| 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
|
|
WOS Category
|
BIOPHYSICS
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
| Resource |
| Cellular slime molds |
G01781 |
