S-Adenosyl-L-methionine modulates CO and NO{middle dot} binding to the human H2S-generating enzyme cystathionine {beta}-synthase [Enzymology]

November 18th, 2015 by Vicente, J. B., Colaco, H. G., Sarti, P., Leandro, P., Giuffre, A.

Cystathionine β-synthase (CBS) is a key enzyme in human (patho)physiology with a central role in hydrogen sulfide metabolism. The enzyme is composed by a pyridoxal 5′-phosphate (PLP)-binding catalytic domain, flanked by two domains: a heme-binding N-terminal domain and a regulatory C-terminal domain binding S-adenosyl-L-methionine (AdoMet). CO or NO· binding at the ferrous heme negatively modulate the enzyme activity. Conversely, AdoMet binding stimulates CBS activity. Herein we provide experimental evidence for a functional communication between the two domains. We report that AdoMet binding significantly enhances CBS inhibition by CO. Consistently, we observed increased affinity (≈5-fold) and faster association (≈10-fold) of CO to the ferrous heme at physiological AdoMet concentrations. NO· binding to reduced CBS was also enhanced by AdoMet, although to a lesser extent (≈2-fold higher affinity) as compared to CO. Importantly, CO and NO· binding were unchanged by AdoMet in a truncated form of CBS lacking the C-terminal regulatory domain. These unprecedented observations demonstrate that CBS activation by AdoMet puzzlingly sensitizes the enzyme towards inhibition by exogenous ligands, like CO and NO·. This further supports the notion that CBS regulation is a complex process, involving the concerted action of multiple physiologically-relevant effectors.
  • Posted in Journal of Biological Chemistry, Publications
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