The human FA2H gene encodes a fatty acid 2-hydroxylase

J Biol Chem. 2004 Nov 19;279(47):48562-8. doi: 10.1074/jbc.M406649200. Epub 2004 Aug 27.

Abstract

2-Hydroxysphingolipids are a subset of sphingolipids containing 2-hydroxy fatty acids. The 2-hydroxylation occurs during de novo ceramide synthesis and is catalyzed by fatty acid 2-hydroxylase (also known as fatty acid alpha-hydroxylase). In mammals, 2-hydroxysphingolipids are present abundantly in brain because the major myelin lipids galactosylceramides and sulfatides contain 2-hydroxy fatty acids. Here we report identification and characterization of a human gene that encodes a fatty acid 2-hydroxylase. Data base searches revealed a human homologue of the yeast ceramide 2-hydroxylase gene (FAH1), which we named FA2H. The FA2H gene encodes a 372-amino acid protein with 36% identity and 46% similarity to yeast Fah1p. The amino acid sequence indicates that FA2H protein contains an N-terminal cytochrome b5 domain and four potential transmembrane domains. FA2H also contains the iron-binding histidine motif conserved among membrane-bound desaturases/hydroxylases. COS7 cells expressing human FA2H contained 3-20-fold higher levels of 2-hydroxyceramides (C16, C18, C24, and C24:1) and 2-hydroxy fatty acids compared with control cells. Microsomal fractions prepared from transfected COS7 cells showed tetracosanoic acid 2-hydroxylase activities in an NADPH- and NADPH: cytochrome P-450 reductase-dependent manner. FA2H lacking the N-terminal cytochrome b5 domain had little activity, indicating that this domain is a functional component of this enzyme. Northern blot analysis showed that the FA2H gene is highly expressed in brain and colon tissues. These results demonstrate that the human FA2H gene encodes a fatty acid 2-hydroxylase. FA2H is likely involved in the formation of myelin 2-hydroxy galactosylceramides and -sulfatides.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Blotting, Northern
  • Blotting, Western
  • Brain / metabolism
  • COS Cells
  • Catalysis
  • Cell Membrane / metabolism
  • Ceramides / chemistry
  • Ceramides / metabolism
  • Chromatography, Liquid
  • Cytochromes b5 / chemistry
  • Databases as Topic
  • Fatty Acids / metabolism*
  • Humans
  • Mass Spectrometry
  • Microsomes / metabolism
  • Mixed Function Oxygenases / chemistry*
  • Mixed Function Oxygenases / metabolism*
  • Molecular Sequence Data
  • Myelin Sheath / chemistry
  • NADP / metabolism
  • Plasmids / metabolism
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
  • Subcellular Fractions / metabolism
  • Tissue Distribution
  • Transfection

Substances

  • Ceramides
  • Fatty Acids
  • NADP
  • Cytochromes b5
  • Mixed Function Oxygenases
  • fatty acid alpha-hydroxylase

Associated data

  • RefSeq/NM_024306