Site-directed mutagenesis and gene replacement were used to inactivate two ketoreductase (KR) domains within the amphotericin polyketide synthase in Streptomyces nodosus. The KR12 domain was inactivated in the DeltaamphNM strain, which...
moreSite-directed mutagenesis and gene replacement were used to inactivate two ketoreductase (KR) domains within the amphotericin polyketide synthase in Streptomyces nodosus. The KR12 domain was inactivated in the DeltaamphNM strain, which produces 16-descarboxyl-16-methyl-amphotericins. The resulting mutant produced low levels of the expected 15-deoxy-15-oxo analogs that retained antifungal activity. These compounds can be useful for further chemical modification. Inactivation of the KR16 domain in the wild-type strain led to production of 7-oxo-amphotericin A and 7-oxo-amphotericin B in good yield. 7-oxo-amphotericin B was isolated, purified, and characterized as the N-acetyl methyl ester derivative. 7-oxo-amphotericin B had good antifungal activity and was less hemolytic than amphotericin B. These results indicate that modification at the C-7 position can improve the therapeutic index of amphotericin B.
ABSTRACT Covering: to mid 2000. Previous review: Nat. Prod. Rep., 1999, 16, 425.
... J., 1993, 296, 143 ChemPort . 6, M. Siggaard-Anderson, M. Wissenbach, J.-A. Chuck, I. Svendsen, JG Olsen and P. Von Wettstein-Knowles, Proc. Natl. Acad. ... Parasitol., 1981, 3, 103 . 125, RA Pascal, Jr., SJ Mannarelli and DL Ziering,...
more... J., 1993, 296, 143 ChemPort . 6, M. Siggaard-Anderson, M. Wissenbach, J.-A. Chuck, I. Svendsen, JG Olsen and P. Von Wettstein-Knowles, Proc. Natl. Acad. ... Parasitol., 1981, 3, 103 . 125, RA Pascal, Jr., SJ Mannarelli and DL Ziering, J. Biol. Chem., 1986, 261, 12 441 ChemPort . ...
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select...
moreABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Enantiopure (S)-(−)-paraconic acid 2 has been synthesised by the stereospecific benzyloxymethylation of a titanium enolate derived from a homochiral oxazolidinone and dihydrocinnamoyl chloride.
Reference Section for: Nat. Prod. Rep., 1999, 16, 425-484 DOI:10.1039/A900566H (Paper). Biosynthesis of polyketides (other than actinomycete macrolides). References. 1, BJ Rawlings, Nat. Prod. Rep., 1998, 15, 275; 1997, 14, 523; 199714335...
moreReference Section for: Nat. Prod. Rep., 1999, 16, 425-484 DOI:10.1039/A900566H (Paper). Biosynthesis of polyketides (other than actinomycete macrolides). References. 1, BJ Rawlings, Nat. Prod. Rep., 1998, 15, 275; 1997, 14, 523; 199714335 . 2, D. O'Hagan, Nat. Prod. ...
ABSTRACT Covering: to mid 2000. Previous review: Nat. Prod. Rep., 1999, 16, 425.
... J., 1993, 296, 143 ChemPort . 6, M. Siggaard-Anderson, M. Wissenbach, J.-A. Chuck, I. Svendsen, JG Olsen and P. Von Wettstein-Knowles, Proc. Natl. Acad. ... Parasitol., 1981, 3, 103 . 125, RA Pascal, Jr., SJ Mannarelli and DL Ziering,...
more... J., 1993, 296, 143 ChemPort . 6, M. Siggaard-Anderson, M. Wissenbach, J.-A. Chuck, I. Svendsen, JG Olsen and P. Von Wettstein-Knowles, Proc. Natl. Acad. ... Parasitol., 1981, 3, 103 . 125, RA Pascal, Jr., SJ Mannarelli and DL Ziering, J. Biol. Chem., 1986, 261, 12 441 ChemPort . ...
The AmphDI glycosyltransferase transfers a mycosaminyl sugar residue from GDP onto 8-deoxyamphoteronolide B, the aglycone of the antifungal amphotericin B. In this study the amphDI gene was inactivated in Streptomyces nodosus strains...
moreThe AmphDI glycosyltransferase transfers a mycosaminyl sugar residue from GDP onto 8-deoxyamphoteronolide B, the aglycone of the antifungal amphotericin B. In this study the amphDI gene was inactivated in Streptomyces nodosus strains lacking the AmphN cytochrome P450. The new mutants produced 8-deoxy-16-methyl-16-descarboxyl amphoteronolides in high yield. These strains and aglycones should prove valuable for in vivo and in vitro glycosylation engineering.
