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Studies on the Biosynthesis of Thiostrepton:..

Insights into Quinaldic Acid Moiety Formation in Thiostrepton Biosynthesis Facilitating Fluorinated Thiopeptide Generation

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Deciphering the biosynthesis pathway of the ..

Nosiheptide (NOS), produced by Streptomyces actuosus ATCC 25421, is one of the oldest known thiopeptides and has been widely used as a feed additive for animal growth (, ). The structure and stereochemistry of NOS was ultimately confirmed by X-ray crystallography (), following extensive analysis of chemically hydrolyzed fragments by NMR spectroscopic methods (, ). While the total synthesis of NOS has not been achieved, NOS, as the model molecule in the e series, was one of the first thiopeptides to be investigated biosynthetically by incorporation of isotope-labeled precursors, along with thiostrepton (TSR), a representative of b series that contains a distinct quinaldic acid side ring system appended to the characteristic thiopeptide macrocyclic core (–). All moieties of the peptidyl backbones of NOS and TSR were shown to originate exclusively from proteinogenic amino acids, including dehydroamino acids (from the Ser or Thr residues undergoing the anti elimination of water), thiazoles (from the Cys residues with cyclodehydration followed by deoxygenation), and the central 6-membered nitrogen heterocycle (produced by cyclization between two corresponding dehydroalanine acids with incorporation of an adjacent carbonyl group). Interestingly, the Trp residue was confirmed as a common precursor for the side ring systems in both NOS and TSR biosynthesis (, ), in spite of the difference in structures of the resulting motifs (i.e. the indolic acid moiety for NOS and the quinalidic acid moiety for TSR) and their linkages to the thiopeptide macrocyclic core ().

Quinolinic acid may undergo further decarboxylation to nicotinic acid : Biosynthesis From ..

In summary, we successfully generated variants of TsrA at the biologically critical Thr7 residue. Although impaired in production titers, the thiostrepton variants were subjected to structural characterization and assessment of their antibacterial activities. The Thr7Ala and Thr7Val substitutions impaired biological activity, confirming key interactions between Thr7 of 1 and the ribosome. Furthermore, the identification of 4 grants insight into the late stages of thiostrepton biosynthesis, suggesting that epoxidation of HEQ and quinaldic acid loop closure occur late during thiostrepton maturation.

the Biosynthesis Pathway of the Antitumor Thiocoraline ..

Biosynthesis of 8-hydroxyquinoline-2-carboxylic acid, an iron chelator from the gut of the lepidopteran Spodoptera littoralis

HEQ is a discrete intermediate in 1 biosynthesis, and can be activated as the adenylate by S. laurentii cell-free extracts., The exact sequence of events governing formation of Loop 2 in 1 awaits elucidation, and its proposed biosynthetic pathway is included in . First, HEQ is tethered to the Thr12 side chain in 7. Epoxidation to 8, proteolysis of the leader peptide, and ultimately a nucleophilic attack from the newly liberated Ile1 N-terminal amine, could then forge the quinaldic acid-containing macrocycle ()., For TsrA Thr7Ala, this process appears to derail at an advanced stage of thiostrepton maturation, likely preceding the proposed epoxidation of the 7 HEQ. Although the HEQ moiety is most likely enzymatically installed even for the shunt product 4, the adventitious and non-enzymatic attachment of an adenylated HEQ to the Thr12 side chain of an advanced intermediate cannot yet be definitively ruled out. Following peptidolysis of the leader peptide and the two N-terminal proteinogenic amino acids, a dehydroalanine is transiently exposed at the N-terminus in 9 prior to tautomerization and hydrolysis to provide the shunt product 4 ().

It had long been controversial whether the thiopeptides are biosynthesized via a ribosome-dependent route of maturation of short peptides to complex, highly functionalized molecules, such as lantibiotics (), bacteriocins () and cyanobactins (), or in a manner similar to peptide antibiotics vancomycin and cyclosporin, whose peptidyl backbones are assembled by non-ribosomal peptide synthetases (NRPSs) (, ). Very recently, we and other research groups cloned, sequenced and characterized the biosynthetic gene clusters of the bicyclic b series thiopeptides TSR and siomycin A (SIO-A), and monocyclic d series thiocillins (TCLs), GE2270A and thiomuracins (TMRs), uncovering a common paradigm for the characteristic macrocyclic core biosynthesis that features conserved posttranslational modifications on a ribosomally synthesized precursor peptide (–). Given the similarities in structures and precursor-labeling patterns, the biosynthesis of NOS likely shares a conserved strategy with those of above thiopeptides to form the thiopeptide macrocyclic core. However, the tailoring of the elementary framework into the e series-specific member, particularly for the indolic acid moiety formation and attachment via a route distinct from the quinaldic acid pathway in TSR biosynthesis, was unclear. To exploit the genetic basis for fulfilling the knowledge gap, we now report the localization of the nos biosynthetic gene cluster from S. actuosus ATCC 25421 by cloning the thiopeptide-specific cyclodehydratase gene nosG using our recently developed PCR approach. The sequence analysis of the entire nos gene cluster allows for assignment of functions to the deduced gene products, setting the stage to propose the NOS biosynthetic pathway. While the finding of the ribosomal origin of NOS along with conserved posttranslational modifications again validates the generality of thiopeptide biosynthesis, in vivo functional investigations of genes involved in the indole side ring formation have revealed new insights into the biosynthesis of the e series-specific thiopeptides, including a novel strategy for the carbon side chain rearrangement to convert the Trp residue into the key 3-methylindole moiety.

