title: Lysosomal prenylcysteine lyase is a FAD-dependent thioether oxidase.
abstract: Prenylated proteins contain either a 15-carbon farnesyl or a 20-carbon geranylgeranyl isoprenoid covalently attached via a thioether bond to a cysteine residue at or near their C terminus. As prenylated proteins comprise up to 2% of the total protein in eukaryotic cells, and the thioether bond is a stable modification, their degradation raises a metabolic challenge to cells. A lysosomal enzyme termed prenylcysteine lyase has been identified that cleaves prenylcysteines to cysteine and an unidentified isoprenoid product. Here we show that the isoprenoid product of prenylcysteine lyase is the C-1 aldehyde of the isoprenoid moiety (farnesal in the case of C-15). The enzyme requires molecular oxygen as a cosubstrate and utilizes a noncovalently bound flavin cofactor in an NAD(P)H-independent manner. Additionally, a stoichiometric amount of hydrogen peroxide is produced during the reaction. These surprising findings indicate that prenylcysteine lyase utilizes a novel oxidative mechanism to cleave thioether bonds and provide insight into the unique role this enzyme plays in the cellular metabolism of prenylcysteines.
authors.affiliation: Departments of Pharmacology and Cancer Biology and Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: Tschantz
authors.forename: J A
authors.initials: JA
authors.lastname: Digits
authors.forename: H J
authors.initials: HJ
authors.lastname: Pyun
authors.forename: R M
authors.initials: RM
authors.lastname: Coates
authors.forename: P J
authors.initials: PJ
authors.lastname: Casey
mesh_terms: D013437:Carbon-Sulfur Lyases / Q000378:metabolism*; D003545:Cysteine / Q000031:analogs & derivatives / Q000378:metabolism; D005204:Farnesol / Q000031:analogs & derivatives* / Q000378:metabolism; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology*; D008956:Models, Chemical; D013440:Sulfides / Q000378:metabolism*
chemical_list: D013440:Sulfides; D005182:Flavin-Adenine Dinucleotide; D005204:Farnesol; C057785:S-farnesylcysteine; D006861:Hydrogen Peroxide; C108083:prenylcysteine lyase; D013437:Carbon-Sulfur Lyases; D003545:Cysteine; C084519:farnesal