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

Area of Science:

• Biochemistry
• Structural Biology
• Parasitology

Background:

• Leishmaniases are devastating neglected tropical diseases with limited therapeutic options.
• Fumarate hydratase (FH) is a key metabolic enzyme in parasites, making it a potential drug target.

Purpose of the Study:

• To determine the crystal structure of the mitochondrial class I fumarate hydratase (FH) from Leishmania major.
• To elucidate the mechanism of action of the first class-specific FH inhibitor, 2-thiomalate.
• To provide a structural basis for developing new anti-parasitic drugs.

Main Methods:

• X-ray crystallography was employed to determine the structures of Leishmania major FH isoforms.
• Inhibition assays were performed to evaluate the efficacy of 2-thiomalate.
• Structural comparison between parasitic and human FH isoforms.

Main Results:

• High structural similarity was observed between the mitochondrial and cytosolic Leishmania major FH isoforms.
• The crystal structures revealed that 2-thiomalate selectively targets class I FH by coordinating to a unique iron-sulfur cluster.
• This unique cluster is present in parasitic FH but absent in human FH, explaining the drug's specificity.

Conclusions:

• Class I fumarate hydratase is a promising drug target for leishmaniases and other parasitic diseases like Chagas disease, sleeping sickness, and malaria.
• The structural insights into 2-thiomalate binding provide a foundation for designing novel, selective FH inhibitors.
• Targeting parasitic FH offers a potential strategy to combat neglected tropical diseases.