WO2008026883A1 - Process for mass production of mycophenolic acid by using urea as nitrogen source - Google Patents
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- WO2008026883A1 WO2008026883A1 PCT/KR2007/004167 KR2007004167W WO2008026883A1 WO 2008026883 A1 WO2008026883 A1 WO 2008026883A1 KR 2007004167 W KR2007004167 W KR 2007004167W WO 2008026883 A1 WO2008026883 A1 WO 2008026883A1
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- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
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Abstract
The present invention relates to methods for producing mycophenolic acid using urea as a nitrogen source. More particulary, the present invention provides the method for producing mycophenolic acid by culturing PeniciIlium brevi-compactum in a culture solution comprising 3-9g urea, carbon source, nitrogen source, and trace elements.
Description
[DESCRIPTION] [Invention Title]
PROCESS FOR MASS PRODUCTION OF MYCOPHENOLIC ACID BY USING UREA AS NITROGEN SOURCE
[Technical Field]
The present invention relates to process for mass production of mycophenolic acid (MPA) by using urea as nitrogen source and medium composition for mass production of mycophenolic acid.
[Background Art]
Mycophenolic acid is a fermented product from PencilHum glaucum. It was reported in 1896 for the first time (E.L. Jones, et al. , 1975, J. Invest. Dermatol. 65, 537). The structure was determined in 1952. It was known to have antibacterial, antifungal effects at first time, but it has been reported that it also has antiviral effects and inhibiting effects of cancer tissue growth and immune rejection response. Mycophenolic acid has been approved recently by the U. S. Food and Drug Administration (FDA) as an immunosuppressive drug preventing rejection responses of patients received the same kind of heart or kidney transplant. It is known that it has effects on hemmolytic anemia, bullous pemphigoid, inflammatory enteritis, myasthenia gravis, nephropathy, psoriasis, and rheumarthritis etc. which are caused by a liver transplant and autoimmune. So clinical applications of mycophenolic acid are developing.
It was reported that such various activities of mycophenolic acid in vivo have effects on blocking the de novo pathway (which is a kind of biosynthesis pathway producing GMP from amino acid) of purine biosynthesis and inhibiting DNA synthesis by inhibiting activity of inosine monophosphate dehydrogenase (IMPDH) alternatively, reversibly and uncompetitiveIy. When IMPDH is blocked, the amount of guanosine nucleotides in cell decreases, while ATP is not affected by it. Moreover, mycophenolic acid inhibits growth
of T lymphocyte and B lymphocyte, and humoral immunity by B lymphocyte. But, it does not inhibit production of cytokines (IL-I and IL-2). Mycophenolic acid has more specific effects on lymphocytes than other cells have because lymphocytes are more dependent on de novo pathway in GMP synthesis than other cells.
The physical and chemical characteristics of the above mycophenolic acid are as follows.
The chemical name is 6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-5- isobenzofranyl)-4-methyl-4-hexenoic acid. The molecular formula is C17H2OO6.
The molecular weight is 320.34. The structure is the same as the following structural formula I.
(Structural formula I)
The above mycophenolic acid can be biosynthesized by fermentation by microorganisms, especially fungi. So industrial techniques of preservation, culture and improvement of strains producing mycophenolic acid need to be developed.
Fungi frequently used as industrial strains belong to Mycete and have homologous chromosomes and alleles. Also their genes are much bigger and more complex than those of bacterium or Actinomyces. They belong to a microorganism group which is hard to handle because they have complex metabolic processes, for example unique growth forms like hyphal form, cell division processes like sporogenesis, and biosynthesis of the secondary metabolic products, etc. So each company possessing a unique strain needs to
develope its own protocol and technique corresponding to characteristics of the strain.
Korea Patent Application No. 10-2002-7003830 discloses methods for producing mycophenolic acid and its derivatives. PeniciIlium waksmani strain was used as a mycophenolic acid producing strain in the invention. Also it discloses the specific culture condition like nitrogen source, pH, and temperature. But, industrial application of the above invention for mass production of mycophenolic acid is not easy because an optimal condition of the production corresponding to a specific strain is not disclosed.
