flavin-adenine-dinucleotide and Peroxisomal-Disorders

Ether phospholipids are essential constituents of eukaryotic cell membranes. Rhizomelic chondrodysplasia punctata type 3 is a severe peroxisomal disorder caused by inborn deficiency of alkyldihydroxyacetonephosphate synthase (ADPS). The enzyme carries out the most characteristic step in ether phospholipid biosynthesis: formation of the ether bond. The crystal structure of ADPS from Dictyostelium discoideum shows a fatty-alcohol molecule bound in a narrow hydrophobic tunnel, specific for aliphatic chains of 16 carbons. Access to the tunnel is controlled by a flexible loop and a gating helix at the protein-membrane interface. Structural and mutagenesis investigations identify a cluster of hydrophilic catalytic residues, including an essential tyrosine, possibly involved in substrate proton abstraction, and the arginine that is mutated in ADPS-deficient patients. We propose that ether bond formation might be orchestrated through a covalent imine intermediate with the flavin, accounting for the noncanonical employment of a flavin cofactor in a nonredox reaction.

Topics: Alkyl and Aryl Transferases; Amino Acid Sequence; Amino Acid Substitution; Animals; Binding Sites; Catalysis; Chondrodysplasia Punctata, Rhizomelic; Conserved Sequence; Crystallography, X-Ray; Dictyostelium; Dimerization; Flavin-Adenine Dinucleotide; Histidine; Humans; Hydrogen Bonding; Lipid Metabolism, Inborn Errors; Models, Biological; Models, Chemical; Models, Molecular; Molecular Sequence Data; Molecular Structure; Peroxisomal Disorders; Phenylalanine; Phospholipid Ethers; Protein Binding; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Recombinant Proteins; Sequence Homology, Amino Acid; Spectrum Analysis, Raman; Substrate Specificity; Tyrosine