Two multifunctional peptide synthetases and an O-methyltransferase are involved in the biosynthesis of the DNA-binding antibiotic and antitumour agent saframycin Mx1 from Myxococcus xanthus.
Saframycin Mx1 is a DNA-binding antibiotic and antitumour agent produced by Myxococcus xanthus. It is a heterocyclic quinone, thought to be synthesized via the linear peptide intermediate AlaGlyTyrTyr. Analysis of 14.1 kb DNA sequence involved in saframycin production revealed genes for two large multifunctional peptide synthetases of 1770 and 2605 amino acids, respectively, and a putative O-methyltransferase of 220 amino acids. The three ORFs read in the same direction and are separated by short non-translated gaps of 44 and 49 bp. The peptide synthetases contain two amino-acid-activating domains each. The first domain lacks two of the most conserved 'core' sequences, and the last domain is followed by a putative reductase functionality, not previously seen in peptide synthetases. Complementation tests showed that antibiotic-non-producing mutant strains lacking one of the peptide synthetases secrete a substrate, presumably a modified amino acid precursor, that can be used by O-methyltransferase-deficient mutant strains to synthesize saframycin Mx1.
Pospiech
Andreas
A
Ciba-Geigy Ltd, Core Drug Discovery Technologies, CH-4002 Basel, Switzerland.
Bietenhader
Jürg
J
Ciba-Geigy Ltd, Core Drug Discovery Technologies, CH-4002 Basel, Switzerland.
Schupp
Thomas
T
Ciba-Geigy Ltd, Core Drug Discovery Technologies, CH-4002 Basel, Switzerland.
D000595:Amino Acid Sequence; D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis* / Q000737:chemistry; D001426:Bacterial Proteins; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004269:DNA, Bacterial / Q000235:genetics; D018390:Gene Targeting; D005798:Genes, Bacterial; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D015394:Molecular Structure; D005810:Multigene Family; D016941:Myxococcus xanthus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D016366:Open Reading Frames; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism*; D011497:Protein O-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D000903:Antibiotics, Antineoplastic; D001426:Bacterial Proteins; D017931:DNA Primers; D004269:DNA, Bacterial; D007546:Isoquinolines; D011498:Protein Precursors; C057297:saframycin Mx1; D011497:Protein O-Methyltransferase; D010453:Peptide Synthases; C095944:SafA protein, Myxococcus xanthus