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full...
moreChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Amphotericin B (AmB) is a polyene macrolide antibiotic widely used to treat mycotic infections. In this paper, we focus on the role of the polyol moiety of AmB in sterol selectivity using 7-oxo-AmB, 7α-OH-AmB, and 7β-OH-AmB. The 7-OH...
moreAmphotericin B (AmB) is a polyene macrolide antibiotic widely used to treat mycotic infections. In this paper, we focus on the role of the polyol moiety of AmB in sterol selectivity using 7-oxo-AmB, 7α-OH-AmB, and 7β-OH-AmB. The 7-OH analogs were prepared from 7-oxo-AmB. Their K(+) flux activity in liposomes showed that introduction of an additional ketone or hydroxy group on the polyol moiety reduces the original activity. Conformational analyses of these derivatives indicated that intramolecular hydrogen-bonding network possibly influenced the conformational rigidity of the macrolactone ring, and stabilized the active conformation in the membrane. Additionally, the flexible polyol leads to destabilization of the whole macrolactone ring conformation, resulting in a loss of sterol selectivity.
... Carmel M. McNamara,a Stephen Box,b James M. Crawforth,a Benjamin S. Hickman,a Timothy J. Norwood ,a and Bernard J. Rawlings *,a ... The two polyenes, now in their anionic forms, formion pairs with the cationic Aliquat 336, increasing...
more... Carmel M. McNamara,a Stephen Box,b James M. Crawforth,a Benjamin S. Hickman,a Timothy J. Norwood ,a and Bernard J. Rawlings *,a ... The two polyenes, now in their anionic forms, formion pairs with the cationic Aliquat 336, increasing their solubility in the ethyl acetate. ...
... SYNTHESIS OF REOIOSPECIFICALLY 2ALKrtATED3 DEUTERIATED1AMlNOCitLOPROPANE1 CARBOXYUC ACILY JACK E. BALDWIN ... 8. MJ ODonnell, WA Bruder, TM Eckrich, CF Schullenberger, and GS ... MJ O'Donnell, WA Bruder, TM Eckrich, DF...
more... SYNTHESIS OF REOIOSPECIFICALLY 2ALKrtATED3 DEUTERIATED1AMlNOCitLOPROPANE1 CARBOXYUC ACILY JACK E. BALDWIN ... 8. MJ ODonnell, WA Bruder, TM Eckrich, CF Schullenberger, and GS ... MJ O'Donnell, WA Bruder, TM Eckrich, DF Schullenberger and GS ...
... THE RESOLUTION OF RACEMIC 2ALKYL1AMINOCYCLOPROPANE1CARBOXYLIC ACIDS Jack E. Baldwin*, Robert M. Adlington, Bernard J. Rawlings and Richard H. Jones ... P. Main, SJ Fiske, SE Hull, L. Lessinger, G. Germain, JP Declerq, and MM Woolfson,...
more... THE RESOLUTION OF RACEMIC 2ALKYL1AMINOCYCLOPROPANE1CARBOXYLIC ACIDS Jack E. Baldwin*, Robert M. Adlington, Bernard J. Rawlings and Richard H. Jones ... P. Main, SJ Fiske, SE Hull, L. Lessinger, G. Germain, JP Declerq, and MM Woolfson, MULTAN 80, A ...
A convenient, low cost, large scale synthesis of (L)-β-cyclopropylalanine is reported.
Amphotericin B is a powerful but toxic drug used against fungal infections and leishmaniases. These diseases would be treated more effectively if non-toxic amphotericin derivatives could be produced on a large scale at low cost. Genetic...
moreAmphotericin B is a powerful but toxic drug used against fungal infections and leishmaniases. These diseases would be treated more effectively if non-toxic amphotericin derivatives could be produced on a large scale at low cost. Genetic manipulation of the amphotericin B producer, Streptomyces nodosus, has previously led to the detection and partial characterisation of 8-deoxyamphotericin B, 16-descarboxyl-16-methyl-amphotericin B, 15-deoxy-16-descarboxyl-16-methyl-15-oxo-amphotericin B, 7-oxo-amphotericin B and pentaene analogues. Here we report improved production and purification protocols that have allowed detailed chemical analyses of these compounds. The polyketide synthase product 8-deoxy-16-descarboxyl-16-methyl-amphoteronolide B was identified for the first time. In addition, the ketoreductase 10 domain of the polyketide synthase was specifically inactivated by targeted gene replacement. The resulting mutants produced truncated polyketide intermediates as linear polyenyl-pyrones.
... (4) (a) Cane, DE; Rawlings, BJ; Yang, C.-C. J. Antibior. ... Both (1R)- and (lS)-[l-zH]FPP (2e and 2f)ISa wereseparately incubated with crude aristolochene synthase from A. terreus, and the purified product from each incubation was...
more... (4) (a) Cane, DE; Rawlings, BJ; Yang, C.-C. J. Antibior. ... Both (1R)- and (lS)-[l-zH]FPP (2e and 2f)ISa wereseparately incubated with crude aristolochene synthase from A. terreus, and the purified product from each incubation was analyzed by 61.42-MHz 2H NMR spectroscopy. ...
