Thermorubin biosynthesis: evidence for the involvement of both salicylic acid and an undecaketide

Aragozzini, Fabrizio; Craveri, R.; Maconi, Elisabetta; Ricca, Giuliana; Scolastico, Carlo

doi:10.1039/p19880001865

Cited by 8 publications

(14 citation statements)

References 2 publications

(2 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…One known example is that of thermorubin, in which the salicylate moiety is thought to be incorporated as a starter unit. 27 A related modification is the addition of a 6-methylsalicylic acid which is typically synthesized via a dedicated type I PKS, such as those found in the chlorothricin 28 or polyketomycin 29 pathways. Sequence analysis of ssf gene cluster revealed a likely mech-anism of salicylate 19 synthesis from the shikimate pathway (Scheme 2), similar to that utilized in the biosynthesis of siderophores yersinobactin 30 and mycobactin.…”

Section: Genes Putatively Involved In the Biosynthesis Of Salicylatementioning

confidence: 99%

“…The 2-OH substituent is clearly not essential for binding, as benzoic acid 26, 2-chlorobenzoic acid 31 and 2-methoxy benzoic acid 35 all supported similar rates of pyrophosphate release. Surprisingly, three dihydroxybenzoic acids (27)(28)(29), as well as 4-aminosalicylic acid 34 were significantly better substrates than 19, indicating substantial plasticity in the binding pocket of SsfL1.…”

Section: Genes Putatively Involved In the Biosynthesis Of Salicylatementioning

confidence: 99%

See 1 more Smart Citation

Biochemical Analysis of the Biosynthetic Pathway of an Anticancer Tetracycline SF2575

et al. 2009

View full text Add to dashboard Cite

SF2575 1 is a tetracycline polyketide produced by Streptomyces sp. SF2575 and displays exceptionally potent anticancer activity towards a broad range of cancer cell lines. The structure of SF2575 is characterized by a highly substituted tetracycline aglycon. The modifications include methylation of the C-6 and C-12a hydroxyl groups, acylation of the 4-(S)-hydroxyl with salicylic acid, C-glycosylation of the C-9 of the D-ring with D-olivose and further acylation of the C4′-hydroxyl of D-olivose with the unusual angelic acid. Understanding the biosynthesis of SF2575 can therefore expand the repertoire of enzymes that can modify tetracyclines, and facilitate engineered biosynthesis of SF2575 analogs. In this study, we identified, sequenced and functionally analyzed the ssf biosynthetic gene cluster which contains 40 putative open reading frames. Genes encoding enzymes that can assemble the tetracycline aglycon, as well as installing these unique structural features are found in the gene cluster. Biosynthetic intermediates were isolated from the SF2575 culture extract to suggest the order of pendant groups addition is C-9 glycosylation, C-4 salicylation and O-4′ angelycylation. Using in vitro assays, two enzymes that are responsible for C-4 acylation of salicylic acid were identified. These enzymes include an ATP-dependent salicylyl-CoA ligase SsfL1 and a putative GDSL family acyltransferase SsfX3, both of which were shown to have relaxed substrate specificity towards substituted benzoic acids. Since the salicylic acid moiety is critically important for the anticancer properties of SF2575, verification of the activities of SsfL1 and SsfX3 sets the stage for biosynthetic modification of the C-4 group towards structural-activity relationship studies of SF2575. Using heterologous biosynthesis in Streptomyces lividans, we also determined that biosynthesis of the SF2575 tetracycline aglycon 8 parallels that of oxytetracycline 4 and diverges after the assembly of 4-keto-anhydrotetracycline 51. The minimal ssf polyketide synthase together with the amidotransferase SsfD produced the amidated decaketide backbone that is required for the formation of 2-naphthacenecarboxamide skeleton. Additional enzymes, such as cyclases, C-6 methyltransferase and C-4/C-12a dihydroxylase were functionally reconstituted. Keywordstopoisomerase; polyketide; salicylate; biosynthesis; acyltransferase yitang@ucla.edu. Supporting Information Available: Additional Experimental procedures, and compound characterizations. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Am Chem Soc. Author manuscript; available in PMC 2010 December 9. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptBacterial aromatic polyketide natural products comprise a group of molecules that displays diverse structures and bioactivities yet share common biosynthetic origins. The poly-β-ketone backbone is synthesized by a minimal polyketide synthase (PKS) consisting of a ketosynt...

show abstract

Section: Genes Putatively Involved In the Biosynthesis Of Salicylatementioning

confidence: 99%

Section: Genes Putatively Involved In the Biosynthesis Of Salicylatementioning

confidence: 99%

Biochemical Analysis of the Biosynthetic Pathway of an Anticancer Tetracycline SF2575

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Feeding experiments with 13 C-labeled acetates by Aragozzini and coworkers revealed a mixed biosynthetic origin of this polyaromatic polyketide of presumed type II PKS origin. 209 The undecaketide moiety, which is entirely acetate derived, undergoes an interesting oxidative rearrangement in a later stage of the biosynthesis. Successful incorporation of [1-13 C]salicylate supports the involvement of salicyl-CoA as the novel priming unit (Scheme 32).…”

Section: Salicylatementioning

confidence: 99%

Biosynthesis and attachment of novel bacterial polyketide synthase starter units

2001

View full text Add to dashboard Cite

show abstract

“…In a competition experiment, [4'-14C]rot-2'-enonic acid was incorporated stereospecifically into rotenone, labelling C-7', and [4'-SH]-4'-hydroxyrot-2'-enonic acid was specifically incorporated into amorphigenin, labelling C-8', but in marked contrast, the 14C label in amorphigenin was scrambled between C-7' and C-8'. Rotenone appeared a better precursor of amorphigenin than 4'-hydroxyrot-2'-enonic acid, but the two geometrical isomers (136) and (137) were equally acceptable. It was suggested that a major route to amorphigenin is via rotenone which involves first a stereospecific cyclization, then non-specific hydroxylation, but a minor route may involve first non-specific hydroxylation followed by chemospecific cyclization (Scheme 30).…”

Section: Isoflavonoidsmentioning

confidence: 93%

The biosynthesis of shikimate metabolites

Dewick¹

1990

Nat. Prod. Rep.

View full text Add to dashboard Cite

Thermorubin biosynthesis: evidence for the involvement of both salicylic acid and an undecaketide

Cited by 8 publications

References 2 publications

Biochemical Analysis of the Biosynthetic Pathway of an Anticancer Tetracycline SF2575

Biochemical Analysis of the Biosynthetic Pathway of an Anticancer Tetracycline SF2575

Biosynthesis and attachment of novel bacterial polyketide synthase starter units

The biosynthesis of shikimate metabolites

Contact Info

Product

Resources

About