Characterization of aklavinone-11-hydroxylase from Streptomyces purpurascens

Niemi, Jarmo; Wang, Yulong; Airas, Kalervo; Ylihonko, Kristiina; Hakala, Juha; Mäntsälä, Pekka

doi:10.1016/s0167-4838(98)00265-9

Cited by 18 publications

(29 citation statements)

References 14 publications

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“…RdmE catalyzing aklavinone-11-hydroxylation in Streptomyces purpurascens) (21) and some novel oxygenases. Aclacinomycin 10-hydroxylase involved in rhodomycin biosynthesis in S. purpurascens was reported as the first unveiled hydroxylase using S-adenosyl-L-methionine as a cofactor (22).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Investigation of the Roles of FdmM and FdmM1 in Fredericamycin Biosynthesis Unveiling a New Family of Oxygenases

Chen

Wendt-Pienkoski

Rajski

et al. 2009

Journal of Biological Chemistry

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Fredericamycin (FDM) A, a highly oxidized aromatic pentadecaketide natural product, exhibits potent cytotoxicity and has been studied as a new anticancer drug lead. The FDM biosynthetic gene cluster has been previously cloned from Streptomyces griseus ATCC 49344 and successfully expressed in the heterologous host Streptomyces albus J1074. The fdmM and fdmM1 genes code for two proteins with high sequence homology to each other but unknown function. In-frame deletion of each of the genes from the fdm cluster was accomplished in the S. albus host. Each mutant failed to produce FDM A and the key biosynthetic intermediate FDM E but produced various new metabolites, the titers of which were dramatically increased via overexpression of an fdm pathway-specific activator fdmR1. The ⌬fdmM mutant strain accumulated three new compounds FDM M-1, FDM M-2, and FDM M-3, whereas the ⌬fdmM1 mutant strain produced one new compound FDM M1-1. Isolation and structural characterization of these compounds enable us to propose that FdmM and FdmM1 catalyze the C-6 and C-8 hydroxylations for FDM biosynthesis, respectively. Homologs of FdmM and FdmM1 can be found in biosynthetic gene clusters of many other aromatic polyketides, ranging from dodecaketides to pentadecaketides, but to date all of them were annotated as proteins of unknown function. Based on the findings reported here for FdmM and FdmM1, we now propose similar functions for those proteins, and FdmM and FdmM1 therefore represent an emerging family of novel oxygenases responsible for hydroxylation of aromatic polyketide natural products.Studies on natural product biosynthetic pathways have uncovered a number of intriguing oxygenases. For instance, the first reported metal-and cofactor-free monooxygenase TcmH is responsible for quinone moiety formation in tetracenomycin D3 and represents a rapidly growing family of antibiotic biosynthetic monooxygenases (1, 2). Another example is DpgC, which is involved in the biosynthesis of vancomycin building block 3, 5-dihydroxyphenylglycine. The crystal structure of DpgC has been used to understand the reaction mechanism of metal-and cofactor-free dioxygenases (3). MomA, involved in mompain biosynthesis (4) is a metal ion-dependent monooxygenase belonging to the cupin superfamily of oxidases bearing no prosthetic group. The discovery of enzymes such as TcmH, DpgC, and MomA continually encourage the community to search for and characterize new oxygenases from proteins of unknown functions involved in natural products biosynthesis.Whereas octaketides (C-16), nonaketides (C-18), and decaketides (C-20) are the most common aromatic polyketide natural products whose biosyntheses have been extensively investigated, aromatic polyketides ranging from dodecaketides (C-24) to pentadecaketides (C-30) are also known including biologically active compounds such as fredericamycin (FDM) 2 A (1) (5, 6), pradimicin A (2) (7), lysolipin X (3) (8), griseorhodin A (4) (9), benastatin A (5) (10), and ␥-rubromycin (6) ( Fig. 1 and Ref. 11). The highly oxidized nat...

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Section: Discussionmentioning

confidence: 99%

In Vivo Investigation of the Roles of FdmM and FdmM1 in Fredericamycin Biosynthesis Unveiling a New Family of Oxygenases

Chen

Wendt-Pienkoski

Rajski

et al. 2009

Journal of Biological Chemistry

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“…Protein Purification and Crystallization-RdmC from S. purpurascens was expressed in Streptomyces lividans and purified as previously described (11). AcmT was produced from AcmA (Calbiochem) by partial hydrolysis as previously described (5).…”

Section: Methodsmentioning

confidence: 99%

“…Enzymes encoded by this gene cluster include RdmA, an aklanonic acid methylester cyclase, and aklavinone-11-hydroxylase RdmE, which converts aklavinone to ⑀-rhodomycinone (11). Genetic evidence suggests that rdmB and rdmC code for two enzymes that catalyze the steps leading from ⑀-rhodomycinone glycoside to ␤-rhodomycinone glycoside (16).…”

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confidence: 99%

Crystal Structure of Aclacinomycin Methylesterase with Bound Product Analogues

Jansson

Niemi

Mäntsälä

et al. 2003

Journal of Biological Chemistry

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“…10,12 RdmE encodes an aklavinone-11-hydroxylase, a NAD (P)H-and flavin adenine dinucleotide (FAD)-dependent monooxygenase. 13 The enzyme catalyzes the incorporation of a hydroxyl group at position C-11 of aklavinone, resulting in ɛ-rhodomycinone (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…This tailoring reaction is shared between biosynthetic pathways leading to different anthracyclines, for instance, daunorubicin in S. peucetius 14,15 and rhodomycin in S. purpurascens. 13 Aklavinone hydroxylases act before the glycosylation step; that is, they cannot accept glycosylated substrates. RdmE is also specific for the C-9R configuration of anthracyclines and does not hydroxylate compounds with C-9S configuration.…”

Section: Introductionmentioning

confidence: 99%