Macrolide biosynthesis. Origin of the oxygen atoms in the erythromycins

Cane, David E.; Hasler, Heinz; Liang, Tzyy-Chyau

doi:10.1021/ja00409a077

Cited by 34 publications

(14 citation statements)

References 4 publications

(8 reference statements)

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“…Elegant biosynthetic applications of the 1 8 0 isotope shift in I3C nmr have recently been reported by Cane et al on monensin and erythromycins A and B (35) and by Sankawa et al on complex biological transformations (36).…”

mentioning

confidence: 97%

Biosynthetic studies using ¹⁸O isotope shifts in ¹³C nuclear magnetic resonance

Vederas¹

1982

Can. J. Chem.

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JOHN C. VEDERAS. Can. J. Chem. 60, 1637 (1982). Isotopic substitution with oxygen-18 induces an observable upfield shift in the 13C nmr positions ofdirectly-attached carbons, and in some cases, P-carbons. The magnitudes of these shifts range from about 0.05 ppm to 0.01 ppm, and are dependent on structure in an empirically predictable fashion. Incorporation of doubly labeled (I3C, 180) precursors into polyketides followed by I3C nmr analysis can identify carbon-oxygen bonds remaining intact during microbial biosynthesis. This technique has been applied to studies on antibiotics such as brefeldin A, cytochalasin B, granaticin, and lasalocid A, as well as aflatoxin precursors such as averufin, versicolorin A, and sterigmatocystin. JOHN C. VEDERAS. Can. J. Chem. 60, 1637 (1982). La substitution isotopique par de I'oxygkne-18 induit, en rmn du "C, un dkplacement chimique observable vers les hauts champs des positions des atomes de carbone qui leur sont directement liCs et, dans certains cas, des dkplacements des atomes de carbone en position p. L'ordre de grandeur de ces dkplacements varie de 0,OSppm 2 0.01 ppm et ils dkpendent d'une f a~o n empirique de la structure. L'incorporation de prkcurseurs doublement marquks (13C, 180) dans les polycktides suivie d'une analyse par rmn du I3C permet d'identifier les liaisons carbone-oxygene qui demeurent intactes durant la synthkse microbienne. On a utilise cette technique pour ktudier les antibiotiques tels la brefeldine A, la cytochalasine B, la granaticine et la lasalocide A de m&me que des prkcurseurs d'aflatoxine tels que I'avkrufine, la versicolorine A et la stkrigmatocystine.[Traduit par le journal]During the last decade the development of I3C nmr techniques in biosynthesis has elucidated the arrangement of precursor units in carbon skeletons of most classes of secondary metabolites (1). However, the mechanisms and sequence by which these units are linked remain largely speculative, partly because of lack of methods to follow changes in intermediate oxidation states. In response there is agrowing interest in determination of the biosynthetic fate of precursor hydrogens using 2H nmr (2) and of oxygens using mass spectrometry (3,4). The latter technique can detect both commonlyemployed stable isotopes of oxygen, I7O and IsO, but ascertaining the exact structure of the mass spectrometric fragments in partially-labeled polyoxygenated molecules is often difficult. Frequently preliminary specific labeling experiments or chemical degradations are necessary (4). Unlike 160 and IsO, oxygen-17 has a nuclear spin (512) and can be observed directly by nmr. Unfortunately its use in biological studies (5, 6) has been limited by low natural abundance (0.037%) and consequent expense, as well as by broadness of nmr signals due to its quadrupole and spin-spin coupling. Recently, investigations by Boyer and coworkers (7), Risley and Van Etten (8), Darensbourg et 01. (9), and our group (10) have confirmed the theoretical prediction (1 1) that the more abundant oxygen-18 (0.204%) can be in...

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confidence: 97%

Biosynthetic studies using ¹⁸O isotope shifts in ¹³C nuclear magnetic resonance

Vederas¹

1982

Can. J. Chem.

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“…We efficiently synthesized 13 C-labelled putative erythromycin biosynthetic intermediates, 10a and 2b, via aldol condensation of aldehyde derived from the optically active synthetic intermediate 13 (obtained in our previous work for erythromycin A synthesis) and benzyl ester 14 derived from sodium [1][2][3][4][5][6][7][8][9][10][11][12][13] C]propionate (4) for investigations on the biosynthesis of erythromycin.…”

Section: Resultsmentioning

confidence: 99%

“…The suspension was filtered and the filtrate was evaporated. Chromatography of the crude product on silica gel with AcOEt/hexane (2:1) gave 10a (114 mg, 50%), 1 A solution of 16b (441 mg, 0.847 mmol) in 48% HF/CH 3 CN (1:9, 10 ml) was stirred for 8 h at room temperature, then added dropwise to a suspension of NaHCO 3 in CH 2 Cl 2 , and the whole was stirred for 30 min at room temperature. To this suspension was added anhydrous MgSO 4 and the whole was stirred for 30 min at room temperature.…”

Section: Benzyl (2s3s4s5r6r7r)-and Benzyl (2r3s4s5r6r7r)-7-mentioning

confidence: 99%

“…Cane et al obtained much information about the chain elongation process in the erythromycin biosynthetic pathways from feeding experiments with 2 H-, 13 C-and/or 18 O-labelled compounds in S. erythraea. [1][2][3][4][5] In addition, groups led by Leadlay and Katz have employed a genetic approach to study the biosynthesis of 6-deoxyerythronolide B, the first biosynthetic macrolide intermediate of erythromycin A, in S. erythraea. [6][7][8][9] We are interested in the biosynthetic pathways to 6-deoxyerythronolide B, especially the chain elongation mechanism in erythromycin biosynthesis.…”

