The milbemycins, a group of potent, broad-spectrum antiparasitic and pesticidal agents, are architecturally novel antibiotics of 16-membered macrocyclic lactone. Seven new milbemycin analogues designed as milbemycins D, E, F, G, H, J and K were isolated from the fermentation broth of the mutant strain of Streptomyces hygroscopicus subsp. aureolacrimosus. The structural determination of these new components was made mainly by comparing with mass spectra, and 1H and 13C NMR spectra of milbemycin alpha- and beta-series previously published from our laboratory. Milbemycins D, E, F, G and H have characteristically an isopropyl side chain at C-25 which differs from the known milbemycin family bearing methyl or ethyl group at C-25. Milbemycins J and K possess a ketone group at C-5 instead of a hydroxyl or methoxy group. Apart from X-ray crystallography, the R-configuration of the hydroxyl group at C-5 could be best explained both by application of CD allylic benzoate method to the n-N, N-dimethylaminobenzoate of milbemycin D and by comparison of the specific rotation of milbemycin D itself and its acetate with the epimeric isomers at C-5.

Milbemycins, a new family of macrolide antibiotics. Structure determination of milbemycins D, E, F, G, H, J and K.

THE BIOSYNTHETIC ROUTW,. . . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . . . . . . . ... . . . . . . . . . . . . . . . . . . . . . .. . . 51 CHARACTERIZATION OF I3-LACTAM-SPECIFIC ENZyMES . . . . . . . . . . . . . . . . . . . . . . . . . . 54 MECHANISMS CONTROLLING ONSET OF I3-LACTAM BIOSYNTHESIS . . . . . . . . . . 58 Supply of a-Aminoadipic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Role of Sulfur Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . 59 Cystathionine-'y-�yl!se in Actinomycetes That Produce Sulfur-Containing . AntlblOtlcs" . . . . . . . , ...... , ....... ,", 62 Role of S-Sulfocysteine and Cystathionine . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 M ECHANISMS THAT AFFECT FLUX IN THE PATHWAy. . . . .. . . . . . . . . . . . . .. . . . . . . . . . . 64 Carbon and Nitrogen Catabolite Regulation . . . . . .. . . . . .. . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Compartmental Localization of End Products and Intermediates in the Pathway . . . , 65 MUTASYNTHESIS AND IN VITRO SUBSTRATE SPECIFICITIES OF PURIFIED ENZYMES ..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . 66 FUTURE OUTLOOK . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . 69

The Biosynthesis of Sulfur-Containing β-Lactam Antibiotics

Sir: The biosynthesis of macrolide antibiotics is inhibited by ammonium ions.1) Previous papersl~3) from this laboratory reported that when producing organisms were grown in the presence of ammonium ion-trapping agents such as magnesium phosphate, the inhibitory effect of ammonium ion was reduced and macrolide production increased. In an attempt to clarify the mechanism of the effect of ammonium ion, we studied the correlation between amino acid metabolism and macrolide biosynthesis. The present communication describes that valine catabolism plays an important role in supplying both n-butyrate and propionate units for the biosynthesis of aglycones of the 16-membered macrolide antibiotics, leucomycin and tylosin. Preliminary results showed that the addition of valine or leucine increased the production of leucomycin, tylosin and protylonolide in Streptoverticillium kitasatoensis KA-468 (68-69-1), Streptomyces fradiae KA-427 and its mutant, strain KA-427-261, respectively. Since protylonolide is a biosynthetic intermediate with a lactonic structure corresponding to the aglycone moiety of tylosin,4) these increases in production imply that valine serves as a precursor or a regulatory effector for the biosynthesis of these aglycones. This assumption led us to examine if the carbons of valine were incorporated into the carbon skeleton of aglycones of the antibiotics. The 13C NMR spectrum of leucomycin A5 labeled by [2-13C]valine with S. kitasatoensis KA-468 revealed that carbon 5 of the aglycone moiety and carbon 8\" of the n-butyryl moiety, which should be derived from the carboxyl carbon atom of n-butyrate,5) were enriched to the extent of 5.0 and 1.6 times, respectively, in comparison with natural abundance with virtually no enrichment on the other carbons. Valine is known to be metabolized to methylmalonyl-CoA via iso-butyrate in various biolo-

