9fxq

Ancestral Prenylcysteine Oxidase 1 (PCYOX1)

spinqualitylabelsall models 9fxq, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9fxq is a 1 chain structure with sequence from Mammalia. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.1Å Ligands: CPS, FAD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Prenylcysteine oxidases (PCYOXs) metabolize prenylated cysteines produced by protein degradation. They utilize oxygen as co-substrate to produce free cysteine, an aldehyde, and hydrogen peroxide through the unusual oxidation of a thioether bond. In this study, we explore the evolution, structure, and mechanism of the two mammalian PCYOXs. A gene duplication event in jawed vertebrates originated these two paralogs. Both enzymes are active on farnesyl- and geranylgeranylcysteine, but inactive on molecules with shorter prenyl groups. Kinetics experiments outline a mechanism where flavin reduction and re-oxidation occur rapidly without any detectable intermediates, with the overall reaction rate limited by product release. The experimentally determined three-dimensional structure of PCYOX1 reveals long and wide tunnels leading from the surface to the flavin. They allow the isoprene substrate to curl up within the protein and position its reactive cysteine group close to the flavin. A hydrophobic patch on the surface mediates membrane association, enabling direct substrate and product exchange with the lipid bilayer. Leveraging established knowledge on flavoenzyme inhibition, we designed sub-micromolar PCYOX inhibitors. Additionally, we discovered that PCYOXs bind and slowly degrade salisirab, an anti-RAS compound. This activity suggests potential and previously unknown roles of PCYOXs in drug metabolism. Evolution, Structure, and Drug-Metabolising Activity of Mammalian Prenylcysteine Oxidases.,Barone M, Pizzorni L, Fraaije MW, Mascotti ML, Mattevi A J Biol Chem. 2024 Sep 23:107810. doi: 10.1016/j.jbc.2024.107810. PMID:39322016 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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