Characterisation of an N-terminal variant of acetyl-CoA carboxylase-alpha: expression in human tissues and evolutionary aspects.
mRNA encoding a variant acetyl-CoA carboxylase (ACC)-alpha isozyme, transcribed from a downstream promoter, PIII, was detected in human tissues. Such exon 5A-containing transcripts (E5A-mRNA) encode ACC-alpha with a distinct N-terminus, with 15/17 residues identical to those encoded by the ovine mRNA. In the current study we used antisera directed against the E5A N-terminus to verify that ovine E5A translates are present in tissues consistent with the distribution of E5A-mRNA. The presence of E5A alters the context of adjacent regulatory phosphorylation sites in E6, which may indicate altered regulation of activity for this isozyme. Sequences with high identity to the proximal promoter of PIII and E5A are present in the mouse and rat ACC-alpha genes, however, the coding region of E5A is not conserved, and E5A transcripts are not detected in tissues. Thus E5A must have been present in a common ancestor of rodents, primates, and ruminants, and has become nonfunctional in the former. A minor human PIII-derived mRNA containing an additional 111-bp sequence encoded by a downstream exon, E5B, was also detected. E5B encodes an in-frame stop-codon such that the E5A open-reading frame is terminated, however, ACC-alpha translation may be re-initiated from a downstream AUG in E6, potentially generating an isozyme lacking the N-terminal phosphorylation sites. Transcription of human ACC-alpha from at least three promoters and the potential to generate ACC-alpha isozymes with differential susceptibilities to phosphorylation indicate that the regulation of fatty acid synthesis in human tissues is likely to be complex.
Travers
Maureen T
MT
Cell Biochemistry Group, Hannah Research Institute, Hannah Research Park, Ayr, Scotland KA6 5HL, UK.
Vallance
Amanda J
AJ
Clegg
Roger A
RA
Thomson
Ross
R
Price
Nigel T
NT
Barber
Michael C
MC
D000103:Acetyl-CoA Carboxylase / Q000096:biosynthesis / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D018388:Codon, Terminator; D019143:Evolution, Molecular; D014644:Genetic Variation; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D010766:Phosphorylation; D010802:Phylogeny; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D016415:Sequence Alignment; D012756:Sheep; D014018:Tissue Distribution
D018388:Codon, Terminator; D007527:Isoenzymes; D012333:RNA, Messenger; D000103:Acetyl-CoA Carboxylase