Nitrogen occupies about 10-14% of total weight of dried biomass. Ammonia, ammonium salt (NH4Cl, (NH4)SO4, NH4NO3), protein, peptide, or amino acid are most commonly used nitrogen sources. Nitrogen is used for cell growth in the form of protein or nucleic acid. Some microorganisms such as Azotobacter sp., cyanobacteria produce ammonium by fixing nitrogen in the air. Urea is also used as a nitrogen source by some organisms. Organic nitrogen sources like yeast extract or pepton are more expensive than ammonium salt.
Most of industrial microorganisms can use both inorganic and organic nitrogen sources. Inorganic nitrogen is supplied in the form of ammonia gas, ammonium salt, nitrate, etc. (Hunter, 1972). Ammonia has been used as not only pH control but also an important nitrogen source in limited medium for commercial production of human serum albumin using Saccharomyces cerivisiae (Collins, 1990).
If we use ammonium sulfate, culture solution becomes acidic because ammonium ions are consumed by microorganisms and sulfuric acid ions remain in the media. On the other hand, if we use nitrate, culture solution becomes alkali with consumption of it.
In the case of ammonium nitrate, culture solution becomes acidic in the early stage of culture because ammonia is consumed and the consumption of nitrate is inhibited. But, culture solution becomes alkali as ammonia is exhausted and nitrogen of nitrate starts to be consumed instead of ammonia
(Morton and MacMillan, 1954). The exception of this case is the metabolism of Gibberella fujikuroi (Brow etc., 1961, 1964). In the existence of nitric acid ion, assimilation of ammonia by the strain is inhibited from pH 2.8 to 3.0 and the use of nitric acid ion continues until assimilation of ammonia is resumed by increase of pH.
The activity of nitrate reductase which reduce nitrate to ammonium ion is repressed in the existence of ammonia (Brown, etc., 1974). So there are many cases that ammonia or ammonium ion is used as a nitrogen source. According to a research of a fungus, ammonium ion inhibits intake of amino acid by general and specific amino acid permease (Whitaker, 1976). Besides, ammonia regulates the production of alkali and neutral protease in Aspergillus nidulans (Cohen, 1973). Therefore, if a nitrogen source is a mixture, selective assimilation continues until some nitrogen compound disappears by assimilation because each nitrogen compound is related to control of metabolism individually.
It is reported that production of antibiotic by many microorganisms is affected by density and form of nitrogen source in culture medium (Aharonowitz, 1980). Production of antibiotic can be inhibited when nitrogen sources like NH4 , NO3 , or some amino acid are used fastIy. The production of
an antibiotic in culture solution begins to increase after most nitrogen sources are consumed. If mild acidic salts like ammonium succinate are used as a nitrogen source, extreme pH change which may be occurred by chloride or sulfuric acid ion can be prevented. We can use phosphoric acid at lower density in buffer medium. High phosphate density inhibits production of many secondary metabolites.
It is reported that nitrogen source in medium affects production and form of gibberellin (Jefferys, 1970). Moreover, characteristics of various processes also affect selection of nitrogen source. Rhodes (1963) reported that optimal density of nitrogen for producing griseofulvin is somewhat different according to seed or type of fermenter.
Some mixed nitrogen sources cannot be used by microorganism and can bring about some problems in wastewater treatment. So this can also be an important factor in a choice of a substrate. Therefore, medium condition needs to be optimized for industrial mass production of mycophenolic acid. The present inventor found that urea is the most excellent nitrogen source among nitrogen sources and developed the present invention.
[Disclosure]
[Technical Problem]
The present invention provides fermentation medium compositions for industrial mass production of mycophenolic acid through fermentation by using fungi and methods for mass production of mycophenolic acid by using it.
[Technical Solution]
The present invention provides fermentation medium compositions for mass production of mycophenolic acid as follows. In addtion, the present invention also provides methods for mass production of mycophenolic acid by using the compositions.
[Advantageous Effects]
We can produce mycophenolic acid in large quantities by using the medium comprising urea as a nitrogen source according to the present invention. [Description of Drawings]
FIG. 1 shows the structural formula of mycophenolic acid. [Best Mode]
To achieve the above aim, the present invention provides the following fermentation medium composition for mass production of mycophenolic acid. Glucose 100-12Og , urea 3-9 g , K2HPO44-6 g , MgSO4 • 7H2O 0.5-2 g , yeast extract
0.5-2g, trace element stock solution l-3in£ (distilled water 10OnA added 5N-HC1 lmfc where FeSO4 • 7H2O 0.1 g , CuSO4 • 5H2O 0.015 g , ZnSO4 • 7H2O 0.1 g ,
MnSO4 • 4H2O 0.01 g , (NHJ6Mo7O24 ■ 4H2O 0.001 g are dissolved) are dissolved per distilled water IL. The production of mycophenolic acid can't be achieved efficiently below the lowest limit of the above composition range due to the lack of nutrients, while above the upper limit of the above composition range inhibition by excessive nutrients and water shortage by increased osmotic pressure occurs.
