Arginine Decarboxylase and Agmatinase: An Alternative Pathway for De Novo Biosynthesis of Polyamines for Development of Mammalian Conceptuses

Ornithine decarboxylase (ODC1) is considered the rate-controlling enzyme for the classical de novo biosynthesis of polyamines (putrescine, spermidine, spermine) in mammals. However, metabolism of arginine to agmatine via arginine decarboxylase (ADC) and conversion of agmatine to polyamines via agmatinase (AGMAT) is an alternative pathway long recognized in lower organisms, but only recently suggested for neurons and liver cells of mammals. We now provide evidence for a functional ADC/AGMAT pathway for synthesis of polyamines in mammalian reproductive tissue for embryonic survival and development. We first investigated cellular functions of polyamines by in vivo knockdown of translation of mRNA for ODC1 in ovine conceptus trophectoderm using morpholino antisense oligonucleotides (MAO) and found that one-half of the conceptuses were morphologically and functionally either normal or abnormal. Furthermore, we found that increases in ADC/AGMAT mRNA levels and in the translation of AGMAT mRNA among conceptuses in MAO-ODC1 knockdown compensated for the loss of ODC1 to support polyamine synthesis from arginine and account for the normal and abnormal phenotypes of conceptuses. We conclude that the majority of polyamine synthesis is by the conventional ODC1-dependent pathway (arginine-ornithine-putrescine) and that deficiencies in ODC1 result in increased activity of the rescue ADC/AGMAT-dependent pathway (arginine-agmatine-putrescine) for production of polyamines. Presence of an alternative ADC/AGMAT pathway for converting arginine into putrescine is functionally important for supporting survival and development of mammalian conceptuses.