Biosynthesis of antibiotics of the virginiamycin family. 3. Biosynthesis of virginiamycin M1

Kingston, David G. I.; Kolpak, Michael X.; LeFevre, Joseph W.; Borup-Grochtmann, I.

doi:10.1021/ja00353a041

Cited by 56 publications

(42 citation statements)

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“…However, incorporation studies of precursors labelled with radioactive and stable isotopes have established the origin of the 28 carbon atoms of PII A (16)(17)(18). These carbon atoms come from seven molecules of acetate, four amino acids (valine, glycine, serine, and proline), and the methyl group of methionine.…”

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Purification of the two-enzyme system catalyzing the oxidation of the D-proline residue of pristinamycin IIB during the last step of pristinamycin IIA biosynthesis

et al. 1995

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High levels of conversion of 14 C-labelled pristinamycin II B (PII B ) to pristinamycin II A (PII A ) were obtained in vivo in Streptomyces pristinaespiralis and in some other streptogramin A producers. This established that PII B was an intermediate on the pathway to PII A . In addition, in vitro studies with cell-free protein preparations demonstrated that the oxidation of PII B to PII A is a complex process requiring NADH, riboflavin 5-phosphate (FMN), and molecular oxygen. Two enzymes were shown to be necessary to catalyze this reaction. Both were purified to homogeneity from S. pristinaespiralis by a coupled enzyme assay based on the formation of PII A and by requiring addition of the complementing enzyme. One enzyme was purified about 3,000-fold by a procedure including a decisive affinity chromatography step on FMN-agarose. It was shown to be a NADH:FMN oxidoreductase (E.C. 1.6.8.1.) (hereafter called FMN reductase), providing reduced FMN (FMNH 2 ) to the more abundant second enzyme. The latter was purified only 160-fold and was called PII A synthase. Our data strongly suggest that this enzyme catalyzes a transient hydroxylation of PII B by molecular oxygen immediately followed by a dehydration leading to PII A . The native PII A synthase consists of two different subunits with M r s of around 50,000 and 35,000, as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, while the FMN reductase seems to be a monomer with a M r of around 28,000 and containing one molecule of tightly bound FMN. Stepwise Edman degradation of the entire polypeptides or some of their trypsin-digested fragments provided amino acid sequences for the two isolated proteins.Pristinamycins I and pristinamycins II (PII), the two families of bacteriostatic components associated in the bactericidal antibiotic pristinamycin, are produced by Streptomyces pristinaespiralis (22,23). Pristinamycins I are cyclohexadepsipeptides belonging to the B group of streptogramins, while PII are polyunsaturated macrolactones of the A group of streptogramins (Fig. 1). Both streptogramins A and B are secondary metabolites synthesized by a large number of different Streptomycetes, and most of the members of these families have received several names, often related to the species from which they were isolated (6, 28). Thus, the main component of PII, pristinamycin II A (PII A ), is also called mikamycin A, ostreogrycin A, staphylomycin M1, streptogramin A, synergistin A, vernamycin A, virginiamycin M1, and PA-114 A1, while the minor component pristinamycin II B (PII B ) is also known as ostreogrycin G and virginiamycin M2 (7).Pristinamycin is poorly water soluble, and its therapeutic use has remained rather restricted until now. The development of a water-soluble streptogramin, RP 59500, has recently revived interest in this old family of antibiotics (1). Pristinamycin is active against both gram-positive bacteria, especially Staphylococcus and Streptococcus spp., and some gram-negative bacteria, such as Haemophilus spp. Interestingly, both ...

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Purification of the two-enzyme system catalyzing the oxidation of the D-proline residue of pristinamycin IIB during the last step of pristinamycin IIA biosynthesis

et al. 1995

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“…3) [15]. The antibiotic produced in the presence of [1-13 C] acetate exhibited enrichment at C5, C7, C12, C14, C16, and C18, while 1 produced in the presence of [2-13 C] acetate exhibited enrichment at C4, C6, C11, C13, C15, C17, as well as at C33.…”

Section: Biosynthesis Of Virginiamycin M1mentioning

confidence: 99%

“…Reduction of the isopropyl ester, subsequent protection of the 1° alcohol and Li metal reduction of the unsaturated lactone gave the lactol 13. Oxidative elimination of the pyrrolidine from 13 afforded the enal 14, which was protected at the t-BuPh2Si ether (15). Horner-Emmons olefination gave the E,E-dienyl nitrile 16 which upon reduction with alane gave the dienyl amine 17.…”

Section: Schlessinger/li Synthesis Of Virginiamycin M2mentioning

confidence: 99%

Chemistry and Biology of the Streptogramin A Antibiotics

Ahmed¹,

Donaldson²

2007

MROC

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Section: Structures and Biosynthesismentioning

confidence: 99%

“…23 The C-terminal dehydroproline predictably arises from Pro. 23 A twoenzyme system comprised of an FMN-dependent monooxygenase and an FMN reductase that catalyzes Pro oxidation has been purified and characterized from the pristinamycin II A producer Streptomyces pristinaespiralis. 24,25 The oxazole ring is derived from Ser, 23,26 which cyclizes in a fashion reminiscent of other natural product antibiotics such as microcin (reviewed in ref 27).…”

Section: Structures and Biosynthesismentioning

confidence: 99%

Streptogramins, Oxazolidinones, and Other Inhibitors of Bacterial Protein Synthesis

Mukhtar

Wright

2005

ChemInform

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Biosynthesis of antibiotics of the virginiamycin family. 3. Biosynthesis of virginiamycin M1

Cited by 56 publications

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Purification of the two-enzyme system catalyzing the oxidation of the D-proline residue of pristinamycin IIB during the last step of pristinamycin IIA biosynthesis

Purification of the two-enzyme system catalyzing the oxidation of the D-proline residue of pristinamycin IIB during the last step of pristinamycin IIA biosynthesis

Chemistry and Biology of the Streptogramin A Antibiotics

Streptogramins, Oxazolidinones, and Other Inhibitors of Bacterial Protein Synthesis

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