Common features of the biosynthetic pathways of lincomycin,some pyrrolo-1,4-benzodiazepines and hormaomycin

Lincosamides, pyrrolo-1,4-benzodiazepines (PBD) and hormaomycin are biologically active substances differing in their structure and mode of action. Lincosamides lincomycin and clindamycin are clinically used antibiotics, PBD exhibit antitumor activity and hormaomycin is a bacterial hormone. Unusual precursor, 4-propyl-L-proline (PPL) derived from L-tyrosine is incorporated in the lincomycin structure. Surprisingly, structurally and functionally dissimilar hormaomycin and some PBD (tomaymycin, anthramycin, sibiromycin) incorporate L-proline derivative with two- or three- carbon side chain of the same biosynthetic origin. Accordingly, a set of orthologous genes coding for biosynthesis of these structurally similar precursors has been found in appropriate biosynthetic gene clusters. There is a clear evolutionary relationship among the biosynthesis of lincomycin, hormaomycin and some PBD. However, the evolutionary origin of PPL pathway is not known as well as its further development. Only a limited number of naturally occured modifications of the pathway has been described and the history of supposed horizontal gene transfers of biosynthetic genes remains unknown. Answers to these questions are particularly important due to the preparation of new hybrid substances with improved bioactive effects using methods..