Crystal structure of an Fe-S cluster-containing fumarate hydratase enzyme from Leishmania major reveals a unique protein fold

Autor(es)

Feliciano, Patricia R. ; Drennan, Catherine L. ; Cristina Nonato, M.

• Tipo de documento: Artigo Científico
• Fonte: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 113, n. 35, p. 6-pg., 2016-08-30.

Resumo

Fumarate hydratases (FHs) are essential metabolic enzymes grouped into two classes. Here, we present the crystal structure of a class I FH, the cytosolic FH from Leishmania major, which reveals a previously undiscovered protein fold that coordinates a catalytically essential [4Fe-4S] cluster. Our 2.05 angstrom resolution data further reveal a dimeric architecture for this FH that resembles a heart, with each lobe comprised of two domains that are arranged around the active site. Besides the active site, where the substrate S-malate is bound bidentate to the unique iron of the [4Fe-4S] cluster, other binding pockets are found near the dimeric enzyme interface, some of which are occupied bymalonate, shown here to be a weak inhibitor of this enzyme. Taken together, these data provide a framework both for investigations of the class I FH catalytic mechanism and for drug design aimed at fighting neglected tropical diseases. (AU)

• Processo FAPESP: 08/08262-6 - Caracterização cinética, estrutural e funcional dos genes LmjF24.0320. e LmjF29.1960 que codificam a enzima fumarato hidratase em Leishmania major
• Beneficiário: Maria Cristina Nonato
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/19674-6 - Determinação da estrutura cristalográfica das isoformas fumarato hidratase de Leishmania major
• Beneficiário: Patrícia Rosa Feliciano
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado
• Processo FAPESP: 09/10454-3 - Estudos da correlação entre estrutura e função da enzima fumarato hidratase em Leishmania major
• Beneficiário: Patrícia Rosa Feliciano
• Modalidade de apoio: Bolsas no Brasil - Doutorado