SBSPKS: structure based sequence analysis of polyketide synthases

Anand, Swadha; Prasad, Manoj; Yadav, Gitanjali; Kumar, Narendra; Shehara, Jyoti; Ansari, Mohd Zeeshan; Mohanty, Debasisa

doi:10.1093/nar/gkq340

Cited by 167 publications

(124 citation statements)

References 50 publications

(65 reference statements)

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“…A major limitation is the unpredictable loss of enzyme catalytic activity. The polyketide biosynthesis is brought about by complex machinery consisting of a tightly coupled network of core catalytic and structural domains (33). Changes of domains or/and modules will probably cause the PKS complex to fold incorrectly and lose a necessary activity or lead to a modified polyketide chain that is not recognized as a substrate by a subsequent PKS activity (34).…”

Section: Discussionmentioning

confidence: 99%

Gene Replacement for the Generation of Designed Novel Avermectin Derivatives with Enhanced Acaricidal and Nematicidal Activities

Huang

Chen²,

Zhang

et al. 2015

Appl Environ Microbiol

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c Avermectin (AVM) and ivermectin (IVM) are potent pesticides and acaricides which have been widely used during the past 30 years. As insect resistance to AVM and IVM is greatly increasing, alternatives are urgently needed. Here, we report two novel AVM derivatives, tenvermectin A (TVM A) and TVM B, which are considered a potential new generation of agricultural and veterinary drugs. The molecules of the TVMs were designed based on structure and pharmacological property comparisons among AVM, IVM, and milbemycin (MBM). To produce TVMs, a genetically engineered strain, MHJ1011, was constructed from Streptomyces avermitilis G8-17, an AVM industrial strain. In MHJ1011, the native aveA1 gene was seamlessly replaced with milA1 from Streptomyces hygroscopicus. The total titer of the two TVMs produced by MHJ1011 reached 3,400 mg/liter. Insecticidal tests proved that TVM had enhanced activities against Tetranychus cinnabarinus and Bursaphelenchus xylophilus, as desired. This study provides a typical example of exploration for novel active compounds through a new method of polyketide synthase (PKS) reassembly for gene replacement. The results of the insecticidal tests may be of use in elucidating the structure-activity relationship of AVMs and MBMs.A vermectins (AVMs) are a series of 16-membered macrocyclic lactone derivatives with potent anthelmintic and insecticidal properties (1, 2). Ivermectin (IVM), a hydrogenated product of AVM B1, has been one of the best-selling antiparasitics since 1981 (3). However, as insect resistance to AVM (4) and IVM (5-7) is on the rise, alternatives or new products with enhanced potency and expanded spectra of activity are urgently needed.Milbemycins (MBMs) are another group of 16-membered macrolides that share similar structures with AVMs. The insecticidal activity of milbemectin (a mixture of MBMs A3 and A4) against some parasites is higher than those of AVM and IVM, while the toxicity is significantly lower (8).The structural differences among AVM, IVM, and MBM are in C-25, C-22-23, and C-13 ( Fig. 1) (9). IVM differs from AVM in C-22-23 (the former has a saturated bond, whereas the latter has a double bond in that position), but its toxicity is lower than that of AVM (10), implying that the single bond in C-22-23 should be the better structure in terms of safety. The major structural difference between IVM and MBM is a bisoleandrosyloxy substituent attached at C-13 of IVM, whereas that position is unsubstituted in MBM. Also, there are different alkyl substituents at C-25: in IVM, the substituent can be isopropyl or secondary butyl, while in MBM, it can be methyl or ethyl. However, MBM is more potent against some parasites and is safer than IVM, suggesting that one or both of the moieties in C-25 and C-13 of MBM is (are) the better structure(s) in these ways than that (those) of IVM. Another conclusion is that the two oleandroses in C-13 are important to the antiparasitic activity of IVM, since their removal will reduce the activity significantly, about 30-fold (10). Based on the curr...

