Crystal Structures of Fumarate Hydratases from Leishmania major in a Complex with Inhibitor 2-Thiomalate

Author(s)

Feliciano, Patricia R. ^{[1, 2, 3, 4]} ; Drennan, Catherine L. ^{[1, 2, 4]} ; Nonato, Maria Cristina ^[3]

Affiliation

^[1] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 - USA

^[2] MIT, Dept Chem, Cambridge, MA 02139 - USA

^[3] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Lab Cristalog Prot, BR-14040903 Sao Paulo - Brazil

^[4] MIT, Dept Biol, 77 Massachusetts Ave, Cambridge, MA 02139 - USA

• Document type: Journal article
• Source: ACS Chemical Biology; v. 14, n. 2, p. 266-275, FEB 2019.
• Web of Science Citations: 1

Abstract

Leishmaniases affect the poorest people on earth and have no effective drug therapy. Here, we present the crystal structure of the mitochondrial isoform of class I fumarate hydratase (FH) from Leishmania major and compare it to the previously determined cytosolic Leishmania major isoform. We further describe the mechanism of action of the first class specific FH inhibitor, 2-thiomalate, through X-ray crystallography and inhibition assays. Our crystal structures of both FH isoforms with inhibitor bound at 2.05 angstrom resolution and 1.60 angstrom resolution show high structural similarity. These structures further reveal that the selectivity of 2-thiomalate for class I FHs is due to direct coordination of the inhibitor to the unique Fe of the catalytic {[}4Fe-4S] cluster that is found in class I parasitic FHs but is absent from class II human FH. These studies provide the structural scaffold in order to exploit class I FHs as potential drug targets against leishmaniases as well as Chagas diseases, sleeping sickness, and malaria. (AU)

• FAPESP's process: 13/14988-8 - Elucidation of the mechanism of action of fumarate hydratase from Leishmania major
• Grantee: Patrícia Rosa Feliciano
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 14/22246-4 - Mutational analysis of active site residues in fumarate hydratase from Leishmania major
• Grantee: Patrícia Rosa Feliciano
• Support type: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 08/08262-6 - Kinetic, Structural and functional characterization of LmjF24.0320. e LmjF29.1960 genes that code for fumarate hydratase in Leishmania major
• Grantee: Maria Cristina Nonato
• Support type: Regular Research Grants