Fumarate hydratase isoforms of Leishmania major: Subcellular localization, structural and kinetic properties

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• 作者：Patrí ; cia R. Feliciano^a ; Shreedhara Gupta^b ; Fabio Dyszy^c ; Marcelo Dias-Baruffi^d ; Antonio J. Costa-Filho^e ; Paul A.M. Michels^b ; M. Cristina Nonato^a ; ^{cristy@fcfrp.usp.br}
• 关键词：FH ; fumarate hydratase ; LmFH ; fumarate hydratase from Leishmania major ; LmFH-1 ; fumarate hydratase from L. major encoded by LmjF24.0320 gene ; LmFH-2 ; fumarate hydratase from L. major encoded by LmjF29.1960 gene
• 刊名：International Journal of Biological Macromolecules
• 出版年：2012
• 期刊代码：62_01418130
• 类别：abs
• 出版时间：July-August, 2012
• 卷：51
• 期：1-2
• 页码：25-31
• 文件大小：716 K

摘要

Fumarate hydratases (FHs; EC 4.2.1.2) are enzymes that catalyze the reversible hydration of fumarate to S-malate. Parasitic protists that belong to the genus Leishmania and are responsible for a complex of vector-borne diseases named leishmaniases possess two genes that encode distinct putative FH enzymes. Genome sequence analysis of Leishmania major Friedlin reveals the existence of genes LmjF24.0320 and LmjF29.1960 encoding the putative enzymes LmFH-1 and LmFH-2, respectively. In the present work, the FH activity of both L. major enzymes has been confirmed. Circular dichroism studies suggest important differences in terms of secondary structure content when comparing LmFH isoforms and even larger differences when comparing them to the homologous human enzyme. CD melting experiments revealed that both LmFH isoforms are thermolabile enzymes. The catalytic efficiency under aerobic and anaerobic environments suggests that they are both highly sensitive to oxidation and damaged by oxygen. Intracellular localization studies located LmFH-1 in the mitochondrion, whereas LmFH-2 was found predominantly in the cytosol with possibly also some in glycosomes. The high degree of sequence conservation in different Leishmania species, together with the relevance of FH activity for the energy metabolism in these parasites suggest that FHs might be exploited as targets for broad-spectrum antileishmanial drugs.