The crucial step in ether phospholipid biosynthesis: structural basis of a noncanonical reaction associated with a peroxisomal disorder.
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.
Razeto
Adelia
A
Dipartimento di Genetica e Microbiologia, Università di Pavia, via Ferrata 1, 27100 Pavia, Italy.
Mattiroli
Francesca
F
Carpanelli
Elena
E
Aliverti
Alessandro
A
Pandini
Vittorio
V
Coda
Alessandro
A
Mattevi
Andrea
A
D019883:Alkyl and Aryl Transferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D018902:Chondrodysplasia Punctata, Rhizomelic / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004023:Dictyostelium / Q000201:enzymology; D019281:Dimerization; D005182:Flavin-Adenine Dinucleotide / Q000737:chemistry / Q000378:metabolism; D006639:Histidine / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008052:Lipid Metabolism, Inborn Errors; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D018901:Peroxisomal Disorders / Q000201:enzymology* / Q000235:genetics; D010649:Phenylalanine / Q000378:metabolism; D010742:Phospholipid Ethers / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013059:Spectrum Analysis, Raman; D013379:Substrate Specificity; D014443:Tyrosine / Q000378:metabolism
D010742:Phospholipid Ethers; D011994:Recombinant Proteins; D005182:Flavin-Adenine Dinucleotide; D014443:Tyrosine; D010649:Phenylalanine; D006639:Histidine; D019883:Alkyl and Aryl Transferases; C019654:alkylglycerone-phosphate synthase