Menendez N, Nur-e-Alam M, Brana AF, Rohr J, Salas JA, Mendez C.
Biosynthesis of the antitumor chromomycin A3 in Streptomyces
griseus: analysis of the gene cluster and rational design of
novel chromomycin analogs.
Chem Biol. 2004 Jan;11(1):21-32.
Departamento de Biología Funcional e Instituto Universitario
de Oncología del Principado de Asturias, Universidad de Oviedo,
33006 Oviedo, Spain.
The biosynthetic gene cluster of the aureolic acid type
antitumor drug chromomycin A3 from S. griseus subsp. griseus has
been identified and characterized. It spans 43 kb and contains
36 genes involved in polyketide biosynthesis and modification,
deoxysugar biosynthesis and sugar transfer, pathway regulation
and resistance. The organization of the cluster clearly differs
from that of the closely related mithramycin. Involvement of the
cluster in chromomycin A3 biosynthesis was demonstrated by
disrupting the cmmWI gene encoding a polyketide reductase
involved in side chain reduction. Three novel chromomycin
derivatives were obtained, named chromomycin SK, chromomycin SA,
and chromomycin SDK, which show antitumor activity and differ
with respect to their 3-side chains. A pathway for the
biosynthesis of chromomycin A3 and its deoxysugars is proposed.
PMID: 15112992 |
