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New Microbial Product, Oudenone, Inhibiting 514 THE JOURNAL OF ANTIBIOTICS OCT. 197O dry yeast and 1.5 % agar sterilized at 120°C NEW MICROBIAL PRODUCT, for 20 minutes (pH after the sterilization OUDENONE, INHIBITING was5.6). The mycelial growth on this agar A TYROSINE HYDROXYLASE medium was inoculated to the saw-dust medium described above and cultured for Sir: 10-20 days at 27°C. Then a sterilized solu- Considering the ability of microorganisms tion consisting of 2.0% glucose and 0.5% to produce various types of compounds, we dry yeast (250ml/flask containing the my- undertook a systematic study of specific celial growth on the saw-dust (10g) me- enzyme inhibitors of microbial origin. We dium described above) was added to obtain thought that microorganisms which produced suspension of the mycelium. This mycelium proteinases in their culture liquids might suspension was used as the inoculum. Ou- produce the inhibitors. We thought also denone was produced in the shaking culture that inhibitors of enzymes involved in nor- and fermentation tanks in media containing epinephrine biosynthesis would be useful for various kinds of carbon sources and nitrogen analysis of the role of this amine in hyper- sources. Media containing 2.0% glucose tensive disease. Thus, first we studied and1.0% corn steep liquor (pH 5.6), or inhibitors of microbial origin against these containing 2.0 % glucose, 1.0% soybean meal enzymes. As reported in previous papers, leu- and0.5% dry yeast (pH 5.6) are examples peptins1'2'3'4) inhibiting trypsin and papain, of media suitable for the production. During pepstatin5>6) inhibiting pepsin, and chymo- 5-8 days of the shaking culture at 27°C, statin7) inhibiting chymotrypsins and weakly pH turned to 4.4-4.8, thereafter in creased papain were isolated, and production of these to5.0-5.6, and the production reached inhibitors was found distributed widely a maximum on 10-15 days of the shak- among Actinomycetes. We isolated aquaya- ing culture. In fermentation tanks con- mycin8'9>10) from Streptomyces misawaensis taining 150 liters of a medium consisting of and chrothiomycin11} from Streptomyces 2.0 % glucose, 0.5 % peptone, 0.3 % dry yeast, pluricoloresces, both of which inhibited 0.3 % KH2PO4 and 0.1 % MgSO4.?H2O under tyrosine hydroxylase and dopamine /?-hy- aeration and stirring at 27°C, the growth droxylase. A compound which inhibited reached a maximumat about 80 hours and dopamine /?-hydroxylase was isolated from the production reached a maximum (607 Fusarium sp. and found to be fusaric mcg/ml) at about 90 hours, when the pH acid12>13'14). In this paper, we report isola- tion of a new compound named oudenone w as 4.8. Oudenone can be determined by measuring inhibiting tyrosine hydroxylase and exhibit- the tyrosine hydroxylase activity by the ing a hypotensive effect. method described in a previous paper9). It The oudenone-producing strain was iso- can also be determined by spectrophotometric lated under a needle-leaved tree at Kirizu- method based on the UV maximum at 246 miyama, GummaPrefecture, and designated va/ULat pH 7.0 which disappears at acid pH. strain 10F in the authors' laboratory. The The method is as follows: a test solution morphological properties of the fruit body is diluted with phosphate buffer of pH 7.0 which was formed on a saw-dust medium or with 0.1N HC1 and the optical density (10% of saw-dust was mixed with60ml of (a) at 246 mju of the phosphate buffer solu- a medium containing2.0 % glucose and 0.5 % tion and that (Jb) of the solution diluted dry yeast, and sterilized at 120°C for 20 with 0.1N HC1 are read and the concentra- minutes) in a flask of 500ml volume were tion of oudenone (mcg/ml) in the test solu- similar to those of Oudemansiella (Mucidula) tion is calculated by (a-b)n x 107(1,000 -60), and among the known species of this genus where n is the dilution. this strain was most closely related to Oude- In the cultured broth oudenone is found mansiella radicata. both in the liquid and the mycelium. After This strain can be transferred on an ager strain 10F was shake-cultured in 125 ml of medium consisting of 2.0 % glucose, 0.5 % a medium consisting of 2.0 % glucose, 0.5 % VOL. XXIII NO. IO THE JOURNAL OF ANTIBIOTICS 515 peptone, 0.3% dry yeast, 0.3% KH2PO4 methyl isobutyl ketone, pH2 1, pH3 ly and0.1 % MgSO4-7H2O the following amo- pH4 0.3,pH5 0.1, pH6 0.1 (thecoeffici- unts of oudenone were found in the liquid ents of methyl isobutyl ketone were deter- and mycelium of 10ml of cultured broth: mined by inhibition of tyrosine hydroxylase 5 days, 372meg (liq.), 185meg (myc); 7 and the others by the spectrophotometric days, 845 meg (liq.), 365 meg (myc); 8 days method). 