Elucidation of the kijanimicin gene cluster: insights into the biosynthesis of spirotetronate antibiotics and nitrosugars.
The antibiotic kijanimicin produced by the actinomycete Actinomadura kijaniata has a broad spectrum of bioactivities as well as a number of interesting biosynthetic features. To understand the molecular basis for its formation and to develop a combinatorial biosynthetic system for this class of compounds, a 107.6 kb segment of the A. kijaniata chromosome containing the kijanimicin biosynthetic locus was identified, cloned, and sequenced. The complete pathway for the formation of TDP-l-digitoxose, one of the two sugar donors used in construction of kijanimicin, was elucidated through biochemical analysis of four enzymes encoded in the gene cluster. Sequence analysis indicates that the aglycone kijanolide is formed by the combined action of a modular Type-I polyketide synthase, a conserved set of enzymes involved in formation, attachment, and intramolecular cyclization of a glycerate-derived three-carbon unit, which forms the core of the spirotetronate moiety. The genes involved in the biosynthesis of the unusual deoxysugar d-kijanose [2,3,4,6-tetradeoxy-4-(methylcarbamyl)-3-C-methyl-3-nitro-d-xylo-hexopyranose], including one encoding a flavoenzyme predicted to catalyze the formation of the nitro group, have also been identified. This work has implications for the biosynthesis of other spirotetronate antibiotics and nitrosugar-bearing natural products, as well as for future mechanistic and biosynthetic engineering efforts.
Zhang
Hua
H
Division of Medicinal Chemistry, College of Pharmacy, Institute of Cellular and Molecular Biology, Austin, Texas 78712, USA.
White-Phillip
Jess A
JA
Melançon
Charles E
CE
Kwon
Hyung-jin
HJ
Yu
Wei-luen
WL
Liu
Hung-wen
HW
D039903:Actinobacteria / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000617:Aminoglycosides / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D005810:Multigene Family / Q000235:genetics*; D017672:Nitrogen Compounds / Q000737:chemistry / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D017672:Nitrogen Compounds; D013141:Spiro Compounds; C033276:kijanimicin