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Alessandra Astegno

University of Verona, Italy

Title: Characterization of cystathionine γ-lyase from T. gondii: A target for drug development?


Biography: Alessandra Astegno


Toxoplasma gondii is a protozoan parasite of medical and veterinary relevance responsible for toxoplasmosis in humans. As there
is currently no vaccine available for human, the identifi cation of good target candidates for future drug development is urgently
required. A recent proteomic analysis of partially sporulated oocysts of T. gondii showed that oocyctes have a greater capability of
de novo amino acid biosynthesis, shedding light on a stage-specifi c subset of proteins whose functional profi le is consistent with
the oocyst need to resist various environmental stresses. Among these putative oocyst/sporozoite-specifi c proteins, three enzymes
involved in cysteine metabolism, i.e., cystathionine β-synthase, cystathionine γ-lyase (CGL) and cysteine synthase, were found.
However, despite the central metabolic roles of these enzymes, the functionality of none of them has so far been investigated. Herein,
CGL from T. gondii (TgCGL) has been cloned, expressed and physiochemically and enzymatically characterized. Th e purifi ed TgCGL
is a functional enzyme which splits L-cystathionine almost exclusively at the CγS bond to yield L-cysteine. Th is fi nding likely implies
that the reverse transsulfuration pathway is operative in the parasite. Th e enzyme displays only marginal reactivity toward L-cysteine,
which is also a mixed-type inhibitor of TgCGL activity, therefore indicating a tight regulation of cysteine intracellular levels in the
parasite. Structure-guided homology modelling revealed two striking amino acid diff erences between human and parasite CGL active
sites (Glu59 and Ser340 in human to Ser77 and Asn360 in toxoplasma). Mutation of these two residues to the corresponding residues
in human revealed their importance in modulating both substrate and reaction specifi city of the parasitic enzyme. Our fi ndings might
have far-reaching implications for the use of TgCGL as anti-toxoplasmosis drug target.