9FXQ
Ancestral Prenylcysteine Oxidase 1 (PCYOX1)
Summary for 9FXQ
| Entry DOI | 10.2210/pdb9fxq/pdb |
| Descriptor | Ancestral Prenylcysteine Oxidase 1 (PCYOX1), 3-[(3-CHOLAMIDOPROPYL)DIMETHYLAMMONIO]-1-PROPANESULFONATE, FLAVIN-ADENINE DINUCLEOTIDE (3 entities in total) |
| Functional Keywords | oxidoreductase, flavoprotein, oxidative metabolism, protein prenylation, ancestral enzyme |
| Biological source | Mammalia |
| Total number of polymer chains | 1 |
| Total formula weight | 55340.57 |
| Authors | Barone, M.,Mattevi, A. (deposition date: 2024-07-02, release date: 2024-10-16, Last modification date: 2024-10-30) |
| Primary citation | Barone, M.,Pizzorni, L.,Fraaije, M.W.,Mascotti, M.L.,Mattevi, A. Evolution, structure, and drug-metabolizing activity of mammalian prenylcysteine oxidases. J.Biol.Chem., 300:107810-107810, 2024 Cited by PubMed Abstract: Prenylcysteine oxidases (PCYOXs) metabolize prenylated cysteines produced by protein degradation. They utilize oxygen as a 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 in 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 of 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. PubMed: 39322016DOI: 10.1016/j.jbc.2024.107810 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.1 Å) |
Structure validation
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