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Structurally CAP is related to the E. coli transcription factor FNR [J Mol Biol] [FNR at UniProtKB].  FNR (Fumarate-Nitrate Reduction) is a global regulator acting upon the availability of oxygen in the environment [J Biol Chem] [Proc Natl Acad Sci U S A].  The FNR regulon was characterized by microarray studies [J Biol Chem].  In vivo regulation by FNR was shown to involve cycling of FNR between active and inactive states [Microbiology].  Studies of transcriptional regulation by FNR using artificial FNR-dependent promoters [J Bacteriol] and mutagenesis [J Bacteriol] have uncovered some differences between FNR and CAP.

The third member in the E. coli family of proteins affiliated to CAP is YeiL, the product of the yeiL gene [Microbiology].

The CAP/FNR family has expanded to a superfamily of versatile transcriptional regulators [Medline].  Interestingly E. coli FNR was shown to respond not only to  oxygen but also to nitric oxyde (NO) [EMBO J], and accumulation of NO may inactivate FNR in mutant strains lacking the NO-detoxifying flavohaemoglobin Hmp [J Biol Chem].  In Paracoccus denitrificans NNR (the nitrite reductase and nitric oxide reductase regulator, a member of the CAP/FNR family) also senses both oxygen and NO [Microbiology].  In Salmonella enterica serovar Typhimurium FNR (OxrA) plays a major role in virulence [J Bacteriol].

Cyclic nucleotide-binding domains homologous to CAP cAMP-binding domain are present in regulatory subunits of cAMP-dependent protein kinases [Proc Natl Acad Sci U S A] as well as cyclic nucleotide-gated (CNG) ion channels.  CNG channels are opened upon binding of cyclic nucleotides, especially cAMP or cGMP [Physiol Rev].  A fusion between the cyclic nucleotide-binding domain of the bovine retinal rod channel (alpha subunit) and the DNA-binding domain of CAP was shown to be functional [Biochemistry].

Proteins bearing a CAP like cAMP-binding domain are members of COG0664 [COG database].  Additional eukaryotic members of COG0664 are from Drosophila melanogaster (fruit fly) and Caenorhabditis elegans (soil nematode).

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