Pyrroindomycins, novel antibiotics produced by Streptomyces rugosporus sp. LL-42D005. I. Isolation and structure determination.

Ding, Weidong; Williams, David R.; Northcote, Peter T.; Siegel, Marshall M.; Tsao, Rushung; Ashcroft, Joseph; Morton, George O.; Alluri, Mahender R.; Abbanat, Darren; Maiese, William M.; Ellestad, George A.

doi:10.7164/antibiotics.47.1250

Cited by 58 publications

(37 citation statements)

References 17 publications

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“…155–157 A subclass of this family of natural products has drawn particular interest, because the tetronate or tetramate namesake appears to have undergone an intramolecular Diels-Alder reaction with a 1,3-diene to form a cyclohexene ring with a tertiary carbon joint. 12,157 Examples of such spirotetronates and spirotetramates are shown in Figure 6 and include versipelostatin ( 74 ), 158–161 pyrroindomycin ( 75 ), 162–166 chlorothricin ( 76 ), 167–175 kijanimicin ( 77 ), 176–181 the quartromicins ( 78 ), 182–186 the abyssomicins ( 79 ), 187–192 tetrocarcin, 193–198 the lobophorins, 199–205 nomimicin, 206 maklamicin, 207–209 and tetronothiodin. 210–214 Furthermore, several of these compounds also possess a second, decalin ring system, the formation of which is highly reminiscent of the reactions catalyzed by LovB and solanapyrone synthase (see above).…”

Section: Spirotetronates and Spirotetramatesmentioning

confidence: 99%

“…162,163,166 Liu and coworkers began by using comparative genomics to identify PyrI4 as a homolog of VstJ implicating it the formation of the spirotetramate functionality. 221 The PyrE3 gene product also drew attention given the absence of homologous genes in the clusters for abyssomicin C ( 79 ) 191 and quartromicin D1 ( 78 ), 185 both of which lack a decalin group (see Figure 6).…”

Section: Spirotetronates and Spirotetramatesmentioning

confidence: 99%

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Natural [4 + 2]-Cyclases

et al. 2016

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[4 + 2]-Cycloadditions are increasingly being recognized in the biosynthetic pathways of many structurally complex natural products. A relatively small collection of enzymes from these pathways have been demonstrated to increase rates of cyclization and impose stereochemical constraints on the reactions. While mechanistic investigation of these enzymes is just beginning, recent studies have provided new insights with implications for understanding their biosynthetic roles, mechanisms of catalysis and evolutionary origin.

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Section: Spirotetronates and Spirotetramatesmentioning

confidence: 99%

Section: Spirotetronates and Spirotetramatesmentioning

confidence: 99%

Natural [4 + 2]-Cyclases

et al. 2016

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“…The pyrroindomycins (PYRs, Figure 1) are spirotetramate natural products; they were isolated from Streptomyces rugosporus during the screening of agents active against drug-resistant bacterial pathogens, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium (Ding et al, 1994;Singh et al, 1994). These molecules possess a characteristic aglycone that contains two cyclohexene units present in both the dialkyldecalin and the tetramate spiro-conjugate portions.…”

Section: Introductionmentioning

confidence: 99%

Enzyme-Dependent [4 + 2] Cycloaddition Depends on Lid-like Interaction of the N-Terminal Sequence with the Catalytic Core in PyrI4

Zheng

Guo

Yang

et al. 2016

Cell Chemical Biology

112

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The Diels-Alder [4 + 2] cycloaddition reaction is one of the most powerful and elegant organic synthesis methods for forming 6-membered molecules and has been known for nearly a century. However, whether and how enzymes catalyze this type of reaction is still not completely clear. Here we focus on PyrI4, an enzyme found in the biosynthetic pathway of pyrroindomycins where it catalyzes the formation of a spiro-conjugate via an enzyme-dependent exo-selective [4 + 2] cycloaddition reaction. We report the crystal structures of PyrI4 alone and in complex with its product. Comparative analysis of these structures, combined with biochemical analysis, lead us to propose a unique trapping mechanism whereby the lid-like action of the N-terminal tail imposes conformational constraints on the β barrel catalytic core, which enhances the proximity and polarization effects of reactive groups (1,3-diene and alkene) to drive cyclization in a regio- and stereo-specific manner. This work represents an important step toward the wider application of enzyme-catalyzed [4 + 2] cyclization for synthetic purposes.

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“…1a), which were isolated from Streptomyces rugosporus during the screening of agents active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium 1,2 , represent what are to our knowledge the first spirotetramates found in nature. These molecules are structurally related to the spirotetronates chlorothricin (CHL), tetrocarcin A (TC-A), kijanimicin (KIJ) and the lobophorins (LOBs) 3 , all of which belong to a large natural product family with two cyclohexene units present in both the dialkyldecalin and the tetramate or tetronate spiro-conjugate portions of the aglycone (Supplementary Results, Supplementary Fig.…”

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confidence: 99%

An enzymatic [4+2] cyclization cascade creates the pentacyclic core of pyrroindomycins

et al. 2015

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The [4+2] cycloaddition remains one of the most intriguing transformations in synthetic and natural products chemistry. In nature, however, there are remarkably few enzymes known to have this activity. We herein report an unprecedented enzymatic [4+2] cyclization cascade that has a central role in the biosynthesis of pyrroindomycins, which are pentacyclic spirotetramate natural products. Beginning with a linear intermediate that contains two pairs of 1,3-diene and alkene groups, the dedicated cyclases PyrE3 and PyrI4 act in tandem to catalyze the formation of two cyclohexene rings in the dialkyldecalin system and the tetramate spiro-conjugate of the molecules. The two cyclizations are completely enzyme dependent and proceed in a regio- and stereoselective manner to establish the enantiomerically pure pentacyclic core. Analysis of a related spirotetronate pathway confirms that homologs are functionally exchangeable, establishing the generality of these findings and explaining how nature creates diverse active molecules with similar rigid scaffolds.

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Pyrroindomycins, novel antibiotics produced by Streptomyces rugosporus sp. LL-42D005. I. Isolation and structure determination.

Cited by 58 publications

References 17 publications

Natural [4 + 2]-Cyclases

Natural [4 + 2]-Cyclases

Enzyme-Dependent [4 + 2] Cycloaddition Depends on Lid-like Interaction of the N-Terminal Sequence with the Catalytic Core in PyrI4

An enzymatic [4+2] cyclization cascade creates the pentacyclic core of pyrroindomycins

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