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Applied and Environmental Microbiology, January 2006, p. 167-177, Vol. 72, No. 1
0099-2240/06/$08.00+0     doi:10.1128/AEM.72.1.167-177.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Deoxysugar Transfer during Chromomycin A3 Biosynthesis in Streptomyces griseus subsp. griseus: New Derivatives with Antitumor Activity{dagger}

Nuria Menéndez,1 Mohammad Nur-e-Alam,2 Carsten Fischer,2 Alfredo F. Braña,1 José A. Salas,1 Jürgen Rohr,2* and Carmen Méndez1*

Departamento de Biología Funcional e Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain,1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky2

Received 20 June 2005/ Accepted 28 September 2005

Chromomycin A3 is an antitumor drug produced by Streptomyces griseus subsp. griseus. It consists of a tricyclic aglycone with two aliphatic side chains and two O-glycosidically linked saccharide chains, a disaccharide of 4-O-acetyl-D-oliose (sugar A) and 4-O-methyl-D-oliose (sugar B), and a trisaccharide of D-olivose (sugar C), D-olivose (sugar D), and 4-O-acetyl-L-chromose B (sugar E). The chromomycin gene cluster contains four glycosyltransferase genes (cmmGI, cmmGII, cmmGIII, and cmmGIV), which were independently inactivated through gene replacement, generating mutants C60GI, C10GII, C10GIII, and C10GIV. Mutants C10GIV and C10GIII produced the known compounds premithramycinone and premithramycin A1, respectively, indicating the involvement of CmmGIV and CmmGIII in the sequential transfer of sugars C and D and possibly also of sugar E of the trisaccharide chain, to the 12a position of the tetracyclic intermediate premithramycinone. Mutant C10GII produced two new tetracyclic compounds lacking the disaccharide chain at the 8 position, named prechromomycin A3 and prechromomycin A2. All three compounds accumulated by mutant C60GI were tricyclic and lacked sugar B of the disaccharide chain, and they were named prechromomycin A4, 4A-O-deacetyl-3A-O-acetyl-prechromomycin A4, and 3A-O-acetyl-prechromomycin A4. CmmGII and CmmGI are therefore responsible for the formation of the disaccharide chain by incorporating, in a sequential manner, two D-oliosyl residues to the 8 position of the biosynthetic intermediate prechromomycin A3. A biosynthetic pathway is proposed for the glycosylation events in chromomycin A3 biosynthesis.

* Corresponding author. Mailing address for Carmen Méndez (molecular biological questions): Departamento de Biología Funcional, Área de Microbiología, Facultad de Medicina, Universidad de Oviedo, c/ Julián Clavería s/n, 33006 Oviedo, Spain. Phone: 34 985 103558. Fax: 34 985 103652. E-mail: cmendezf{at}uniovi.es. Mailing address for Jürgen Rohr (chemical questions): Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536-0082. Phone: (859) 323-5031. Fax: (859) 257-7564. E-mail: jrohr2{at}email.uky.edu

{dagger} Supplemental material for this article may be found at http://aem.asm.org/.

Applied and Environmental Microbiology, January 2006, p. 167-177, Vol. 72, No. 1
0099-2240/06/$08.00+0     doi:10.1128/AEM.72.1.167-177.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Menendez, N., Brana, A. F., Salas, J. A., Mendez, C. (2007). Involvement of a chromomycin ABC transporter system in secretion of a deacetylated precursor during chromomycin biosynthesis. Microbiology 153: 3061-3070 [Abstract] [Full Text]  


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