7qgt | pdb_00007qgt

Crystal structure of human cystathionine beta-synthase (delta516-525) in complex with AOAA.

spinqualitylabelsall models 7qgt, resolution 2.69Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7qgt is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.691Å Ligands: HEM, IK2, PLP 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 Cystathionine beta-synthase (CBS) is a pivotal enzyme of the transsulfuration pathway responsible for diverting homocysteine to the biosynthesis of cysteine and production of hydrogen sulfide (H2S). Aberrant upregulation of CBS and overproduction of H2S contribute to pathophysiology of several diseases including cancer and Down syndrome. Therefore, pharmacological CBS inhibition has emerged as a prospective therapeutic approach. Here, we characterized binding and inhibitory mechanism of aminooxyacetic acid (AOAA), the most commonly used CBS inhibitor. We found that AOAA binds CBS tighter than its respective substrates and forms a dead-end PLP-bound intermediate featuring an oxime bond. Surprisingly, serine, but not cysteine, replaced AOAA from CBS and formed an aminoacrylate reaction intermediate, which allowed for the continuation of the catalytic cycle. Indeed, serine rescued and essentially normalized the enzymatic activity of AOAA-inhibited CBS. Cellular studies confirmed that AOAA decreased H2S production and bioenergetics, while additional serine rescued CBS activity, H2S production and mitochondrial function. The crystal structure of AOAA-bound human CBS showed a lack of hydrogen bonding with residues G305 and Y308, found in the serine-bound model. Thus, AOAA-inhibited CBS could be reactivated by serine. This difference may be important in a cellular environment in multiple pathophysiological conditions and may modulate the CBS-inhibitory activity of AOAA. In addition, our results demonstrate additional complexities of using AOAA as a CBS-specific inhibitor of H2S biogenesis and point to the urgent need to develop a potent, selective and specific pharmacological CBS inhibitor. H2S biogenesis by cystathionine beta-synthase: mechanism of inhibition by aminooxyacetic acid and unexpected role of serine.,Petrosino M, Zuhra K, Kopec J, Hutchin A, Szabo C, Majtan T Cell Mol Life Sci. 2022 Jul 21;79(8):438. doi: 10.1007/s00018-022-04479-9. PMID:35864237 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Cystathionine β-synthase 3D structures

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