an undercover agent in multiple rare diseases?

Histamine is a biogenic amine performing pleiotropic effects in humans, involving tasks within the immune and neuroendocrine systems, neurotransmission, gastric secretion, cell life and death, and development. It is the product of the histidine decarboxylase activity, and its effects are mainly mediated through four different G‐protein coupled receptors. Thus, histamine‐related effects are the results of highly interconnected and tissue‐specific signalling networks. Consequently, alterations in histamine‐related factors could be an important part in the cause of multiple rare/orphan diseases. Bearing this hypothesis in mind, more than 25 rare diseases related to histamine physiopathology have been identified using a computationally assisted text mining approach. These newly integrated data will provide insight to elucidate the molecular causes of these rare diseases. The data can also help in devising new intervention strategies for personalized medicine for multiple rare diseases.

Molecular characterization of five patients with homocystinuria due to severe methylenetetrahydrofolate reductase deficiency

Urreizti R, Moya‐García AA, Pino‐ Ángeles A, Cozar M, Langkilde A, Fanhoe U, Esteves C, Arribas J, Vilaseca MA, Pérez‐Dueñas B, Pineda M, González V, Artuch R, Baldellou, A, Vilarinho L, Fowler B, Ribes A, Sánchez‐Jiménez F, Grinberg D, Balcells S. Molecular characterization of five patients with homocystinuria due to severe MTHFR deficiency.

Structural Perspective on the Direct Inhibition Mechanism of EGCG on Mammalian Histidine Decarboxylase and DOPA Decarboxylase

Histidine decarboxylase (HDC) and l-aromatic amino acid decarboxylase (DDC) are homologous enzymes that are responsible for the synthesis of important neuroactive amines related to inflammatory, neurodegenerative, and neoplastic diseases. Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, has been shown to target histamine-producing cells and to promote anti-inflammatory, antitumor, and antiangiogenic effects. Previous experimental work has demonstrated that EGCG has a direct inhibitory effect on both HDC and DDC. In this study, we investigated the binding modes of EGCG to HDC and DDC as a first step for designing new polyphenol-based HDC/DDC-specific inhibitors.

Substrate uptake and protein stability relationship in mammalian histidine decarboxylase.

There is some evidence linking the substrate entrance in the active site of mammalian histidine decarboxylase and an increased stability against proteolytic degradation. In this work, we study the basis of this relationship by means of protein structure network analysis and molecular dynamics simulations. We find that the substrate binding to the active site influences the conformation of a flexible region sensible to proteolytic degradation and observe how formation of the Michaelis–Menten complex increases stability in the conformation of this region. Proteins 2010.

Candidate gene study of TRAIL and TRAIL receptors: association with response to interferon beta therapy in multiple sclerosis patients.

TRAIL and TRAIL Receptor genes have been implicated in Multiple Sclerosis pathology as well as in the response to IFN beta therapy. The objective of our study was to evaluate the association of these genes in relation to the age at disease onset (AAO) and to the clinical response upon IFN beta treatment in Spanish MS patients. We carried out a candidate gene study of TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 genes. A total of 54 SNPs were analysed in 509 MS patients under IFN beta treatment, and an additional cohort of 226 MS patients was used to validate the results. Associations of rs1047275 in TRAILR-2 and rs7011559 in TRAILR-4 genes with AAO under an additive model did not withstand Bonferroni correction. In contrast, patients with the TRAILR-1 rs20576-CC genotype showed a better clinical response to IFN beta therapy compared with patients carrying the A-allele (recessive model: p = 8.88×10−4, pc = 0.048, OR = 0.30). This SNP resulted in a non synonymous substitution of Glutamic acid to Alanine in position 228 (E228A), a change previously associated with susceptibility to different cancer types and risk of metastases, suggesting a lack of functionality of TRAILR-1. In order to unravel how this amino acid change in TRAILR-1 would affect to death signal, we performed a molecular modelling with both alleles. Neither TRAIL binding sites in the receptor nor the expression levels of TRAILR-1 in peripheral blood mononuclear cell subsets (monocytes, CD4+ and CD8+ T cells) were modified, suggesting that this SNP may be altering the death signal by some other mechanism. These findings show a role for TRAILR-1 gene variations in the clinical outcome of IFN beta therapy that might have relevance as a biomarker to predict the response to IFN beta in MS.

New structural insights to help in the search for selective inhibitors of mammalian pyridoxal 5’-phosphate-dependent histidine decarboxylase

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AMMO-Prot: amine system project 3D-model finder

BackgroundAmines are biogenic amino acid derivatives, which play pleiotropic and very important yet complex roles in animal physiology. For many other relevant biomolecules, biochemical and molecular data are being accumulated, which need to be integrated in order to be effective in the advance of biological knowledge in the field. For this purpose, a multidisciplinary group has started an ontology-based system named the Amine System Project (ASP) for which amine-related information is the validation bench.ResultsIn this paper, we describe the Ontology-Based Mediator developed in the Amine System Project (http://asp.uma.es) using the infrastructure of Semantic Directories, and how this system has been used to solve a case related to amine metabolism-related protein structures.ConclusionsThis infrastructure is used to publish and manage not only ontologies and their relationships, but also metadata relating to the resources committed with the ontologies. The system developed is available at http://asp.uma.es/WebMediator.

Enzymology in Histamine Biogenesis

Histamine is a multifunctional biogenic amine with relevant roles in intercellular communication, inflammatory processes and many emergent pathologies. Histamine biosynthesis depends on the single decarboxylation of the amino acid histidine. In Gram-negative bacteria and animals, this reaction is carried out by a PLP-dependent histidine decarboxylase activity (HDC, EC 4.1.1.22), an enzyme that has been rather difficult to experimentally characterize. Interest in the mammalian HDC has increased due to recent findings on physiological consequences observed in HDC knockout animals. During the last few years, important advances have been made in the study of the structure/function relationship that explains its catalytic behaviour, mainly through a combination of both biophysical and biocomputational approaches. This chapter provides a comprehensive review of the current knowledge on this topic and how this knowledge could be extracted, which could give insights to characterize other unstable and minor proteins with physiopathological relevance. A model for the structure of the enzyme allowed us to understand its topology and to locate the catalytic environment, which was validated by direct-mutagenesis. Hybrid quantum mechanics and molecular mechanics simulations made it possible to understand the decarboxylation reaction at atomic level, as well as the conformational changes of the enzyme caused by the substrate binding. At this point, the search for and design of new and more selective modulators of the activity are possible. We also point out some important outstanding problems: (i) the exact role of the carboxy-terminal portion of the primary translation product; (ii) the putative binding proteins that can explain several intracellular features deduced for this enzyme; and (iii) the need for a deeper comparison to the unsolved PLP-dependent bacterial counterpart and other homologous enzymes.