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A Clinically Relevant Variant of the Human Hydrogen Sulfide-Synthesizing Enzyme Cystathionine β-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity?
Oxid Med Cell Longev. 2017; 2017:8940321.OM

Abstract

The human disease classical homocystinuria results from mutations in the gene encoding the pyridoxal 5'-phosphate- (PLP-) dependent cystathionine β-synthase (CBS), a key enzyme in the transsulfuration pathway that controls homocysteine levels, and is a major source of the signaling molecule hydrogen sulfide (H2S). CBS activity, contributing to cellular redox homeostasis, is positively regulated by S-adenosyl-L-methionine (AdoMet) but fully inhibited upon CO or NO• binding to a noncatalytic heme moiety. Despite extensive studies, the molecular basis of several pathogenic CBS mutations is not yet fully understood. Here we found that the ferrous heme of the reportedly mild p.P49L CBS variant has altered spectral properties and markedly increased affinity for CO, making the protein much more prone than wild type (WT) CBS to inactivation at physiological CO levels. The higher CO affinity could result from the slightly higher flexibility in the heme surroundings revealed by solving at 2.80-Å resolution the crystallographic structure of a truncated p.P49L. Additionally, we report that p.P49L displays impaired H2S-generating activity, fully rescued by PLP supplementation along the purification, despite a minor responsiveness to AdoMet. Altogether, the results highlight how increased propensity to CO inactivation of an otherwise WT-like variant may represent a novel pathogenic mechanism in classical homocystinuria.

Authors+Show Affiliations

Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.Instituto Gulbenkian da Ciência, Oeiras, Portugal.CNR Institute of Molecular Biology and Pathology, Rome, Italy. Department of Biochemical Sciences, Sapienza University of Rome, Rome, Italy.Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal. Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal. Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.Research Institute for Medicines and Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.CNR Institute of Molecular Biology and Pathology, Rome, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28421128

Citation

Vicente, João B., et al. "A Clinically Relevant Variant of the Human Hydrogen Sulfide-Synthesizing Enzyme Cystathionine β-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity?" Oxidative Medicine and Cellular Longevity, vol. 2017, 2017, p. 8940321.
Vicente JB, Colaço HG, Malagrinò F, et al. A Clinically Relevant Variant of the Human Hydrogen Sulfide-Synthesizing Enzyme Cystathionine β-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity? Oxid Med Cell Longev. 2017;2017:8940321.
Vicente, J. B., Colaço, H. G., Malagrinò, F., Santo, P. E., Gutierres, A., Bandeiras, T. M., Leandro, P., Brito, J. A., & Giuffrè, A. (2017). A Clinically Relevant Variant of the Human Hydrogen Sulfide-Synthesizing Enzyme Cystathionine β-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity? Oxidative Medicine and Cellular Longevity, 2017, 8940321. https://doi.org/10.1155/2017/8940321
Vicente JB, et al. A Clinically Relevant Variant of the Human Hydrogen Sulfide-Synthesizing Enzyme Cystathionine β-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity. Oxid Med Cell Longev. 2017;2017:8940321. PubMed PMID: 28421128.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Clinically Relevant Variant of the Human Hydrogen Sulfide-Synthesizing Enzyme Cystathionine β-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity? AU - Vicente,João B, AU - Colaço,Henrique G, AU - Malagrinò,Francesca, AU - Santo,Paulo E, AU - Gutierres,André, AU - Bandeiras,Tiago M, AU - Leandro,Paula, AU - Brito,José A, AU - Giuffrè,Alessandro, Y1 - 2017/03/22/ PY - 2016/12/09/received PY - 2017/01/10/revised PY - 2017/01/16/accepted PY - 2017/4/20/entrez PY - 2017/4/20/pubmed PY - 2017/5/5/medline SP - 8940321 EP - 8940321 JF - Oxidative medicine and cellular longevity JO - Oxid Med Cell Longev VL - 2017 N2 - The human disease classical homocystinuria results from mutations in the gene encoding the pyridoxal 5'-phosphate- (PLP-) dependent cystathionine β-synthase (CBS), a key enzyme in the transsulfuration pathway that controls homocysteine levels, and is a major source of the signaling molecule hydrogen sulfide (H2S). CBS activity, contributing to cellular redox homeostasis, is positively regulated by S-adenosyl-L-methionine (AdoMet) but fully inhibited upon CO or NO• binding to a noncatalytic heme moiety. Despite extensive studies, the molecular basis of several pathogenic CBS mutations is not yet fully understood. Here we found that the ferrous heme of the reportedly mild p.P49L CBS variant has altered spectral properties and markedly increased affinity for CO, making the protein much more prone than wild type (WT) CBS to inactivation at physiological CO levels. The higher CO affinity could result from the slightly higher flexibility in the heme surroundings revealed by solving at 2.80-Å resolution the crystallographic structure of a truncated p.P49L. Additionally, we report that p.P49L displays impaired H2S-generating activity, fully rescued by PLP supplementation along the purification, despite a minor responsiveness to AdoMet. Altogether, the results highlight how increased propensity to CO inactivation of an otherwise WT-like variant may represent a novel pathogenic mechanism in classical homocystinuria. SN - 1942-0994 UR - https://www.unboundmedicine.com/medline/citation/28421128/A_Clinically_Relevant_Variant_of_the_Human_Hydrogen_Sulfide_Synthesizing_Enzyme_Cystathionine_β_Synthase:_Increased_CO_Reactivity_as_a_Novel_Molecular_Mechanism_of_Pathogenicity L2 - https://doi.org/10.1155/2017/8940321 DB - PRIME DP - Unbound Medicine ER -