Method of mass production of mycophenolic acid using the above fermentation medium composition is another aspect of the present invention. The above mycophenolic acid includes compounds having the structure represented by the following structural formula HI and derivatives thereof.
(Structural formula HI)
R1 is methyl or hydroxymethyl ; and R2 is hydroxy or amino group.
More specifically, the present invention is about the method of mass production of mycophenolic acid characterized by culturing PeniciIlium brevi-compacturn strain in medium containing urea 3-9 g /L as nitrogen source, carbon source which can be assimilated, nitrogen source, and trace elements in culture media.
Mycophenolic acid produced by the present invention can be derivatized by known methods (Korea Patent Application No. 1987-0014353, etc.). Purity of mycophenolic acid which is used clinically is over 95%. Also it dissolves well in ethanol, but it is insoluble in water.
In oral administration of mycophenolic acid, it needs to be esterificated into Mycophenolate Mofetil (MPM) for absorption.
MPM is a prodrug. It is absorbed into body radpidly after administration and then transformed into active form, mycophenolic acid. MPM was developed by Syntex co. (U.S.A) in 1987 as an immunosuppressant and was registered as a composition of matter patent. Then it has been sold in the name of Cellcept after Syntex co. assigned its right to Roche co. (Switzerland).
The physical and chemical characteristics of the MPM are as follows.
The chemical name is 2-morpholinoethyl(E)-6-(l,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxo~5-isobenzofranyl )-4-methyl-4-hexenoic acid. The molecular formula is 023H31NO7. The molecular weight is 433.50. The structure is the structural formula II as follows.
(Structural formula II )
MPM has been used mainly as a multifunctional immunosuppressant. However, it is reported recently that it can prevent a recurrence of systemic lupus erythematosus without side-effects, while adrenal cortical hormone inhibitors have not only effect on prevention of the recurrence but also side-effects (KISTI, 2003.6.2.). Systemic lupus erythematosus can be caused by production of antibody against double stranded DNA and recurred in six months after medication. According to the above report, administration of MPM to patients after increase of the antibody can decrease anti-double stranded DNA and activity of B cell without side-effects and prevent recurrence of the disease. It indicates that mycophenolic acid can be used as a multifunctional remedy.
The strain which is used in the present invention is PeniciIlium brevi- compactum, preferably deposited Penicillium brevi-compacturn ATCC46514.
[Mode for Invention]
Hereinafter, the present invention will be described in further detail with reference to examples. It is to be understood, however, that these examples are for illustrative purposes only and are not to be construed to limit the scope of the present invention.
Example 1. Composition of medium for mass production of mycophenolic acid (MPA) comprising urea as nitrogen source
Density of glucose (carbon source) was 12%. A period of incubation time was 7 days. Comparative analysis was performed by using pH, PMV, and activity of MPA (HPLC). The medium had the same basic composition as the known medium (Table 1). It was cultured in 250ml flask, at 23 °C , 150rpm, for 7 days.
5g/L inorganic nitrogen source and 10g/L organic nitrogen source was added considering their nitrogen content in order to balance with the level of NH4NO35.2g/L (1.82g/L as N) .
[Table 1] Basic composition of media for producing mycophenolic acid
* Glucose was added separately after sterilization.
Urea usually makes pH increase when it is sterilized. But, measured pH was 6.05 before sterilization and 6.63 after sterilization. The result indicated that the rate of increase was not so high. Also the reason seemed that decomposition of urea was not enough because the media was close to acidic unlike other media.
According to table 2, among inorganic nitrogen sources urea was the only nitrogen source with higher productivity than NH4NO3 (control). In the scale of flask, urea indicated high productivity over l,000mg/L and can be considered as an outstanding inorganic nitrogen source. P. brevi-compaction has urase, so it can decompose urea into NH4. But, the rate of decomposition
is so slow that catabolite repression by NH4 seems to be removed by itself.
