New Rimocidin/CE-108 Derivatives Obtained by a Crotonyl-CoA Carboxylase/Reductase Gene Disruption in Streptomyces diastaticus var. 108: Substrates for the Polyene Carboxamide Synthase PcsA.
The rimJ gene, which codes for a crotonyl-CoA carboxylase/reductase, lies within the biosynthetic gene cluster for two polyketides belonging to the polyene macrolide group (CE-108 and rimocidin) produced by Streptomyces diastaticus var. 108. Disruption of rimJ by insertional inactivation gave rise to a recombinant strain overproducing new polyene derivatives besides the parental CE-108 (2a) and rimocidin (4a). The structure elucidation of one of them, CE-108D (3a), confirmed the incorporation of an alternative extender unit for elongation step 13. Other compounds were also overproduced in the fermentation broth of rimJ disruptant. The new compounds are in vivo substrates for the previously described polyene carboxamide synthase PcsA. The rimJ disruptant strain, constitutively expressing the pcsA gene, allowed the overproduction of CE-108E (3b), the corresponding carboxamide derivative of CE-108D (3a), with improved pharmacological properties.
Centro Nacional de Biotecnología (CNB-CSIC), Campus de la Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain.
Leticia
L
Escudero
Department of Organic and Biomolecular Chemistry, University of Göttingen, Tammannstrasse 2, D-37077, Göttingen, Germany.
Mahmoud
M
Al-Refai
Centro Nacional de Biotecnología (CNB-CSIC), Campus de la Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain.
Cristina
C
Nieto
Department of Organic and Biomolecular Chemistry, University of Göttingen, Tammannstrasse 2, D-37077, Göttingen, Germany.
Hartmut
H
Laatsch
Centro Nacional de Biotecnología (CNB-CSIC), Campus de la Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain.
Francisco
F
Malpartida
Centro Nacional de Biotecnología (CNB-CSIC), Campus de la Universidad Autónoma de Madrid, Cantoblanco, 28049, Madrid, Spain.
Elena M
EM
Seco
D019732:Amide Synthases / Q000378:metabolism*; D019735:Carbon-Carbon Ligases / Q000235:genetics* / Q000378:metabolism; D005818:Genetic Engineering; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism*; D009005:Monosaccharides / Q000737:chemistry / Q000378:metabolism*; D011090:Polyenes / Q000737:chemistry / Q000378:metabolism; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D013379:Substrate Specificity
C485858:CE-108; D018942:Macrolides; D009005:Monosaccharides; D011090:Polyenes; C003273:rimocidin; D019732:Amide Synthases; D019735:Carbon-Carbon Ligases