Tags

Type your tag names separated by a space and hit enter

S-Adenosyl-l-methionine Modulates CO and NO• Binding to the Human H2S-generating Enzyme Cystathionine β-Synthase.
J Biol Chem. 2016 Jan 08; 291(2):572-81.JB

Abstract

Cystathionine β-synthase (CBS) is a key enzyme in human (patho)physiology with a central role in hydrogen sulfide metabolism. The enzyme is composed of a pyridoxal 5'-phosphate-binding catalytic domain, flanked by the following 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 modulates the enzyme activity. Conversely, AdoMet binding stimulates CBS activity. Here, 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 with CO. Importantly, CO and NO(•) binding was 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 toward 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.

Authors+Show Affiliations

From the Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, 2781-156 Oeiras, Portugal, jvicente@itqb.unl.pt.the Metabolism and Genetics Group, Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal.the Department of Biochemical Sciences and Istituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, I-00185 Rome, Italy.the Metabolism and Genetics Group, Research Institute for Medicines, Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal, the Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, 1640-003 Lisbon, Portugal, and.the Institute of Molecular Biology and Pathology, National Research Council of Italy, I-00185 Rome, Italy alessandro.giuffre@uniroma1.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26582199

Citation

Vicente, João B., et al. "S-Adenosyl-l-methionine Modulates CO and NO• Binding to the Human H2S-generating Enzyme Cystathionine Β-Synthase." The Journal of Biological Chemistry, vol. 291, no. 2, 2016, pp. 572-81.
Vicente JB, Colaço HG, Sarti P, et al. S-Adenosyl-l-methionine Modulates CO and NO• Binding to the Human H2S-generating Enzyme Cystathionine β-Synthase. J Biol Chem. 2016;291(2):572-81.
Vicente, J. B., Colaço, H. G., Sarti, P., Leandro, P., & Giuffrè, A. (2016). S-Adenosyl-l-methionine Modulates CO and NO• Binding to the Human H2S-generating Enzyme Cystathionine β-Synthase. The Journal of Biological Chemistry, 291(2), 572-81. https://doi.org/10.1074/jbc.M115.681221
Vicente JB, et al. S-Adenosyl-l-methionine Modulates CO and NO• Binding to the Human H2S-generating Enzyme Cystathionine Β-Synthase. J Biol Chem. 2016 Jan 8;291(2):572-81. PubMed PMID: 26582199.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - S-Adenosyl-l-methionine Modulates CO and NO• Binding to the Human H2S-generating Enzyme Cystathionine β-Synthase. AU - Vicente,João B, AU - Colaço,Henrique G, AU - Sarti,Paolo, AU - Leandro,Paula, AU - Giuffrè,Alessandro, Y1 - 2015/11/18/ PY - 2015/07/25/received PY - 2015/11/20/entrez PY - 2015/11/20/pubmed PY - 2016/5/19/medline KW - S-adenosylmethionine KW - allosteric regulation KW - carbon monoxide KW - heme KW - hydrogen sulfide KW - nitric oxide KW - signal transduction SP - 572 EP - 81 JF - The Journal of biological chemistry JO - J Biol Chem VL - 291 IS - 2 N2 - Cystathionine β-synthase (CBS) is a key enzyme in human (patho)physiology with a central role in hydrogen sulfide metabolism. The enzyme is composed of a pyridoxal 5'-phosphate-binding catalytic domain, flanked by the following 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 modulates the enzyme activity. Conversely, AdoMet binding stimulates CBS activity. Here, 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 with CO. Importantly, CO and NO(•) binding was 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 toward 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/26582199/S_Adenosyl_l_methionine_Modulates_CO_and_NO���_Binding_to_the_Human_H2S_generating_Enzyme_Cystathionine_��_Synthase_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)36191-3 DB - PRIME DP - Unbound Medicine ER -