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WO 2017/005910 Al 12 January 2017 (12.01.2017) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/005910 Al 12 January 2017 (12.01.2017) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C12P 7/42 (2006.01) C12P 7/52 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/EP20 16/066305 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 8 July 2016 (08.07.2016) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 1530613 1.2 ' July 2015 (09.07.2015) EP TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: METABOLIC EXPLORER [FR/FR]; Bi- DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, opole Clermont-limagne, 63360 Saint Beauzire (FR). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventors: SOUCAILLE, Philippe; Chant du Coucou, GW, KM, ML, MR, NE, SN, TD, TG). 31450 Deyme (FR). DISCHERT, Wanda; 67 rue de Coulogne, 63270 Vic-le-Comte (FR). DUMON-SEI- Declarations under Rule 4.17 : GNOVERT, Laurence; 12 rue Marguerite de Valois, — of inventorship (Rule 4.17(iv)) 63430 Pont du Chateau (FR). Published: (74) Agent: REGIMBEAU; 139 rue Vendome, 69477 Lyon Cedex 06 (FR). — with international search report (Art. 21(3)) (81) Designated States (unless otherwise indicated, for every — with sequence listing part of description (Rule 5.2(a)) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, © o (54) Title: METHIONINE HYDROXY ANALOG (MHA) PATHWAYS FOR PRODUCTION BY FERMENTATION (57) Abstract: The present invention relates to a method for the production of 2-Hydroxy-4-(Methylthio) Butyric Acid (HMBA), an analog of the essential amino acid methionine and to a recombinant microorganism useful for the production by fermentation of 2- Hydroxy-4-(Methylthio) Butyric Acid. The microorganism of the invention is modified in a way that the HMBA biosynthesis is im proved by enhancing production of enzymes catalyzing the conversion of methionine into HMBA. METHIONINE HYDROXY ANALOG (MHA) PATHWAYS FOR PRODUCTION BY FERMENTATION FIELD OF THE INVENTION The present invention relates to a method for the production of 2-Hydroxy-4-(Methylthio) Butyric Acid (HMBA), an analog of the essential amino acid methionine. It is also an object of the invention to provide a genetically modified microorganism for the production of HMBA. The microorganism of the invention is modified in a way that the HMBA biosynthesis is improved by enhancing production of enzymes catalyzing the conversion of methionine into HMBA. BACKGROUND OF THE INVENTION Nutritivity-improving feedstuffs additives are nowadays an indispensable constituent of animal nutrition. One of the most important of these additives is the essential amino acid methionine, which occupies a prominent position as a feedstuffs additive above all in poultry rearing. In fact, methionine is the first limiting amino acid in corn and soybean meal based diets of poultry, and probably also in high-yielding cows and second or third amino acid in diets of pigs (Dilger and Baker, 2007). The racemic form of 2- Hydroxy-4-(Methylthio) Butyric Acid (HMBA), commonly referred to as "hydroxymethionine" or "methionine hydroxy analogue" (MHA) is a methionine substitute which has been known for a long time and is chiefly used as a feedstuffs additive in animal nutrition, in particular in the rearing of poultry. This MHA can be used instead of methionine and, like this, improves the yield of breast meat on poultry. It is furthermore also used pharmaceutically in the form of its calcium salt in treatment of renal insufficiency. The methionine hydroxy analogue contains a hydroxyl radical on the a-carbon of the methionine molecule rather than an amino group. It has the formula (1): CH3SCH2CH2CH (OH) COOH (1) In contrast with the amino acid, it is not used directly by the organism in protein synthesis, because it must be anabolically converted into the amino acid to be used as such. HMBA is not used in the pure form, but in various forms according to its application, namely: a mixture of calcium and ammonium salts of HMBA (US 2,745,745 and US 2,938,053), - acidic aqueous solutions (US 4,353,924), calcium salts of HMBA, obtained by the process described in US 3,175,000. It is known for a long time that HMBA can be prepared by a chemical process. It is synthesized by hydratation and successive hydrolysis of 2-hydroxy-4- methylthiobutyronitrile (HMBN) in a sulfuric acid medium. This process is described in EP087481 1, but not exclusively. Several patents applications from NOVUS International (WO 1998/032872), MONSANTO