... The as-(20) We are grateful to Professor George Kotovych and Dr. Albin Otter for a preprint of their work2IC and assistance in obtaining 2D-ROESY spectra. ... Reson. 1985,63, 207-213. (c) Otter, A,; Kotovych, G. Can. J. Chem. 1988,...
more... The as-(20) We are grateful to Professor George Kotovych and Dr. Albin Otter for a preprint of their work2IC and assistance in obtaining 2D-ROESY spectra. ... Reson. 1985,63, 207-213. (c) Otter, A,; Kotovych, G. Can. J. Chem. 1988, 66, 1814-1820. ...
Figure 2.* H decoupled IH," C chemical shift correlation plotsg of cladosporin diacetate (2) derived from sodium [2-13C, 2H3] acetate. Upfield CHD correlations show C-9 and Cl 1 are stereospecifically labeled, but C-13 is...
moreFigure 2.* H decoupled IH," C chemical shift correlation plotsg of cladosporin diacetate (2) derived from sodium [2-13C, 2H3] acetate. Upfield CHD correlations show C-9 and Cl 1 are stereospecifically labeled, but C-13 is not. Spectra were obtained on a Bruker WH400 on ...
Amphotericin B is a medically important antifungal antibiotic that is also active against human immunodeficiency virus, Leishmania parasites, and prion diseases. The therapeutic use of amphotericin B is restricted by severe side effects...
moreAmphotericin B is a medically important antifungal antibiotic that is also active against human immunodeficiency virus, Leishmania parasites, and prion diseases. The therapeutic use of amphotericin B is restricted by severe side effects that can be moderated by liposomal formulation or structural alteration. Chemical modification has shown that suppression of charge on the exocyclic carboxyl group of amphotericin B substantially reduces toxicity. We report targeted deletions of the amphN cytochrome P450 gene from the chromosome of the amphotericin-producing bacterium Streptomyces nodosus. The mutant strains produced amphotericin analogues in which methyl groups replace the exocyclic carboxyl groups. These compounds retained antifungal activity and had reduced hemolytic activity.
Site-directed mutagenesis and gene replacement were used to inactivate two ketoreductase (KR) domains within the amphotericin polyketide synthase in Streptomyces nodosus. The KR12 domain was inactivated in the DeltaamphNM strain, which...
moreSite-directed mutagenesis and gene replacement were used to inactivate two ketoreductase (KR) domains within the amphotericin polyketide synthase in Streptomyces nodosus. The KR12 domain was inactivated in the DeltaamphNM strain, which produces 16-descarboxyl-16-methyl-amphotericins. The resulting mutant produced low levels of the expected 15-deoxy-15-oxo analogs that retained antifungal activity. These compounds can be useful for further chemical modification. Inactivation of the KR16 domain in the wild-type strain led to production of 7-oxo-amphotericin A and 7-oxo-amphotericin B in good yield. 7-oxo-amphotericin B was isolated, purified, and characterized as the N-acetyl methyl ester derivative. 7-oxo-amphotericin B had good antifungal activity and was less hemolytic than amphotericin B. These results indicate that modification at the C-7 position can improve the therapeutic index of amphotericin B.
Actinoplanes caeruleus produces 67-121C, a heptaene macrolide modified with a D-mannosyl-D-mycosaminyl disaccharide. Draft genome sequencing revealed genes encoding mycosaminyltransferase, mycosamine synthase, a cytochrome P450 that...
moreActinoplanes caeruleus produces 67-121C, a heptaene macrolide modified with a D-mannosyl-D-mycosaminyl disaccharide. Draft genome sequencing revealed genes encoding mycosaminyltransferase, mycosamine synthase, a cytochrome P450 that modifies the macrolactone core, and the extending mannosyltransferase. Only the mycosamine synthase and P450 were active in the biosynthesis of amphotericins in Streptomyces nodosus, the amphotericin producer.
The AmphDI glycosyltransferase transfers a mycosaminyl sugar residue from GDP onto 8-deoxyamphoteronolide B, the aglycone of the antifungal amphotericin B. In this study the amphDI gene was inactivated in Streptomyces nodosus strains...
moreThe AmphDI glycosyltransferase transfers a mycosaminyl sugar residue from GDP onto 8-deoxyamphoteronolide B, the aglycone of the antifungal amphotericin B. In this study the amphDI gene was inactivated in Streptomyces nodosus strains lacking the AmphN cytochrome P450. The new mutants produced 8-deoxy-16-methyl-16-descarboxyl amphoteronolides in high yield. These strains and aglycones should prove valuable for in vivo and in vitro glycosylation engineering.