Therefore, we can expect more production increasement when urea is mixed with nitrate. Moreover, urea can be an ingredient of the medium composition which can prevent inhibition by acidic pH because urea does not cause sharp change
+ of pH compared with NH4 or NO3.
P. brevicompacturn can also use NH4 or NO3 as an inorganic nitrogen
source easily. So we expected that we could get similar results in productivity when (NH4^SO4 or NH4Cl was used. However, they hardly yield MPA while KNO3 synthesized MPA (Table 2). The reason seems that the growth of the strain was inhibited in the early step because of sharply decreased pH with
+ consumption of NH4. We can deduce it from the facts that pH of the culture
solution was below 2.0 and PMV was low after incubation. Therefore we can consider the usage of buffer like CaCC^ when we use ammonium salts of strong acids.
[Table 2]
Growth of P. brevicompacturn ATCC46514 and production of mycophenolic acid in inorganic and organic nitrogen source
* Density of added inorganic nitrogen source is 5g/L.
Example 2. Optimal density of urea for producing mycophenolic acid
NH4Nθ35.2g/L corresponds to 1.82g nitrogen/L. So, about 5g/L inorganic nitrogen sources were used to balance with the density in example 1. When
5g/L urea was added, about 3.3 times higher productivity was estimated than control .
To determine the optimal density, we performed the second experiment (table 3). As shown in table 3, production of MPA was 2-3 times higher than NH4NO3 (control) in 3-9g/L urea. Therefore, it is confirmed that urea is an outstanding nitrogen source having effect on increase of MPA production in the range and the optimum density is 5g/L.
[Table 3]
Effect of urea on growth of P. brevicompacturn ATCC46514 and production of mycophenolic acid
[Industrial Applicability]
In the method for producing mycophenolic acid using PeniciIlium brevi- compactum of the present invention, if urea is used as nitrogen source, mycophenolic acid can be produced efficiently, so it can be useful for many industrial purpose.
Claims
[Claim 1]
A method for producing mycophenolic acid of following structural formula HI and derivatives thereof using PeniciIlium brevi-compacturn in a culture solution containing ordinary carbon source, trace elements, and inorganic nitrogen source comprising 3g/L - 9g/L urea:
(Structural formula HI) wherein,
R1 is methyl or hydroxymethyl ; and R2 is hydroxy or amino group.
[Claim 2]
The method according to claim 1, wherein the culture solution comprises 4g/L - 6g/L urea. [Claim 3]
The method according to claim 1, wherein the culture solution comprises 100-12Og glucose,
3-9g urea, 4-6g K2HPO4, 0.5-2g MgSO4 • 7H2O, 0.5-2g yeast extract, and l-3mL trace elements solution (100ml distilled water added ImI 5N-HC1 where O.lg FeSO4 • 7H2O, 0.015g CuSO4 • 5H2O, O.lg ZnSO4 • 7H2O, O.Olg MnSO4
4H2O, Q.QOIg (N^)6Mo7O24 • 4H2O are dissolved) per IL distilled water.
[Claim 4]
A culture solut ion compr i sing 100-12Og glucose , 3~9g urea , 4-6g K2HPO4 ,
0.5-2g MgSO4 • 7H2O, 0.5~2g yeast extract , and l-3mL trace elements solut ion (100ml dist i l led water added ImI 5N-HC1 where O . lg FeSO4 • 7H2O, 0.015g CuSO4 • 5H2O, O . lg ZnSO4 - 7H2O, O . Olg MnSO4 ■ 4H2O, O . OOlg (NH4)Jo7O24 • 4H2O are dissolved) per IL distilled water.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020060082477A KR20080019928A (en) | 2006-08-29 | 2006-08-29 | Process for mass production of mycophenolic acid by using urea as nitrogen source |
| KR10-2006-0082477 | 2006-08-29 |
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| WO2008026883A1 true WO2008026883A1 (en) | 2008-03-06 |
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| PCT/KR2007/004167 WO2008026883A1 (en) | 2006-08-29 | 2007-08-29 | Process for mass production of mycophenolic acid by using urea as nitrogen source |
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| KR (1) | KR20080019928A (en) |
