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Author Notes:

To whom correspondence should be addressed. E-mail: andrea.mattevi@unipv.it.

Author contributions: S.N., A.J.R.H., D.E.E., and A.M. designed research

S.N., V. Piano, S.R., A.A., and V. Pandini performed research

S.N., A.A., M.W.F., A.J.R.H., D.E.E., and A.M. analyzed data

S.N. and A.M. wrote the paper.

The authors declare no conflict of interest.

Subjects:

Research Funding:

This study was supported by Telethon Grant GGP12007.

A visiting professorship was supported by Fondazione Cariplo Grant 2008.3148 (to D.E.E.).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MULTIDISCIPLINARY SCIENCES
  • peroxisomal disorder
  • phospholipid biosynthesis
  • plasmalogen
  • rhizomelic chondrodysplasia punctata
  • ACYL DIHYDROXYACETONE PHOSPHATE
  • EHRLICH ASCITES TUMOR
  • ALKYL LIPID-SYNTHESIS
  • CRYSTAL-STRUCTURES
  • NITROALKANE OXIDASE
  • SYNTHASE
  • BIOSYNTHESIS
  • MECHANISM
  • ENZYME
  • 5-DEAZAFLAVIN

Precursor of ether phospholipids is synthesized by a flavoenzyme through covalent catalysis

Tools:

Journal Title:

Proceedings of the National Academy of Sciences

Volume:

Volume 109, Number 46

Publisher:

, Pages 18791-18796

Type of Work:

Article | Final Publisher PDF

Abstract:

The precursor of the essential ether phospholipids is synthesized by a peroxisomal enzyme that uses a flavin cofactor to catalyze a reaction that does not alter the redox state of the substrates. The enzyme crystal structure reveals a V-shaped active site with a narrow constriction in front of the prosthetic group. Mutations causing inborn ether phospholipid deficiency, a very severe genetic disease, target residues that are part of the catalytic center. Biochemical analysis using substrate and flavin analogs, absorbance spectroscopy, mutagenesis, and mass spectrometry provide compelling evidence supporting an unusual mechanism of covalent catalysis. The flavin functions as a chemical trap that promotes exchange of an acyl with an alkyl group, generating the characteristic ether bond. Structural comparisons show that the covalent versus noncovalent mechanistic distinction in flavoenzyme catalysis and evolution relies on subtle factors rather than on gross modifications of the cofactor environment.

Copyright information:

© Nenci et al.

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