5MMS

Human cystathionine beta-synthase (CBS) p.P49L delta409-551 variant

Summary for 5MMS

• Entry DOI: 10.2210/pdb5mms/pdb
• Descriptor: Cystathionine beta-synthase, PROTOPORPHYRIN IX CONTAINING FE, PYRIDOXAL-5'-PHOSPHATE, ... (5 entities in total)
• Functional Keywords: cystathionine beta-synthase, hydrogen sulfide, transsulfuration, classical homocystinuria, lyase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P35520
• Total number of polymer chains: 6
• Total formula weight: 273654.91

Authors

Vicente, J.B.,Colaco, H.G.,Malagrino, F.,Santo, P.E.,Gutierres, A.,Bandeiras, T.M.,Leandro, P.,Brito, J.A.,Giuffre, A. (deposition date: 2016-12-12, release date: 2017-05-03, Last modification date: 2024-01-17)

Primary citation

Vicente, J.B.,Colaco, H.G.,Malagrino, F.,Santo, P.E.,Gutierres, A.,Bandeiras, T.M.,Leandro, P.,Brito, J.A.,Giuffre, A.
A Clinically Relevant Variant of the Human Hydrogen Sulfide-Synthesizing Enzyme Cystathionine beta-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity?
Oxid Med Cell Longev, 2017:8940321-8940321, 2017

PubMed Abstract: The human disease classical homocystinuria results from mutations in the gene encoding the pyridoxal 5'-phosphate- (PLP-) dependent cystathionine -synthase (CBS), a key enzyme in the transsulfuration pathway that controls homocysteine levels, and is a major source of the signaling molecule hydrogen sulfide (HS). 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 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 HS-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.

PubMed: 28421128
DOI: 10.1155/2017/8940321

Experimental method

X-RAY DIFFRACTION (2.8 Å)