RRC ID 28728
Author Razeto A, Mattiroli F, Carpanelli E, Aliverti A, Pandini V, Coda A, Mattevi A.
Title The crucial step in ether phospholipid biosynthesis: structural basis of a noncanonical reaction associated with a peroxisomal disorder.
Journal Structure
Abstract 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.
Volume 15(6)
Pages 683-92
Published 2007-6-1
DOI 10.1016/j.str.2007.04.009
PII S0969-2126(07)00176-1
PMID 17562315
MeSH Alkyl and Aryl Transferases / chemistry Alkyl and Aryl Transferases / genetics Alkyl and Aryl Transferases / metabolism Amino Acid Sequence Amino Acid Substitution Animals Binding Sites Catalysis Chondrodysplasia Punctata, Rhizomelic / enzymology Chondrodysplasia Punctata, Rhizomelic / metabolism Chondrodysplasia Punctata, Rhizomelic / pathology Conserved Sequence Crystallography, X-Ray Dictyostelium / enzymology Dimerization Flavin-Adenine Dinucleotide / chemistry Flavin-Adenine Dinucleotide / metabolism Histidine / metabolism Humans Hydrogen Bonding Lipid Metabolism, Inborn Errors* Models, Biological Models, Chemical Models, Molecular Molecular Sequence Data Molecular Structure Peroxisomal Disorders / enzymology* Peroxisomal Disorders / genetics Phenylalanine / metabolism Phospholipid Ethers / chemistry Phospholipid Ethers / metabolism* Protein Binding Protein Conformation Protein Structure, Secondary Protein Structure, Tertiary Recombinant Proteins / chemistry Recombinant Proteins / metabolism Sequence Homology, Amino Acid Spectrum Analysis, Raman Substrate Specificity Tyrosine / metabolism
IF 4.862
Times Cited 33
Cellular slime molds G01781