5MMS

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

5MMS の概要

• エントリーDOI: 10.2210/pdb5mms/pdb
• 分子名称: Cystathionine beta-synthase, PROTOPORPHYRIN IX CONTAINING FE, PYRIDOXAL-5'-PHOSPHATE, ... (5 entities in total)
• 機能のキーワード: cystathionine beta-synthase, hydrogen sulfide, transsulfuration, classical homocystinuria, lyase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : P35520
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 273654.91

構造登録者

Vicente, J.B.,Colaco, H.G.,Malagrino, F.,Santo, P.E.,Gutierres, A.,Bandeiras, T.M.,Leandro, P.,Brito, J.A.,Giuffre, A. (登録日: 2016-12-12, 公開日: 2017-05-03, 最終更新日: 2024-01-17)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.8 Å)