Spirotetronate Polyketides as Leads in Drug Discovery

Lacoske, Michelle H.; Theodorakis, Emmanuel A.

doi:10.1021/np500757w

Cited by 76 publications

(85 citation statements)

References 226 publications

(282 reference statements)

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“…[320] Some of the spirotetronates identified also contain a trans -decalin ring system ( 323 ). Both the cyclohexene and trans - decalin rings have been proposed to be assembled via Diels-Alder cycloaddition reactions.…”

Section: Rearrangementmentioning

confidence: 99%

The Enzymology of Organic Transformations: A Survey of Name Reactions in Biological Systems

2017

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Chemical reactions that are named in honor of their true or at least perceived discoverers are known as “name reactions”. This review is a collection of biological representatives of named chemical reactions. Emphasis is placed on reaction types and catalytic mechanisms that showcase both the chemical diversity in natural product biosynthesis as well as the parallels with synthetic organic chemistry. An attempt has been made to describe the enzymatic mechanisms of catalysis within the context of their synthetic counterparts whenever possible and to discuss the mechanistic hypotheses for those reactions that are presently active areas of investigation. This review has been categorized by reaction type, e.g., condensation, nucleophilic addition, reduction and oxidation, substitution, carboxylation, radical-mediated, and rearrangements, which are subdivided by named reactions.

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Section: Rearrangementmentioning

confidence: 99%

The Enzymology of Organic Transformations: A Survey of Name Reactions in Biological Systems

2017

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“…Consistently, two dedicated cyclases in tandem catalyze the formation of two cyclohexene rings (Figure 1): PyrE3, a FAD-dependent enzyme involved in dialkyldecalin formation, generates the partially cyclized intermediate 1; and PyrI4 then acts as a spiro-conjugate synthase to complete the pentacyclic core (2; Tian et al, 2015). This unusual crossbridging strategy is common for the biosynthesis of spirotetronates, e.g., chlorothricin (Jia et al, 2006;Tian et al, 2015) and versipelostatin (Hashimoto et al, 2015), the natural products structurally related to PYRs and sharing a similar pentacyclic aglycone that differs in size, substitution pattern, and composition of the five-membered heterocyclic moiety (Lacoske and Theodorakis, 2015).…”

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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“…Moreover, the discovery of more spirotetronate antibiotics analogs helps to elucidate the structure–activity relationships and potential applications of these compounds. Lobophorin F and H are analogs of lobophorin B, which was previously isolated from an alga-associated actinobacterium; lobophorin B is structurally related to another spirotetronate antibiotic, named kijanimicin [ 35 ]. Recent studies indicate that kijanimicin binds to the TetR family of transcriptional regulators that control the expression of various cytoplasmic proteins in prokaryotes [ 36 ].…”

Section: Antimicrobial Compounds From Marine Microorganismsmentioning

confidence: 99%

Antibiotics from Deep-Sea Microorganisms: Current Discoveries and Perspectives

et al. 2018

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The increasing emergence of new forms of multidrug resistance among human pathogenic bacteria, coupled with the consequent increase of infectious diseases, urgently requires the discovery and development of novel antimicrobial drugs with new modes of action. Most of the antibiotics currently available on the market were obtained from terrestrial organisms or derived semisynthetically from fermentation products. The isolation of microorganisms from previously unexplored habitats may lead to the discovery of lead structures with antibiotic activity. The deep-sea environment is a unique habitat, and deep-sea microorganisms, because of their adaptation to this extreme environment, have the potential to produce novel secondary metabolites with potent biological activities. This review covers novel antibiotics isolated from deep-sea microorganisms. The chemical classes of the compounds, their bioactivities, and the sources of organisms are outlined. Furthermore, the authors report recent advances in techniques and strategies for the exploitation of deep-sea microorganisms.

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Spirotetronate Polyketides as Leads in Drug Discovery

Cited by 76 publications

References 226 publications

The Enzymology of Organic Transformations: A Survey of Name Reactions in Biological Systems

The Enzymology of Organic Transformations: A Survey of Name Reactions in Biological Systems

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

Antibiotics from Deep-Sea Microorganisms: Current Discoveries and Perspectives

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