Cyclophilins are folding helper enzymes belonging to the class of 
peptidyl-prolyl cis-trans isomerases (PPIases; EC 5.2.1.8) that catalyze the 
cis-trans isomerization of peptidyl-prolyl bonds in proteins. They are 
ubiquitous proteins present in almost all living organisms analyzed to date, 
with extremely rare exceptions. Few cyclophilins have been described in 
Actinobacteria, except for three reported in the genus Streptomyces and another 
one in Mycobacterium tuberculosis. In this study, we performed a complete 
phylogenetic analysis of all Actinobacteria cyclophilins available in sequence 
databases and new Streptomyces cyclophilin genes sequenced in our laboratory. 
Phylogenetic analyses of cyclophilins recovered six highly supported groups of 
paralogy. Streptomyces appears as the bacteria having the highest cyclophilin 
diversity, harboring proteins from four groups. The first group was named "A" 
and is made up of highly conserved cytosolic proteins of approximately 18 kDa 
present in all Actinobacteria. The second group, "B," includes cytosolic 
proteins widely distributed throughout the genus Streptomyces and closely 
related to eukaryotic cyclophilins. The third group, "M" cyclophilins, consists 
of high molecular mass cyclophilins ( approximately 30 kDa) that contain 
putative membrane binding domains and would constitute the only membrane 
cyclophilins described to date in bacteria. The fourth group, named "C" 
cyclophilins, is made up of proteins of approximately 18 kDa that are 
orthologous to Gram-negative proteobacteria cyclophilins. Ancestral character 
reconstruction under parsimony was used to identify shared-derived (and likely 
functionally important) amino acid residues of each paralogue. Southern and 
Western blot experiments were performed to determine the taxonomic distribution 
of the different cyclophilins in Actinobacteria.