68-81-5Relevant academic research and scientific papers
Dual phenazine gene clusters enable diversification during biosynthesis
Shi, Yi-Ming,Brachmann, Alexander O.,Westphalen, Margaretha A.,Neubacher, Nick,Tobias, Nicholas J.,Bode, Helge B.
, p. 331 - 339 (2019/04/17)
Biosynthetic gene clusters (BGCs) bridging genotype and phenotype continuously evolve through gene mutations and recombinations to generate chemical diversity. Phenazine BGCs are widespread in bacteria, and the biosynthetic mechanisms of the formation of the phenazine structural core have been illuminated in the last decade. However, little is known about the complex phenazine core-modification machinery. Here, we report the diversity-oriented modifications of the phenazine core through two distinct BGCs in the entomopathogenic bacterium Xenorhabdus szentirmaii, which lives in symbiosis with nematodes. A previously unidentified aldehyde intermediate, which can be modified by multiple enzymatic and non-enzymatic reactions, is a common intermediate bridging the pathways encoded by these BGCs. Evaluation of the antibiotic activity of the resulting phenazine derivatives suggests a highly effective strategy to convert Gram-positive specific phenazines into broad-spectrum antibiotics, which might help the bacteria–nematode complex to maintain its special environmental niche.
Functional and Structural Analysis of Phenazine O -Methyltransferase LaPhzM from Lysobacter antibioticus OH13 and One-Pot Enzymatic Synthesis of the Antibiotic Myxin
Jiang, Jiasong,Guiza Beltran, Daisy,Schacht, Andrew,Wright, Stephen,Zhang, Limei,Du, Liangcheng
, p. 1003 - 1012 (2018/04/30)
Myxin is a well-known antibiotic that had been used for decades. It belongs to the phenazine natural products that exhibit various biological activities, which are often dictated by the decorating groups on the heteroaromatic three-ring system. The three rings of myxin carry a number of decorations, including an unusual aromatic N5,N10-dioxide. We previously showed that phenazine 1,6-dicarboxylic acid (PDC) is the direct precursor of myxin, and two redox enzymes (LaPhzS and LaPhzNO1) catalyze the decarboxylative hydroxylation and aromatic N-oxidations of PDC to produce iodinin (1.6-dihydroxy-N5,N10-dioxide phenazine). In this work, we identified the LaPhzM gene from Lysobacter antibioticus OH13 and demonstrated that LaPhzM encodes a SAM-dependent O-methyltransferase converting iodinin to myxin. The results further showed that LaPhzM is responsible for both monomethoxy and dimethoxy formation in all phenazine compounds isolated from strain OH13. LaPhzM exhibits relaxed substrate selectivity, catalyzing O-methylation of phenazines with non-, mono-, or di-N-oxide. In addition, we demonstrated a one-pot biosynthesis of myxin by in vitro reconstitution of the three phenazine-ring decorating enzymes. Finally, we determined the X-ray crystal structure of LaPhzM with a bound cofactor at 1.4 ? resolution. The structure provided molecular insights into the activity and selectivity of the first characterized phenazine O-methyltransferase. These results will facilitate future exploitation of the thousands of phenazines as new antibiotics through metabolic engineering and chemoenzymatic syntheses.
Total synthesis and antileukemic evaluations of the phenazine 5,10-dioxide natural products iodinin, myxin and their derivatives
Viktorsson, Elvar ?rn,Melling Gr?the, Bendik,Aesoy, Reidun,Sabir, Misbah,Snellingen, Simen,Prandina, Anthony,H?gmoen ?strand, Ove Alexander,Bonge-Hansen, Tore,D?skeland, Stein Ove,Herfindal, Lars,Rongved, P?l
supporting information, p. 2285 - 2293 (2017/03/24)
A new efficient total synthesis of the phenazine 5,10-dioxide natural products iodinin and myxin and new compounds derived from them was achieved in few steps, a key-step being 1,6-dihydroxyphenazine di-N-oxidation. Analogues prepared from iodinin, including myxin and 2-ethoxy-2-oxoethoxy derivatives, had fully retained cytotoxic effect against human cancer cells (MOLM-13 leukemia) at atmospheric and low oxygen level. Moreover, iodinin was for the first time shown to be hypoxia selective. The structure-activity relationship for leukemia cell death induction revealed that the level of N-oxide functionality was essential for cytotoxicity. It also revealed that only one of the two phenolic functions is required for activity, allowing the other one to be modified without loss of potency.
Heterocyclic Aromatic N-Oxidation in the Biosynthesis of Phenazine Antibiotics from Lysobacter antibioticus
Zhao, Yangyang,Qian, Guoliang,Ye, Yonghao,Wright, Stephen,Chen, Haotong,Shen, Yuemao,Liu, Fengquan,Du, Liangcheng
supporting information, p. 2495 - 2498 (2016/06/09)
Heterocyclic aromatic N-oxides often have potent biological activities, but the mechanism for aromatic N-oxidation is unclear. Six phenazine antibiotics were isolated from Lysobacter antibioticus OH13. A 10 gene cluster was identified for phenazine biosynthesis. Mutation of LaPhzNO1 abolished all N-oxides, while non-oxides markedly increased. LaPhzNO1 is homologous to Baeyer-Villiger flavoproteins but was shown to catazlye phenazine N-oxidation. LaPhzNO1 and LaPhzS together converted phenazine 1,6-dicarboxylic acid to 1,6-dihydroxyphenazine N5,N10-dioxide. LaPhzNO1 also catalyzed N-oxidation of 8-hydroxyquinoline.
A novel species of acrocarpospora, a method of preparing iodinin, and the uses of iodinin
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, (2009/01/24)
The present invention provides a novel species of Acrocarpospora gen. that is capable of producing iodinin. The invention also provides a method of preparing iodinin, and uses of iodinin in inducing cytotoxicity and treating cancers.
NOVEL SPECIES OF ACROCARPOSPORA, A METHOD OF PREPARING IODININ, AND THE USES OF IODININ
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, (2009/03/07)
The present invention provides a novel species of Acrocarpospora gen. that is capable of producing iodinin. The invention also provides a method of preparing iodinin, and uses of iodinin in inducing cytotoxicity and treating cancers.