Section: Introductionmentioning

confidence: 99%

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Efficient syntheses of ¹³C‐labelled erythromycin biosynthetic intermediates. 2: (2S,3S,4S,5R,6R,7R)‐3,6,7‐trihydroxy‐2,4,6‐trimethyl[1‐¹³C]nonan‐5‐olide and S‐2‐acetylaminoethyl (2R,3S,4S,5R,6S,7R)‐3,5,6,7‐tetrahydroxy‐2,4,6‐trimethyl[1‐¹³C]nonanethioate

Iida

Kajiwara

Fukui

et al. 2008

Labelled Comp Radiopharmac

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The 13C‐labelled putative erythromycin biosynthetic intermediates, ((2S,3S,4S,5R,6R,7R)‐3,6,7‐trihydroxy‐2,4,6‐trimethyl[1‐13C]nonan‐5‐olide and S‐2‐acetylaminoethyl (2R,3S,4S,5R,6S,7R)‐3,5,6,7‐tetrahydroxy‐2,4,6‐trimethyl[1‐13C]nonanethioate), which would be useful for the investigation of the chain elongation mechanism in erythromycin biosynthesis, were efficiently synthesized via aldol condensation of aldehyde derived from (2S,3R,4R,5R)‐tert‐butyldimethylsilyloxy‐5‐3,4‐O‐isopropylidene‐2,4‐dimethylheptanol, which was obtained in our previous work on erythromycin A synthesis, and sodium [1‐13C]propionate (after conversion to ester). Copyright © 2008 John Wiley & Sons, Ltd.

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“…41 We then extended these finding by determining the origins of oxygen atoms of the antibiotic nargenicin 42,43 and the anti-helminthic agent avermectin. 44 Turning to polyether antibiotics, we also established the derivation of all the oxygens in monensin (15) and the closely related lenoremycin from acetate, propionate or molecular oxygen (Figure 9).…”

Section: Isoprenoid and Polyketide Biosynthesismentioning

confidence: 99%

Nature as organic chemist

Cane

2016

J Antibiot

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Figure 15 Stereospecific reduction of (2R)-2-methyl-3-ketopentanoyl-ACP by recombinant ketoreductase (KR) domains: EryKR6, from module 6 of the 6dEB synthase (DEBS); TylKR1, from module 1 of the tylactone synthase; EryKR1, from DEBS module 1; RifKR7, from module 7 of the rifamycin PKS. The (2R)-2-methyl-3-ketopentanoyl-ACP substrate is generated in situ by a reconstituted mixture of dissected PKS domains, Ery[KS6][AT6] (ketosynthase-acyl transferase didomain) and EryACP6 are both from DEBS module 6. Editorial

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Macrolide biosynthesis. Origin of the oxygen atoms in the erythromycins

Cited by 34 publications

References 4 publications

Biosynthetic studies using ¹⁸O isotope shifts in ¹³C nuclear magnetic resonance

Biosynthetic studies using ¹⁸O isotope shifts in ¹³C nuclear magnetic resonance

Efficient syntheses of ¹³C‐labelled erythromycin biosynthetic intermediates. 2: (2S,3S,4S,5R,6R,7R)‐3,6,7‐trihydroxy‐2,4,6‐trimethyl[1‐¹³C]nonan‐5‐olide and S‐2‐acetylaminoethyl (2R,3S,4S,5R,6S,7R)‐3,5,6,7‐tetrahydroxy‐2,4,6‐trimethyl[1‐¹³C]nonanethioate

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Macrolide biosynthesis. Origin of the oxygen atoms in the erythromycins

Cited by 34 publications

References 4 publications

Biosynthetic studies using 18O isotope shifts in 13C nuclear magnetic resonance

Biosynthetic studies using 18O isotope shifts in 13C nuclear magnetic resonance

Efficient syntheses of 13C‐labelled erythromycin biosynthetic intermediates. 2: (2S,3S,4S,5R,6R,7R)‐3,6,7‐trihydroxy‐2,4,6‐trimethyl[1‐13C]nonan‐5‐olide and S‐2‐acetylaminoethyl (2R,3S,4S,5R,6S,7R)‐3,5,6,7‐tetrahydroxy‐2,4,6‐trimethyl[1‐13C]nonanethioate

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Biosynthetic studies using ¹⁸O isotope shifts in ¹³C nuclear magnetic resonance

Biosynthetic studies using ¹⁸O isotope shifts in ¹³C nuclear magnetic resonance

Efficient syntheses of ¹³C‐labelled erythromycin biosynthetic intermediates. 2: (2S,3S,4S,5R,6R,7R)‐3,6,7‐trihydroxy‐2,4,6‐trimethyl[1‐¹³C]nonan‐5‐olide and S‐2‐acetylaminoethyl (2R,3S,4S,5R,6S,7R)‐3,5,6,7‐tetrahydroxy‐2,4,6‐trimethyl[1‐¹³C]nonanethioate