Aromatase and the three little paralogs

Extract

The rapid progress of scientific knowledge is continuously built on established earlier findings. Integrating previous observations with more recent data can be challenging and occasionally well-established data are unfortunately overlooked. This may lead to unnecessary redundancy in research and, in the worst-case scenario, to misinterpretation of data. In the present contribution, we would like to draw attention to such a circumstance, which has crept into several recent papers on expression and functional relevance of the porcine CYP19 gene cluster that encodes functionally distinct isoforms of aromatase cytochrome P450 (aromatase) in pigs.

Aromatase is the key enzyme required for the synthesis of estrogens. Consistent with paracrine and endocrine modes of action of estrogens, the expression of CYP19 exhibits a complex tissue specific mode of transcriptional regulation in different male and female tissues from early stages of embryonic and placental development to adult ovary, testis, adrenal cortex, and brain. It was once thought that aromatase was encoded by a single gene in all species. As was documented in the early 90’s for the human CYP19 gene, the only copy in the human genome, this is achieved by directing transcription from different tissue-specific promoters, which results in the generation of transcripts with different 5′ untranslated regions, but an identical coding sequence [1]. Also in the 90’s, but in contrast to the human circumstance, it was demonstrated that the pig genome contains three paralogous copies of CYP19 [2] encoding different, functionally distinct, aromatase isoforms now referred to as CYP19A1, CYP19A2, and CYP19A3 (genes 403 331, 403 332, 403 333 in Sscrofa genome, as annotated in 11.1, NCBI). Transcripts encoding these isoforms of aromatase are primarily found in early embryonic stages (CYP19A1), placenta (CYP19A2), and in male and female gonads (CYP19A3), respectively [3, 4]. In other mammalian species, e.g., bovine, rat, or mouse, different functional aromatase isoforms have not been identified, though duplication of CYP19 has led to non-protein-coding copies in cattle (NCBI: LOC503858) and sheep (NCBI: LOC106991281), so that the presence of only one functional genomic copy, referred to as CYP19A1 seems to be the rule in mammals (other than pigs and related Suiformes).