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Teresa Sacadura Santos Silva
Assistant Researcher
Collaborator
Research Group
Structural Molecular Biology
Laboratório de Cristalografia de proteínas, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829 – 516 Caparica
212 948 300
- ext 10940
212 948 550
Research Interests
Research areas of interest are:

(1) Molybdenum enzymes and their Moco-binding proteins.

I have been working with several Mo enzymes form the xanthine oxidase family in order to understand the reaction mechanism of these enzymes upon substrate oxidation. Aldehyde oxidase (AO) has been implicated in the last couple of years on the metabolism of xenobiotics and its importance in drug clearance is major. In collaboration with Prof. S. Leimkhuler (U. Postam, Germany), I am currently refining the structure of human AO. Bacterial aldehyde oxidoreductases (AOR) have also been deeply studied as models for other members of the family of enzymes. AOR from Desulfovibrio gigas can be easily crystallized and high resolution data provides insights into putative reaction mechanisms. Several crystals structures have been determined at atomic resolution with unexpected results regarding substrate binding at the molybdenum active site. EPR, NMR, kinetic assays and X-ray crystallography have been used in a joint approach to derive a new reaction mechanism (manuscript in preparation), outcome of a strong collaboration with Prof. J.J.G. Moura (UNL, Portugal) and Dr. Pablo Gonzalez (UNL, Argentina). The work is part of a financed national project (PTDC/BIA-PRO/118377/2010 “Mammalian and Bacterial Aldehyde Oxidases: Structure, mechanism and insights into cofactor binding and protein maturation”).

(2) Protein crystallography applied to drug design.

Several project of drug design are under development where crystallography plays an important role in understanding the interaction between targets and compounds.

A. Nitric oxide synthases enzymes and interaction with putative radioactive probes. As a team member of another FCT financed project, PTDC/QUI-QUI/121752/2010, I am the crystallographer responsible for the determination of the crystal structures of nitric oxide synthase (NOS) bound to metal complexes, used for imaging purposes. The work has been developed in a collaborative basis with Dr. J. Galamba (ITN, Portugal) for early stage diagnosis of tumor growth.

B. Carbon monoxide molecules (CORMs) as putative drugs in inflammatory processes. The interaction of CORMs with serum proteins is of extreme importance since these are considered the key elements for bio-distribution and the aim of this project is to collect fundamental structural, functional and biological information regarding this interaction, hence providing the basis for the future design of more potent and safer CORMs. This project has emerged from a tight collaboration with the Prof. Carlos Romão (ITQB, Portugal) and the pharmaceutical company Alfama. Financial support is granted by FCT (PTDC/QUI-BIQ/117799/2010, “Protein interaction with CO Releasing Molecules (CORM)”).

C. Protease inhibitors. This is project derived from the collaboration with Dr. J. Spencer (Sussex U., UK), where several crystal structures of trypsin have been obtained with new synthesized compounds bound to the active site. Biological assays are currently under way showing the specificity of the design compounds and contributing for the development of a new family of inhibitors.



D. Recently I have been involved in the characterization of Cyclooxigenase-2 inhibitors complexes in order to understand selectivity. Protein expression and structure determination is going to be attempted in the next months. This work is part of a collaborative project with Dr. Maria Marques (UNL, REQUIMTE), financed by INSTRUCT.
Main publications
*** Jacopo Marangon, Hugo Correia, Carlos D. Brondino, José J.G. Moura, Maria J. Romão, Pablo J. González, Teresa Santos-Silva*, “Hydrogen peroxide-inhibited forms of Desulfovibrio gigas Aldehyde Oxidoreductase”, PlosOne, accepted.

*** Teresa Santos-Silva*, Abhik Mukhopadhyay, João D. Seixas, Gonçalo J. L. Bernardes, Carlos C. Romão, and Maria J. Romão, “Towards Improved Therapeutic CORMs: Understanding the Reactivity of CORM-3 with proteins”, Curr Med Chem (2011), 18, 3361-6. (Review).

*** Teresa Santos-Silva, Abhik Mukhopadhyay, João D. Seixas, Gonçalo J. L. Bernardes, Carlos C. Romão and Maria J. Romão, “CORM-3 Reactivity toward Proteins: The Crystal Structure of a Ru(II)Dicarbonyl-Lysozyme Complex”, JACS, (2011), 133, 1192-1195.

*** Teresa Santos-Silva, Felix Ferroni, Anders Thapper, Jacopo Marangon, Pablo J. Gonzalez, Alberto Rizzi, José J.G. Moura, Maria João Romão and Carlos Brondino, “Kinetic, Structural, and EPR Studies Reveal that Aldehyde Oxidoreductase from Desulfovibrio gigas Does Not Need a Sulfido Ligand for Catalysis and Give Evidence for a Direct Mo-C Interaction in a Biological System”, JACS, (2009), 131, 7990-99.