| WO (1) | WO2008026883A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008127663A1 (en) * | 2007-04-11 | 2008-10-23 | Teva Gyógyszergyár Zártköruen Muködo Részvénytársaság | Method for reducing impurity level in mycophenolic acid fermentation |
| US7683188B2 (en) | 2004-04-26 | 2010-03-23 | TEVA Gyógyszergyár Zártkōrūen Mūkōdō Részvénytársaság | Process for preparation of mycophenolic acid and ester derivatives thereof |
| EP2247737A2 (en) * | 2008-02-06 | 2010-11-10 | Biocon Limited | Fermentation medias and processes thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4452891A (en) * | 1980-09-08 | 1984-06-05 | Ajinomoto Company Incorporated | Method for production of mycophenolic acid by fermentation |
| JPS6087795A (en) * | 1983-10-19 | 1985-05-17 | Ajinomoto Co Inc | Production of mycophenolic acid by fermentation |
| WO2003106690A1 (en) * | 2002-06-18 | 2003-12-24 | Biocon India Limited | Fed batch solid state fermentation for the production of mycophenolic acid |
| EP1624070A1 (en) * | 2004-08-05 | 2006-02-08 | Tecnimede-Sociedade Tecnico-Medicinal, S.A. | Process for the production of mycophenolic acid |
| KR20070013429A (en) * | 2005-07-26 | 2007-01-31 | 충청북도 | Process for the production of mycophenolic acid by culturing penicillium brevi-compactum in low temperature |
| KR20070013430A (en) * | 2005-07-26 | 2007-01-31 | 충청북도 | Process for the production of mycophenolic acid by culturing penicillium brevi-compactum in weak acid condition |
-
2006
- 2006-08-29 KR KR1020060082477A patent/KR20080019928A/en not_active Application Discontinuation
-
2007
- 2007-08-29 WO PCT/KR2007/004167 patent/WO2008026883A1/en active Application Filing
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4452891A (en) * | 1980-09-08 | 1984-06-05 | Ajinomoto Company Incorporated | Method for production of mycophenolic acid by fermentation |
| JPS6087795A (en) * | 1983-10-19 | 1985-05-17 | Ajinomoto Co Inc | Production of mycophenolic acid by fermentation |
| WO2003106690A1 (en) * | 2002-06-18 | 2003-12-24 | Biocon India Limited | Fed batch solid state fermentation for the production of mycophenolic acid |
| EP1624070A1 (en) * | 2004-08-05 | 2006-02-08 | Tecnimede-Sociedade Tecnico-Medicinal, S.A. | Process for the production of mycophenolic acid |
| KR20070013429A (en) * | 2005-07-26 | 2007-01-31 | 충청북도 | Process for the production of mycophenolic acid by culturing penicillium brevi-compactum in low temperature |
| KR20070013430A (en) * | 2005-07-26 | 2007-01-31 | 충청북도 | Process for the production of mycophenolic acid by culturing penicillium brevi-compactum in weak acid condition |
Non-Patent Citations (3)
| Title |
|---|
| BARTMAN C.D. ET AL.: "Mycophenolic acid production by Penicillium brevicompactum on solid media", APPL. ENVIRON. MICROBIOL., vol. 41, no. 3, 1981, pages 729 - 736, XP002442708 * |
| DOERFLER D.L. ET AL.: "Mycophenolic acid production by Penicillium brevicompactum in two media", CAN. J. MICROBIOL., vol. 25, no. 8, 1979, pages 940 - 943, XP000956400 * |
| VINOKUROVA N.G.: "Production of mycophenolic acid by fungi of the genus Penicillium link", APPL. BIOCHEM. MICROBIOL., vol. 41, no. 1, 2005, pages 83 - 86, XP019293748 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7683188B2 (en) | 2004-04-26 | 2010-03-23 | TEVA Gyógyszergyár Zártkōrūen Mūkōdō Részvénytársaság | Process for preparation of mycophenolic acid and ester derivatives thereof |
| WO2008127663A1 (en) * | 2007-04-11 | 2008-10-23 | Teva Gyógyszergyár Zártköruen Muködo Részvénytársaság | Method for reducing impurity level in mycophenolic acid fermentation |
| EP2247737A2 (en) * | 2008-02-06 | 2010-11-10 | Biocon Limited | Fermentation medias and processes thereof |
| EP2247737A4 (en) * | 2008-02-06 | 2012-03-14 | Biocon Ltd | Fermentation medias and processes thereof |
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| Publication number | Publication date |
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| KR20080019928A (en) | 2008-03-05 |
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