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

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

doi:10.1021/acschembio.8b00972

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

Journal Article · Tue Jan 15 00:00:00 EST 2019 · ACS Chemical Biology

DOI:https://doi.org/10.1021/acschembio.8b00972· OSTI ID:1495448

^[1];

^[1]; Nonato, Maria Cristina ^[2]

Univ. of Sao Paulo (Brazil); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
Univ. of Sao Paulo (Brazil)

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 Å resolution and 1.60 Å 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

OSTI ID:: 1495448

Journal Information:: ACS Chemical Biology, Vol. 14, Issue 2; ISSN 1554-8929

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 4 works

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