5mms | pdb_00005mms

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

spinqualitylabelsall models 5mms, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5mms is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: HEM, NA, PLP Gene: CBS (HUMAN) Activity: Cystathionine beta-synthase, with EC number 4.2.1.22 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [CBS_HUMAN] Defects in CBS are the cause of cystathionine beta-synthase deficiency (CBSD) [MIM:236200]. CBSD is an enzymatic deficiency resulting in altered sulfur metabolism and homocystinuria. The clinical features of untreated homocystinuria due to CBS deficiency include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome, and thromboembolic events. Light skin and hair can also be present. Biochemical features include increased urinary homocystine and methionine. Function [CBS_HUMAN] Only known pyridoxal phosphate-dependent enzyme that contains heme. Important regulator of hydrogen sulfide, especially in the brain, utilizing cysteine instead of serine to catalyze the formation of hydrogen sulfide. Hydrogen sulfide is a gastratransmitter with signaling and cytoprotective effects such as acting as a neuromodulator in the brain to protect neurons against hypoxic injury (By similarity). Publication Abstract from PubMed The human disease classical homocystinuria results from mutations in the gene encoding the pyridoxal 5'-phosphate- (PLP-) dependent cystathionine beta-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-A 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. A Clinically Relevant Variant of the Human Hydrogen Sulfide-Synthesizing Enzyme Cystathionine beta-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity?,Vicente JB, Colaco HG, Malagrino F, Santo PE, Gutierres A, Bandeiras TM, Leandro P, Brito JA, Giuffre A Oxid Med Cell Longev. 2017;2017:8940321. doi: 10.1155/2017/8940321. Epub 2017 Mar, 22. PMID:28421128 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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