Cystathionine
![](/i<font color=)
mages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-synthase plays a key role in the intracellular disposal of homocysteine and isthe single most common locus of mutations associated with homocystinuria. Elevated levels of homocysteineare correlated with heart disease, Alzheimer's and Parkinson's diseases, and neural tube defects.Cystathionine
![](/i<font color=)
mages/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-synthase is modular and subjected to complex regulation, but insights into the structuralbasis of this regulation are lacking. We have employed hydrogen exchange
mass spectrometry to
mappeptides whose motions are correlated with transmission of intrasteric inhibition and allosteric activation.The
mass spectrometric data provide an excellent correlation between kinetically and confor
mationallydistinguishable states of the enzyme. We also demonstrate that a pathogenic regulatory do
main mutant,D444N, is confor
mationally locked in one of two states sampled by the wild type enzyme. Our hydrogenexchange data identify surfaces that are potentially involved in the juxtaposition of the regulatory andcatalytic do
mains and form the basis of a docked structural model for the full-length enzyme.