1,300meg (liq.), 410meg (myc); ll days, Oudenone is stable and no decomposition 2,180 meg (liq.), 342 meg (myc). was observed after heating for 30 minutes Oudenoneis soluble in water, methanol, at 60°C orfor5 minutes at 100°C at pH2.0, ethanol, w-butanol, ethyl acetate, chloroform 7.0 or 9.0. and benzene and extracted into water-immis- Oudenone can be extracted from the cul- sible solvents at acid pH. The partition ture nitrate by an anion-exchange resin pro- coefficients, solvent/H2O, were determined as cess, for instance, using IRA 400 resin in Cl~ follows: butanol-water, pH2 8, pH4 4, form followed by elution with dilute hydro- pH5 2.5,pH6 2.5,pH7 3,pH8 3, pH9 chloricacid, or by a precipitation method as 0.6, pH10 0.8; ethyl acetate-water, pH2 thewater-insolublesalt, for instance, as the 5,pH3 4,pH4 5,pH5 0.2, pH6 <0.1; cupric salt. It is also extracted by carbon butyl acetate-water, pH2 3, pH3 2.5, adsorption process. However, most effici- pH4 1, pH5 0.1, pH6 <0.1; chloro- ently and easily it is prepared by extraction form-water, pH4 19, pH5 1, pH6 0.1; with an organic solvent at acid pH and ig. 1. Ultraviolet spectra of oudenone (5 mcg/ml) in neutral (phosphate F buffer, pH 7.0) and acidic solution (0.1N HC1) 0.5 r Phosphate buffer pH7.0 O.IN HCl 0.4 : o,3 LU 0.2 0./ 0,'2/0 220 240 260 280 300 320mu Fig. 2. Infrared absorption spectrum of oudenone (KBr). 650 cm"1 4000 3000 2000 1800 1600 1400 1200 1000 800 516 THE JOURNAL OF ANTIBIOTICS OCT. 197O reextraction from the solvent with Fig. 3. Lineweaver-Burk plot of L-tyrosine concentration water at neutral pH. The follow- against rate of 3, 4-dihydroxyphenylalanine for- mation with or without oudenone (4.8xlO~5~2.4 ing is an example: 100 liters of XlO"4M). the culture filtrate containing Reaction mixture contained 200 jumoles of acetate buffer, pH 6.0, various concentrations of L-tyrosine labelled with L-tyro- oudenone at 500 mcg/ml were ex- in-14C, 100 jumoles of mercaptoethanol, 1 //mole of DMPH4, 2.5 jumoles of FeSO4, enzyme preparation, and distilled water of tracted with 100 and 60 liters of inal volume of 1.0 ml. 72-butanol successively ; the butanol s f The Km value obtained from the figure is 1.0xl0~4M. extracts were combined and con- l/VxlO~5 4\ L-Tyrosine plus centrated to a syrup under reduced udenone2.4 x tcr4M pressure ; the syrup was dissolved in 4 and 1 liter of ethyl acetate L-Tyrosine plus successively and oudenone in the oudenone1.2 xio~4M ethyl acetate extracts was trans- L -Tyrosine plus oudenone4.8xlO~5M ferred into 1.5 liters of water ad- justed to pH 7.0 with 10N NaOH; L- Tyroslne the aqueous solution was extracted with 3 and 1 liter of ethyl acetate at pH 3 with 10N HC1; evaporation of the ethyl acetate extracts under reduced pressure yielded oudenone crystals and syrup; recrystallization from warmhexane (3 liters) yielded 29 g of crystalline oudenone. Oudenone is recrystallized from 1 2 3 4 hexane or mixture of hexane and l/L- Tyrosine x io~4 benzene and obtained as white plate crystals, m.p. 77~79°C. The Fig. 4. Lineweaver-Burk plot of DMPH4 concentration against rate of 3, 4-dihydroxyphenylalanine for- formula of C12H16O3 was determin- mation with or without oudenone (1.2x10~4m). ed by high resolution mass spectro- The reaction mixture contained 200 jumoles of acetate buffer, scopy and elemental analysis. It is pH 6.0, various concentrations of DMPH4, 0.1 jumole of L-tyro- optically active : [all0 -10.6° (c 0.5, sine containing l.lxlO5 c.p.m. of L-tyrosine-14C, 100 //moles of mercaptoethanol, 2.5 ^moles of FeSO4, enzyme preparation, ethanol). Asshown in Fig. 1, ou- nddistilled water to final volume of 1.0 ml. The Kmvalue obtained from the figure is 4.26x10~4 M and the denone in phosphate buffer of pH a Ki value is 7.58x10"5m. 7.0 shows a maximum at 246mjut (El?m 1,000) and its hydrochloric acid solution shows maxima at 221 mju (El?m 625) and 285 mju (E}?m963). DMPH4 P'us oudenone l.2xicr4M Carbonyl bands are seen in the in- frared spectrum which is shown in Fig. 2. The structure and the synthesis of oudenone will be reported in another paper. Oudenone has no DMPH4 carboxyl group, but it is acidic with a pKa'4.1 as shown by titra- tion. The sodium salt (m.p.
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