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Section: Discussionmentioning

confidence: 99%

Gene Replacement for the Generation of Designed Novel Avermectin Derivatives with Enhanced Acaricidal and Nematicidal Activities

Huang

Chen²,

Zhang

et al. 2015

Appl Environ Microbiol

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“…Oftentimes, the distribution of the ion of interest is interfacial and the producer is ambiguous. By employing analytical and biological approaches, such as microbial IMS, IMS of multiple time points (67), traditional solvent extraction, purification, and structural determination methods, such as tandem MS and nuclear magnetic resonance (NMR) (18,30,33,67,68), genetics and microbiology, 16S rRNA sequencing (54), established MALDI-TOF protocols (12,49,53), genome mining approaches (7,13,15,45,63) and predictive programs (2,3,16,33, 40,48,55,62,65,68), peptidogenomics (31), and literature and database searches (23, 52) (AntiMarin database, Dictionary of Natural Products, the National Institute of Standards and Technology [NIST] databases, and the SciFinder database), one can typically annotate microbial IMS data. Two main strategies to confirm the producing microbe and the resultant phenotype are genetic knockout and complementation studies or assays with purified compound, in combination with more IMS.…”

Section: Challenges In Microbial Imsmentioning

confidence: 99%

Primer on Agar-Based Microbial Imaging Mass Spectrometry

et al. 2012

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Matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) imaging mass spectrometry (IMS) applied directly to microbes on agar-based medium captures global information about microbial molecules, allowing for direct correlation of chemotypes to phenotypes. This tool was developed to investigate metabolic exchange factors of intraspecies, interspecies, and polymicrobial interactions. Based on our experience of the thousands of images we have generated in the laboratory, we present five steps of microbial IMS: culturing, matrix application, dehydration of the sample, data acquisition, and data analysis/interpretation. We also address the common challenges encountered during sample preparation, matrix selection and application, and sample adherence to the MALDI target plate. With the practical guidelines described herein, microbial IMS use can be extended to bio-based agricultural, biofuel, diagnostic, and therapeutic discovery applications.

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“…Prediction of the nonribosomal peptide/polyketide synthetase cluster (NRPS/PKS) pathway was done using antiSMASH software (33). To further identify the acyl carrier protein (ACP) domain of the PKS pathway, structure-based sequence analysis of polyketide synthases (SBSPKS) was used (34). Phylogenetic analysis of the ketosynthase (KS) and condensation (C) domains was done using Natural Product Domain Seeker (NaPDoS) (35).…”

Section: ϫ8mentioning

confidence: 99%

Genomic Insights into the Evolutionary Origin of Xanthomonas axonopodis pv. citri and Its Ecological Relatives

Midha

Patil

2014

Appl Environ Microbiol

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Xanthomonas axonopodis pv. citri (Xac) is the causal agent of citrus bacterial canker (CBC) and is a serious problem worldwide. Like CBC, several important diseases in other fruits, such as mango, pomegranate, and grape, are also caused by Xanthomonas pathovars that display remarkable specificity toward their hosts. While citrus and mango diseases were documented more than 100 years ago, the pomegranate and grape diseases have been known only since the 1950s and 1970s, respectively. Interestingly, diseases caused by all these pathovars were noted first in India. Our genome-based phylogenetic studies suggest that these diverse pathogens belong to a single species and these pathovars may be just a group of rapidly evolving strains. Furthermore, the recently reported pathovars, such as those infecting grape and pomegranate, form independent clonal lineages, while the citrus and mango pathovars that have been known for a long time form one clonal lineage. Such an understanding of their phylogenomic relationship has further allowed us to understand major and unique variations in the lineages that give rise to these pathovars. Whole-genome sequencing studies including ecological relatives from their putative country of origin has allowed us to understand the evolutionary history of Xac and other pathovars that infect fruits.

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SBSPKS: structure based sequence analysis of polyketide synthases

Cited by 167 publications

References 50 publications

Gene Replacement for the Generation of Designed Novel Avermectin Derivatives with Enhanced Acaricidal and Nematicidal Activities

Gene Replacement for the Generation of Designed Novel Avermectin Derivatives with Enhanced Acaricidal and Nematicidal Activities

Primer on Agar-Based Microbial Imaging Mass Spectrometry

Genomic Insights into the Evolutionary Origin of Xanthomonas axonopodis pv. citri and Its Ecological Relatives

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