In vitro biosynthesis of ring-extended cyclosporins.
Cyclosporin synthetase, a multifunctional polypeptide, catalyses the biosynthesis of the set of natural cyclosporins. We report that this enzyme is also capable of introducing a beta-alanine into position 7 or 8 of the ring instead of the alpha-alanines present at these positions in cyclosporin A. This leads to 34-membered rings in contrast to the 33-membered ring of the cyclo-undecapeptide cyclosporin A. Both [beta Ala7]CyA and [beta Ala8]CyA show immunosuppressive activity. The cyclosporin synthetase-related enzyme peptolide SDZ 214-103 synthetase, on the other hand, does not incorporate either beta-alanine into position 7 or beta-hydroxy acids into position 8, confirming the previously described higher substrate specificity of this enzyme compared with cyclosporin synthetase [Lawen and Traber (1993) J. Biol. Chem. 268, 20452-20465].
Lawen
A
A
Institut für Biochemie und Molekulare Biologie, Technische Universität Berlin, Germany.
Traber
R
R
Reuille
R
R
Ponelle
M
M
D001345:Autoradiography; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D003524:Cyclosporins / Q000096:biosynthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D003904:Mitosporic Fungi / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000378:metabolism; D010453:Peptide Synthases / Q000378:metabolism; D016339:Spectrometry, Mass, Fast Atom Bombardment
D003524:Cyclosporins; D009097:Multienzyme Complexes; C048525:cyclosporin A synthetase; D010453:Peptide Synthases