Structure of Cystathionine β-Synthase from Toxoplasma gondii, a key enzyme in its H2S production machinery

ABSTRACT Cystathionine β-synthase (CBS), the pivotal enzyme of the reverse transsulfuration pathway, catalyzes the pyridoxal-5’-phosphate-dependent condensation of serine with homocysteine to form cystathionine. Additionally, CBS performs alternative reactions that use homocysteine and cysteine as substrates leading to the endogenous biosynthesis of hydrogen sulfide (H 2 S), an important signal transducer in many physiological and pathological processes. Toxoplasma gondii, the causative agent of toxoplasmosis, encodes a functional CBS ( Tg CBS) that contrary to human CBS, is not allosterically regulated by S-adenosylmethionine and can use both, Ser and O -acetylserine (OAS) as substrates. Tg CBS is also strongly implicated in the production of H 2 S, and thus involved in redox homeostasis of the parasite. Here, we report its crystal structure, the first CBS from a protozoan described so far. Our data reveals a basal-like fold that unexpectedly differs from the active conformations found in other organisms, but structurally similar to the pathogenic activated mutant D444N of the human enzyme.