Crystal structure of cystathionine β-synthase from honeybee Apis mellifera

Cystathionine β-synthase (CBS), the key enzyme in the transsulfuration pathway, links methionine metabolism
to the biosynthesis of cellular redox controlling molecules. CBS catalyzes the pyridoxal-5′-phosphate-dependent
condensation of serine and homocysteine to form cystathionine, which is subsequently converted into cysteine.
Besides maintaining cellular sulfur amino acid homeostasis, CBS also catalyzes multiple hydrogen sulfide-generating
reactions using cysteine and homocysteine as substrates. In mammals, CBS is activated by S-adenosylmethionine
(AdoMet), where it can adopt two different conformations (basal and activated), but exists as a
unique highly active species in fruit fly Drosophila melanogaster. Here we present the crystal structure of CBS from
honeybey Apis mellifera, which shows a constitutively active dimeric species and let explain why the enzyme is
not allosterically regulated by AdoMet. In addition, comparison of available CBS structures unveils a substrateinduced
closure of the catalytic cavity, which in humans is affected by the AdoMet-dependent regulation and
likely impaired by the homocystinuria causing mutation T191M.