Substrate specificities of cyclosporin synthetase and peptolide SDZ 214-103 synthetase. Comparison of the substrate specificities of the related multifunctional polypeptides

J Biol Chem. 1993 Sep 25;268(27):20452-65.


The recently discovered multifunctional polypeptide cyclosporin synthetase is capable of synthesizing the cyclic undecapeptide cyclosporin A in a batch reaction. Substrates are the unmethylated constitutive amino acids of cyclosporin A. Exchange of one or more of these by various amino acids gives a picture of the substrate specificity of the enzyme in vitro, which is different from the known picture obtained by in vivo studies. The uncommon amino acid butenylmethylthreonine in position 1 of the cyclosporin ring can be exchanged by an unexpected large spectrum of different amino acids, showing a great flexibility of this site. Position 2, on the other hand, which shows the greatest variability in vivo, has an only slightly lower specificity in vitro. Position 3 has a very high degree of specificity; positions 4, 6, 7, 9, and 10 have marginally less. The variability of positions 5 and 11 is moderate, whereas position 8 shows only low substrate specificity in vitro. In general, most sites of SDZ 214-103 synthetase appear to be more specific than those of cyclosporin synthetase. Site 11 has nearly identical substrate specificity compared with that of cyclosporin synthetase. The D-2-hydroxy acid position (position 8) can be occupied by a large spectrum of substrates varying from D-lactic acid to D-2-hydroxyisocaproic acid. Within the limits of the present data, the addition of further functional groups to the D-2-hydroxy acid moiety are apparently not tolerated by the enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acids / metabolism
  • Chromatography, High Pressure Liquid
  • Chromatography, Thin Layer
  • Cyclosporine / biosynthesis
  • Cyclosporins / biosynthesis*
  • Cyclosporins / chemistry
  • Cyclosporins / isolation & purification
  • Mitosporic Fungi / enzymology*
  • Molecular Sequence Data
  • Molecular Structure
  • Multienzyme Complexes / metabolism*
  • Peptide Synthases / metabolism*
  • Substrate Specificity


  • Amino Acids
  • Cyclosporins
  • Multienzyme Complexes
  • cyclosporin A synthetase
  • SDZ 214-103
  • peptolide SDZ 214-103 synthetase
  • Cyclosporine
  • Peptide Synthases