Human acetyl-CoA carboxylase 1 gene:: Presence of three promoters and heterogeneity at the 5′-untranslated mRNA region

Acetyl-CoA carboxylase 1 (ACC1) catalyzes the formation of malonyl-CoA, the C-2 donor for de novo synthesis of long-chain fatty acids. We have identified 64 exons, including 7 alternatively spliced minor exons (1A, 1B, 1C, 3, 5A', 5A, and 5B) in human ACC1 gene (approximate to330 kb). The gene is regulated by three promoters (PI, PII, and Pill), which are located upstream of exons 1, 2, and 5A, respectively. PI is a constitutive promoter and has no homology with the PI sequences of other mammalian ACC1. PII is regulated by various hormones. PII is expressed in a tissue-specific manner. The presence of several alternatively spliced exons does not alter the translation of the 265-kDa ACC1 protein starting from an ATG present in exon 5. Translation of Pill transcripts from exon 5A generates a 259-kDa isoform in which the N-terminal 75 aa of 265-kDa ACC1 are replaced with a new sequence of 17 aa. Interestingly, the inclusion of exon 513 between 5A and 6 in Pill transcripts would yield a third 257-kDa isoform, which is translated from an ATG in exon 6. However, the presence of exon 513 in PI and PII transcripts leads to an in-frame stop codon that results in an ACC1-related 77-aa peptide. The presence of alternatively spliced exons and three isoforms of ACC1 could contribute to overall ACC1 activity either by influencing the mRNA stability and translational efficiency or by increasing the stability and specific activity of the ACC1 protein, respectively.