19/12/2017 · Thiostrepton Biosynthesis: ..

21/12/2017 · View This Abstract Online; Insights into quinaldic acid moiety formation in thiostrepton biosynthesis facilitating fluorinated thiopeptide generation.

Pesek, J.; Svoboda, J.; Sattler, M.; Bartram, S.; Boland, W. Biosynthesis of 8-hydroxyquinoline-2-carboxylic acid, an iron chelator from the gut of the lepidopteran Spodoptera littoralis. Org. Biomol. Chem. 2015, 13 (1), 178-184.Tajti, J.; Majlath, Z.; Szok, D.; Csati, A.; Toldi, J.; Fulop, F.; Vecsei, L. Novel Kynurenic Acid Analogues in the Treatment of Migraine and Neurodegenerative Disorders: Preclinical Studies and Pharmaceutical Design. Curr. Pharm. Des. 2015, 21 (17), 2250-2258.

Pesek, J.; Svoboda, J.; Sattler, M.; Bartram, S.; Boland, W. Biosynthesis of 8-hydroxyquinoline-2-carboxylic acid, an iron chelator from the gut of the lepidopteran Spodoptera littoralis. Org. Biomol. Chem. 2015, 13 (1), 178-184.

18/09/2017 · Insights into Quinaldic Acid Moiety Formation in Thiostrepton Biosynthesis Facilitating Fluorinated Thiopeptide Generation
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  • Datura stramonium-tropic acid biosynthesis; ..

    Quinolinic acid - Wikipedia

  • e protocatechuic acid 0.03 0.80 U.V

    Broad spectrum excitatory amino acid antagonist4-Hydroxyquinoline-2-carboxylic acid hydrate is used as ..

  • Thiostrepton Biosynthesis: Prototype for a New Family …

    Thiostrepton/biosynthesis*

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Studies on the biosynthesis of thiostrepton: 4 ..

Broad spectrum excitatory amino acid antagonist4-Hydroxyquinoline-2-carboxylic acid hydrate is used as an intermediate in synthetic chemistry. It acts as an antiexcitotoxic and anticonvulsant. It finds application in certain neurobiological disorders therapy.

Biosynthesis of the thiopeptide antibiotic thiostrepton ..

In summary, we have uncovered the biosynthetic machinery of nosiheptide by cloning, sequencing and characterizing the nos gene cluster in S. actuosus ATCC 25421. Our findings extend the current paradigm for thiopeptide biosynthesis into the e series members with distinct features. Thus, consistent with the similarities in structures to the b or c series thiopeptides whose biosynthetic pathways were established, NOS biosynthesis shares the common strategy for forming the characteristic thiopeptide macrocyclic core that features a ribosomally synthesized precursor peptide and conserved posttranslational modifications. However, the NOS biosynthetic machinery is unique, apparently proceeding via a different route for tailoring the intermediate into the final product by installing an unusual indole side ring system and two regiospecific hydroxyl groups, characteristics of e series thiopeptides. Although Trp serves as a common precursor for the indolic acid moiety of NOS and the quinaldic acid moiety of TSR, the distinct pathways for biosynthesis and attachment onto the thiopeptide macrocyclic cores lead to major differences in the side ring systems. The conversion of Trp into the key 3-methylindolyl moiety (2) requires an unusual carbon side chain rearrangement, in which the S-AdoMet-dependent protein NosL may play a central role with a radical-initiated mechanism. NOS biosynthesis involves many novel enzymes and reactions, and the characterization of these will contribute new chemistry and enzymology to thiopeptide biosynthesis. Since all e series members contain these structurally similar features (e.g. the indole side ring system and the hydroxylation pattern) (), their biosyntheses may employ similar approaches in affording the NOS-like scaffold, but with additional oxidoreduction(s) and glycosylation(s) for tailoring into the other individual members, such as nocathiacins. Finally, the success in identification of the novel NOS analog 4 by gene inactivation continuously inspires attempts to apply this knowledge to metabolic engineering for structural derivation in the pharmaceutical development of thiopeptide-like antibiotics.

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