Company (EP0142488), or Rhone Poulenc Animal Nutrition S.A. (US 6,180,359) describe hydrolysis of HMBN into HBMA by a two-stage process. All these technologies rely approximately on the same raw material (3- methylthiopropionaldehyde or MMP) and key intermediates (2-hydroxy-4-methylthio- hydroxybutyronitrile or HMBN and 2-hydroxy-4-(methylthio)butyronitrile or MMP-CN). The general process for the preparation starts from 3-methylthiopropionaldehyde (MMP) which is reacted with hydrogen cyanide (HCN) or sodium cyanide (NaCN) to give the 2- hydroxy-4-methylthiobutyronitrile (HMBN). The MMP-CN formed is then conventionally hydrolysed with strong inorganic acid such as hydrochloric or sulphuric acid. In a subsequent stage, after dilution with water, the hydrolysis is completed at a higher temperature. The HMBA is then extracted with organic solvent which is not very miscible with water, such as ketone, and then the solvent is removed by electroporation. During the past few years, new methods have emerged involving enzymes or biological material. Aventis Animal Nutrition S. A. has for instance described and patented a method for the preparation of HMBA by enzymatic hydrolysis of the 2-hydroxy-4- methylthiobutyronitrile intermediate. The invention is based on bioconversion of HMBN after contacting the molecule with immobilized biological material having nitrilase activity (US 6,180,359). A similar process was described by Novus with the enzymatic conversion of 2-hydroxy-4-(methylthio)-butanenitrile to 2-hydroxy-4-(methylthio)-butaneamide or 2- hydroxy-4-(methylthio)-butanoic acid or salts (WO 1998/032872). The Japanese company Sumitomo has recently protected another technology to produce the methionine hydroxy analogue in three steps; the first two are chemical whereas the third one is a bioconversion. The invention is described in the patent application WO2006/041209 and comprises in step (A) a reaction between l,2-epoxy-3-butene and water to obtain 3-butene-l,2-diol, which reacts in step (B) with methanethiol to obtain 4- (methylthio)butane-l,2-diol, which is finally oxidized in step (C) by interacting with microbial cells having the required activity to convert the 4-(methylthio)butane-l,2-diol into 2-hydroxy-4-(methylthio)butyric acid. Another invention from ADISSEO combines production of HMBA by fermentation and chemistry, the former process to obtain the intermediate 2,4-dihydroxybutyrate (2,4DHB) which is converted chemically into HMBA (WO2014/009435). A completely new invention was disclosed in the patent application WO20 12/090022 which describes the bio-production of the hydroxymethionine by fermentation of a recombinant microorganism modified to produce L-methionine under conditions of nitrogen limitation. This is the only example of one-step production of L-2-hydroxy-4- (methylthio) butyric acid by fermentation from a renewable raw material. From growing oil prices the need for the HMBA production from renewable resources arises. Optimization of production microorganisms often requires rational engineering of metabolic network. Another possibility is the implementation of novel enzymatic systems that catalyze the production of HMBA. Using both approaches, the inventors were able to identify pathways for the production of the methionine hydroxyl analog (MHA) by fermentation from a renewable raw material. BRIEF DESCRIPTION OF THE INVENTION The present invention is related to a method for the production of 2-hydroxy-4- (methylthio) butyric acid wherein in a first enzymatic step methionine is converted into 4- methylthio-2-oxobutanoic acid and in a second enzymatic step 4-methylthio-2-oxobutanoic acid is converted into 2-hydroxy-4-(methylthio) butyric acid. The invention relates more particularly to a genetically modified microorganism for the production of 2-hydroxy-4-(methylthio) butyric acid expressing a transaminase or oxidoreductase for the conversion of methionine into 4-methylthio-2-oxobutanoic acid and an oxidoreductase and/or transferase and/or hydrolase and/or lyase and/or ligase for the conversion of 4-methylthio-2-oxobutanoic acid into 2-hydroxy-4-(methylthio) butyric acid. Method for the production of 2-hydroxy-4-(methylthio) butyric acid comprising culturing the genetically modified microorganism in an appropriate culture medium comprising a source of carbon, a source of sulfur and a source of nitrogen and recovering 2-hydroxy-4- (methylthio) butyric acid from the culture medium is also an object of the invention.
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