- Bacterial Alkaloid Biosynthesis: Structural Diversity via a Minimalistic Nonribosomal Peptide Synthetase
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Chemical and biochemical analyses of one of the most basic nonribosomal peptide synthetases (NRPS) from a Pseudomonas fluorescens strain revealed its striking plasticity. Determination of the potential substrate scope enabled us to anticipate novel secondary metabolites that could subsequently be isolated and tested for their bioactivities. Detailed analyses of the monomodular pyreudione synthetase showed that the biosynthesis of the bacterial pyreudione alkaloids does not require additional biosynthetic enzymes. Heterologous expression of a similar and functional, yet cryptic, NRPS of Pseudomonas entomophila was successful and allowed us to perform a phylogenetic analysis of their thioesterase domains. Nonribosomal peptides are a diverse class of ecologically and clinically relevant natural products. Here, Klapper et al. study one of the simplest bacterial nonribosomal peptide synthetases of different Pseudomonas strains. A single gene, encoding the monomodular pyreudione synthetase, leads to the production of a variety of bioactive alkaloids.
- Klapper, Martin,Braga, Daniel,Lackner, Gerald,Herbst, Rosa,Stallforth, Pierre
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- (4-HYDROXYPYRROLIDIN-2-YL)-HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF
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The present disclosure relates to bifunctional compounds of formula (I), which can be used as modulators of targeted ubiquitination. In particular, the present disclosure is directed to compounds which contain on one end a VHL ligand moiety, which binds to the VHL E3 ubiquitin ligase, and on the other end a moiety that binds a target protein such that degradation of the target protein/polypeptide is effectuated. Also disclosed are VHL ligands of formula (III).
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Paragraph 0710; 0711; 0712
(2019/05/15)
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- Energetic contribution to both acidity and conformational stability in peptide models
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The acidity of N-acyl amino acids is dependent upon the rotameric state of the amide bond. In this work we systematically investigated the acidity difference of the rotamers (ΔpKa) in the frames of various acetylated amino acids. Our results indicated a mutual interaction of two carbonyl groups of an attractive type. We observed conservative ΔpKas for acyclic amino acids (2.2-3.0 kJ mol-1), whereas in the case of alicyclic amino acids, the experimental values revealed a strong dependency on the structural context (1.5-4.4 kJ mol-1). In homologous amino acids (α-, β-, γ-, etc.), the strength of the attraction decays in an exponential fashion. Furthermore, the interaction can accumulate through a chain of amide bonds in a cascade fashion, as demonstrated by an Ac-Pro-Pro dipeptide. As a result, we demonstrate that ΔpKa is an experimental parameter to estimate increments in the carbonyl-carbonyl alignment, as determined by the amino acid or peptidyl context. This parameter is also important in understanding the roles of amino acids in both protein folding and translation in biological systems as well as their evolutionary appearance in the genetic code.
- Kubyshkin, Vladimir,Durkin, Patrick,Budisa, Nediljko
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supporting information
p. 5209 - 5220
(2016/07/06)
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