Combimicins,new kanamycin derivatives bioconverted by some Micromonosporas.

Oka, Yoshihiko; Ishida, Hideyuki; Morioka, Moto; Numasaki, Yoso; Yamafuji, T; Osono, Takashi; Umezawa, Hamao

doi:10.7164/antibiotics.34.777

Cited by 17 publications

(6 citation statements)

References 14 publications

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“…The shuttle vectors pPpT4_S and pPpKan_S, derivatives of pPpT2 [35] with two point mutations in the EM72 promoter and a Smi I restriction site instead of Bgl II, were used for cloning. pPpKan_S contains a kanamycin/geneticin resistance gene instead of a zeocin resistance gene [36,37]. pPpT4_S was used for harboring either the HRP isoenzyme C1A or CalB, which both were codon-optimized for high-level expression in P. pastoris .…”

Section: Methodsmentioning

confidence: 99%

Recombinant protein expression in Pichia pastoris strains with an engineered methanol utilization pathway

et al. 2012

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ΒackgroundThe methylotrophic yeast Pichia pastoris has become an important host organism for recombinant protein production and is able to use methanol as a sole carbon source. The methanol utilization pathway describes all the catalytic reactions, which happen during methanol metabolism. Despite the importance of certain key enzymes in this pathway, so far very little is known about possible effects of overexpressing either of these key enzymes on the overall energetic behavior, the productivity and the substrate uptake rate in P. pastoris strains.ResultsA fast and easy-to-do approach based on batch cultivations with methanol pulses was used to characterize different P. pastoris strains. A strain with MutS phenotype was found to be superior over a strain with Mut+ phenotype in both the volumetric productivity and the efficiency in expressing recombinant horseradish peroxidase C1A. Consequently, either of the enzymes dihydroxyacetone synthase, transketolase or formaldehyde dehydrogenase, which play key roles in the methanol utilization pathway, was co-overexpressed in MutS strains harboring either of the reporter enzymes horseradish peroxidase or Candida antarctica lipase B. Although the co-overexpression of these enzymes did not change the stoichiometric yields of the recombinant MutS strains, significant changes in the specific growth rate, the specific substrate uptake rate and the specific productivity were observed. Co-overexpression of dihydroxyacetone synthase yielded a 2- to 3-fold more efficient conversion of the substrate methanol into product, but also resulted in a reduced volumetric productivity. Co-overexpression of formaldehyde dehydrogenase resulted in a 2-fold more efficient conversion of the substrate into product and at least similar volumetric productivities compared to strains without an engineered methanol utilization pathway, and thus turned out to be a valuable strategy to improve recombinant protein production.ConclusionsCo-overexpressing enzymes of the methanol utilization pathway significantly affected the specific growth rate, the methanol uptake and the specific productivity of recombinant P. pastoris MutS strains. A recently developed methodology to determine strain specific parameters based on dynamic batch cultivations proved to be a valuable tool for fast strain characterization and thus early process development.

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Section: Methodsmentioning

confidence: 99%

Recombinant protein expression in Pichia pastoris strains with an engineered methanol utilization pathway

et al. 2012

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“…In addition to a few sugars highlighted in the previous paragraph found appended at C-6 of aminoglycoside core aglycons ( 2 , 4 , 8 , 10 , 12 ), 54,62,63 additional sugar diversity has been found at C-6 including: α-D-glucose ( 18 ); 64 3′-amino-3′-deoxy-α-D-xylose 21 (gentamicins and sisomicins) 37,65 and its C-4′-methyl branched 19 (prevalent in a range of aminoglycosides); 51,66,67 C-4′-methyl branched 3′-amino-3′-deoxy-α-D-galactose 20 (combimicins); 56 3′-amino-3′-deoxy-β-L-arabinose ( 22 , gentamicins and related compounds); 37,65 2′-amino-2′-deoxy-α-D-xylose 24 and its corresponding 2′,3′-diamino-2′,3′-dideoxy analog 23 (seldomycins); 58,68 as well as 3′-amino-3′-deoxy-β-D-mannose ( 42 ) and the diasaccharide I [comprised of the uniquely C-6′ oxidized mannose 43 and 2′-amino-2′-deoxy-α-D-xylose ( 24 ) in boholmycin]. 50 Other C-6′-appended sugars include L-streptose ( 28 ), 5′-hydroxy-L-streptose ( 30 ) and the corresponding reduced forms 29 and 31 have been found among streptomycins 69–71 wherein further C-2′ glycosylation of the streptose moiety with 2′-amino-2′-deoxy-α-L-glucose ( 32 ) has been observed.…”

Section: Aminoglycosides and Related Secondary Metabolitesmentioning

confidence: 99%

A comprehensive review of glycosylated bacterial natural products

et al. 2015

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A systematic analysis of all naturally-occurring glycosylated bacterial secondary metabolites reported in the scientific literature up through early 2013 is presented. This comprehensive analysis of 15 940 bacterial natural products revealed 3426 glycosides containing 344 distinct appended carbohydrates and highlights a range of unique opportunities for future biosynthetic study and glycodiversification efforts.

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“…50 Kanamycins first isolated from S. kanamyceticus had been found in several Micromonospora strains, such as 3″-N-methyl and 3″-N-methyl-4″-C-methyl derivatives (33−35) from M. inyoensis NRRL 5742 and M. purpurea NRRL 8102, 51 and combimicins (36−38) were isolated from strain K-6993 and its mutant Y-41, as well. 52 Compounds (45−52) belong to a subgroup of 2-deoxystreptamine-type AGs that are structurally close to gentamicin but have a double bond between C-4′ and C-5′ (Figure 5). 10,53−58 Antibiotic 6640 (45), which was designated as a sisomicin analogue that was originally produced by M. inyoensis, was shown to possess an antibacterial spectrum similar to that of gentamicin and exhibit more potent bioactivities at pH values over 7.…”

Section: Bioactive Secondary Metabolites Ofmentioning

confidence: 99%

“…inyoensis NRRL 5742 and M. purpurea NRRL 8102, and combimicins ( 36 – 38 ) were isolated from strain K-6993 and its mutant Y-41, as well …”

Section: Bioactive Secondary Metabolites Of Micromonosporamentioning

confidence: 99%

Micromonospora: A Prolific Source of Bioactive Secondary Metabolites with Therapeutic Potential

et al. 2022

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Micromonospora, one of the most important actinomycetes genera, is well-known as the treasure trove of bioactive secondary metabolites (SMs). Herein, together with an in-depth genomic analysis of the reported Micromonospora strains, all SMs from this genus are comprehensively summarized, containing structural features, bioactive properties, and mode of actions as well as their biosynthetic and chemical synthesis pathways. The perspective enables a detailed view of Micromonospora-derived SMs, which will enrich the chemical diversity of natural products and inspire new drug discovery in the pharmaceutical industry.

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Combimicins,new kanamycin derivatives bioconverted by some Micromonosporas.

Cited by 17 publications

References 14 publications

Recombinant protein expression in Pichia pastoris strains with an engineered methanol utilization pathway

Recombinant protein expression in Pichia pastoris strains with an engineered methanol utilization pathway

A comprehensive review of glycosylated bacterial natural products

Micromonospora: A Prolific Source of Bioactive Secondary Metabolites with Therapeutic Potential

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