Abstract
Despite increasing evidence indicates polyamines as a convergence point for signaling pathways, including cell growth and differentiation, a unifying concept to interpret their role is still missing. The activity of ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, is tightly regulated by a complex molecular machinery, and the demonstration of the existence of multiple ODC paralogs, lacking decarboxylation activity, suggests additional layers of complexity to the intricate ODC regulatory pathway. Because of their extraordinary regenerative abilities and abundance of stem cells, planarians have potential to contribute to our understanding of polyamine function in an in vivo context. We undertook a study on ODC function in planarians and we found six planarian ODCs (ODC1-6). Five out of six ODC homologs carry substitutions of key aminoacids for enzymatic activity, which makes them theoretically unable to decarboxylate ornithine. Silencing of ODC5 and 6 produced a complex phenotype, by prompting animals to an aberrant response, following chronic injury without tissue removal. Phenotype is neither rescued by putrescine, nor mimicked by difluoromethylornithine treatment. Moreover, the co-silencing of other genes of the ODC regulatory pathway did not modulate phenotype outcome or severity, thus suggesting that the function/s of these ODC-like proteins might be unrelated to decarboxylase activity and putrescine production.
Highlights
The role of polyamines has been associated with cell growth, aging, memory performance, neurodegenerative diseases, metabolic disorders and cancer[1,2,3,4,5,6]
In order to investigate whether the six putative ODC isoforms are conserved in the closely related planarian species S. mediterranea, we searched for transcripts annotated as “similar to ornithine decarboxylase” in the Schmidtea mediterranea genome database (SmedGD)[25], and we managed to group the results into five (A to E) classes of sequences, each class representing a S. mediterranea homolog of ODC (Table S2)
According to the expected value (E-value) resulted from alignments of each D. japonica ODC nucleotide sequence, to S. mediterranea representative members of class A, B, C, D and E, we managed to match D. japonica ODCs with their corresponding putative homologs in S. mediterranea
Summary
The role of polyamines has been associated with cell growth, aging, memory performance, neurodegenerative diseases, metabolic disorders and cancer[1,2,3,4,5,6]. Since ODC functions as a dimer and the active site is formed in the interface between the two monomers, the authors proposed one alternative possibility in which some of the inactive paralogs form heterodimers with the enzymatically active paralog, inactivating it, which would make them ornithine decarboxylase inhibitors. This would add yet another layer of complexity to the already known multiple layers of ODC regulation
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