Cyclic CMP and cyclic UMP: new (old) second messengers

Abstract

Historical background As early as 1965 it was proposed that in addition to the well-established second messengers, cyclic AMP and cyclic GMP, the cyclic pyrimidine nucleotides, cyclic CMP (cCMP) and cyclic UMP (cUMP) could play a role as second messenger molecules. This hypothesis was based on the identification of cCMPand cUMP-hydrolyzing phosphodiesterase (PDE) activities in mammalian tissues [1,2]. Additionally, extracellular effects of cCMP on cell proliferation were reported [3], but unfortunately, those effects were not reproduced. Moreover, a specific cytidylyl cyclase activity was proposed, but the methodology used was questionable [4,5]. Furthermore, cCMP and cUMP were supposedly identified by fast atom bombardment mass spectrometry, but the methodology was not sufficiently accurate for unequivocal mass determination of cCMP and cUMP [6]. Because of the substantial methodological problems, the cCMP and cUMP field had been largely abandoned. Our recent discovery that the bacterial “adenylyl” cyclase toxins, CyaA from Bordetella pertussis and edema factor from Bacillus anthracis, also exhibit substantial cytidylyland uridylyl cyclase activity as assessed by radiometric assays [7], renewed interest in the cCMP and cUMP field.