VALINE AS A PRECURSOR OF n-BUTYRATE UNIT IN THE BIOSYNTHESIS OF MACROLIDE AGLYCONE

The milbemycins, a group of potent, broad-spectrum antiparasitic and pesticidal agents, are architecturally novel antibiotics of 16-membered macrocyclic lactone. Seven new milbemycin analogues designated as milbemycins D, E, F, G, H, J and K were isolated from the fermentation broth of the mutant strain of Streptomyces hygroscopicus subsp. aureolacrimosus. The structural determination of these new components was made mainly by comparing with mass spectra, and 1H and 13C NMR spectra of milbemycin α- and β-series previously published from our laboratory. Milbemycins D, E, F, G and H have characteristically an isopropyl side chain at C-25 which differs from the known milbemycin family bearing methyl or ethyl group at C-25. Milbemycins J and K possess a ketone group at C-5 instead of a hydroxyl or methoxy group. A part from X-ray crystallography, the R-configuration of the hydroxyl group at C-5 could be best explained both by application of CD allylic benzoate method to the p-N, N-dimethylaminobenzoate of milbemycin D and by comparison of the specific rotation of milbemycin D itself and its acetate with the epimeric isomers at C-5.

Milbemycins, a new family of macrolide antibiotics. Fermentation, isolation, physico-chemical properties and bioconversion of milbemycins J and K.

Addition of magnesium phosphate [Mg3(PO4)2 x 8H2O] to a complex medium or to an ammonium ion-containing, chemically defined medium stimulated leucomycin production by Streptomyces kitasatoensis. Ammonium ions in high concentrations inhibited leucomycin production, but their limitation by magnesium phosphate led to the high production of the antibiotic.

Stimulation of leucomycin production by magnesium phosphate and its relevance to nitrogen catabolite regulation.

An attempt was made to increase the production of maridomycin III (MDM III) as the major component among the six components of maridomycin (maridomycin I, II, III, IV, V and VI). Addition to the production medium, of amino acids belonging to the aspartic acid family and its related compounds, such as l-isoleucine, l-threonine, l-methionine, l-homoserine, dl-α-amino-n-butyric acid and α-ketobutyric acid, resulted in a yield of a large amount of MDM III.MDM III was also formed by intact cells from 4″-depropionyl MDM III and the same compounds. From 4″-depropionyl MDM III and l-isoleucine-U-14C (or dl-α-amino-n-butyric acid-3-14C), MDM III-14C was formed, and a large amount of radioactivity was incorporated into MDM III. On deacylation at C-4″ of the MDM III-14C, about 90% of radioactivity of MDM III-14C was observed as propionic acid-14CIn the same way, SF-837-14C was formed from leucomycin A7 and l-isoleucine-U-14C (or dl-α-amino-n-butyric acid-3-14C), and deacylation of the SF-837-14C at C–3 also gave pro...

Effect of Aspartic Acid Family Amino Acids on Production of Maridomycin III

To clarify the biosynthetic pathway of maridomycin, the biosynthetic relation among 16-membered macrolide antibiotics belonging to leucomycin-maridomycin group was examined with intact cells or growing cultures of Streptomyces hygroscopicus No. B–5050–HA and its mutants.Carbomycin A, B and leucomycin A3 were converted to maridomycin II in the pH range of 5.5-7.5 with an optimum between 6.0-6.5. But, maridomycin II was not converted to leucomycin A3 or carbomycin B. These findings were confirmed by culture experiment. Leucomycin A3, carbomycin A and B added to the culture at 48 hr were almost completely converted to maridomycin II.On the basis of these facts, we propose a biosynthetic relation among leucomycin A3, carbomycin A, carbomycin B and maridomycin II.

Interconversion among 16-Membered Macrolide Antibiotics Belonging to Leucomycin-Maridomycin Group

Penicillin and cephalosporin antibiotics possess a sulfur atom, derived from cysteine, in the molecule. Cysteine is considered to be synthesized via either the sulfate reduction pathway or the reverse transsulfuration path way. The sulfur of penicillin produced by Penicillium chrysogenum is derived efficiently via the sulfate reduction pathway from sul fate,‚P,2) while that of cephalosporin produced by Cephalosporium acremonium is derived preferentially via the reverse transsulfuration pathway from methionine.3,4) In the course of strain improvement of C. acremonium, we found that the addition of thiosulfate or S-sulfocysteine, which is an intermediate in the conversion of inorganic sulfate to organic sulfur compounds, to the chemically defined medium was effective in the production of cephalosporin C (Table I). This finding suggests that the sulfur of cephalosporin C is derived via the sulfate reduction pathway, and that there are at least two routes for cysteine synthesis in C. acre monium as shown below.

S-Sulfocysteine as a Source of the Sulfur Atom of Cephalosporin C

Effect of Inorganic Phosphate and Dissolved Oxygen on Production of Maridomycin

The Effect of Mechanical Damage on the Production of Maridomycin by Streptomyces hygroscopicus : Studies on the Application of Fermentation Kinetics (V)

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