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(12) Patent Application Publication (10) Pub. No.: US 2015/0240271 A1 Marliere (43) Pub US 20150240271 A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0240271 A1 Marliere (43) Pub. Date: Aug. 27, 2015 (54) METHOD FOR THE PRODUCTION OF (30) Foreign Application Priority Data 3-HYDROXY-3-METHYLBUTYRIC ACID FROMACETONE AND AN ACTIVATED Sep. 15, 2009 (EP) .................................. O917O312.4 ACETYL COMPOUND Publication Classification (71) Applicant: SCIENTIST OF FORTUNE, S.A., (51) Int. Cl. Luxembourg (LU) CI2P 7/52 (2006.01) (72) Inventor: Philippe Marliere, Mouscron (BE) CI2N 9/10 (2006.01) (52) U.S. Cl. CPC ................. CI2P 7/52 (2013.01); C12N 9/1025 (21) Appl. No.: 14/658,170 (2013.01); C12Y 203/0301 (2013.01) (57) ABSTRACT (22) Filed: Mar. 14, 2015 Described is a method for the production of 3-hydroxy-3- methylbutyric acid by enzyme-catalyzed covalent bond for mation between the carbon atom of the oxo group of acetone Related U.S. Application Data and the methyl group of a compound which provides an (63) Continuation of application No. 13/395.293, filed on activated acetyl group. Also described are recombinant May 16, 2012, now Pat. No. 9,017,977, filed as appli organisms which produce 3-hydroxy-3-methylbutyric acid, cation No. PCT/EP2010/063460 on Sep. 14, 2010. and related compositions and methods. Patent Application Publication Aug. 27, 2015 Sheet 1 of 7 US 2015/0240271 A1 OH Figure 1 Figure 2 Patent Application Publication Aug. 27, 2015 Sheet 2 of 7 US 2015/0240271 A1 Accly E-CoA O OH O —2 - O O C S-CoA HC ulus {C} CH EMG-CoA lyase Beta-hydroxy-beta-methylglutaryl-CoA Acetoacetic acid (HMG-CoA) Figure 3 Q O SH Pisc s's 'g sis, Maleak - Pf-ack) s pH Juli. 5-l s: s 1s- S-i,Sir s'---ho * -- ishs's ; airo--- SH 5'--> Pks PKSG ---Pks PksH PksL Pist Pks Figure 4 Patent Application Publication Aug. 27, 2015 Sheet 3 of 7 US 2015/0240271 A1 H Hg" h–ch o=c p'=o HC X H2O X HC H 3. N A HoHc st-chCl-O A HO Figure 5 Patent Application Publication Aug. 27, 2015 Sheet 4 of 7 US 2015/0240271 A1 -Q1: 1.359 to 2.436 min from MT20090720143306, wiff, subtracted (0.656 to 0.937 min) 95% 90% 85% 80% ss Na -- 5 Figure 6 Patent Application Publication Aug. 27, 2015 Sheet 5 of 7 US 2015/0240271 A1 -Q1: 1.587 to 3.174 min from MT20090723161455, wiff, subtracted (0.703 to 1105 min) 100% 95% 90% 85% 80% 75% 70% 65% 60% 55% 50% 45% 40% 35% 30% 25% 20% 15% 10% 220.2O 5% 21.20 11330-130 58.60 2.38 "oo isoso200 "220 2.6 miz, amu Figure 7 Patent Application Publication Aug. 27, 2015 Sheet 6 of 7 US 2015/0240271 A1 -Q1: 1,065 to 3,033 min from MT20090723160718, wiff, subtracted (0.502 to 0.703 min.) 100% 95% 90% 85% 80% 75% 70% 65% 60% 55% 50% 78.70 45% 40% 35% 30% 134.10 25% 20% 220.10 15% 34.90 10% 5% 177.20 21.20 0% O 1249. "L. al 250 2" 80 100 12O 140 60 80 200 220 240 26 m/z, amu Figure 8 Patent Application Publication Aug. 27, 2015 Sheet 7 of 7 US 2015/0240271 A1 1,6 1,4 2s , * ! : X E : 33d5 0.6 - 95d5 4 Q --- ------------------------------------------------------------------------------------------ O O4 C,6 O,8 i acetone, mM Figure 9 US 2015/0240271 A1 Aug. 27, 2015 METHOD FOR THE PRODUCTION OF HIV and cancer and trauma victims with severe injuries. 3-HYDROXY-3-METHYLBUTYRIC ACID Thus, it is of commercial interest because of its use as a FROMACETONE AND AN ACTIVATED muscle enhancer for bodybuilding and as a medicament for ACETYL COMPOUND avoiding muscle wasting. U.S. Pat. No. 7,026,507 describes a process for preparing Solid formulations of sodium 3-hy CROSS REFERENCE TO RELATED droxy-3-methylbutyrate in which, in a first process step, 4.4- APPLICATIONS dimethyloxetan-2-one is reacted with aqueous Sodium 0001. This application is a continuation co-pending U.S. hydroxide to form a solution of sodium 3-hydroxy-3-meth patent application Ser. No. 13/395.293, filed May 16, 2012, ylbutyrate, and then, if appropriate after concentration, the which is the U.S. National Phase of International Application Solution is applied, in a further process step, to synthetic PCT/EP2010/063460, which was published in English on silica, and in which the resultant product is, if appropriate, Mar. 24, 2011, as WO 2011/032934, and claims the benefit of dried. the filing date of European Patent Application No. 09170312. 0008. It would be desirable to provide a process for the 4, filed Sep. 15, 2009, the entire disclosures of which are production of 3-hydroxy-3-methylbutyrate which would be incorporated herein by reference. independent of inorganic production steps and which could be effected in living organisms thereby being environmen FIELD OF THE INVENTION tally sound and inexpensive. In this context, Lee et al. (Appl. Environ. Microbiol. 63 (1997), 4191-4195) describes a 0002 The present invention relates to a method for the method for the production of 3-hydroxy-3-methylbutyrate by production of 3-hydroxy-3-methylbutyric acid (also referred converting 3-methylbutyric acid to 3-hydroxy-3-methylbu to as beta-hydroxyisovalerate or HIV) from acetone and a tyric acid using the microorganism Galactomyces reessii. compound which provides an activated acetyl group compris However, although this process allowed the production of ing the enzymatic conversion of acetone and a compound 3-hydroxy-3-methylbutyrate there is still a need to provide which provides an activated acetyl group into 3-hydroxy-3- alternative efficient and cost effective ways of producing methylbutyric acid. The conversion makes use of an enzyme 3-hydroxy-3-methylbutyrate in particular by biological pro which is capable of catalyzing the formation of a covalent CCSSCS. bond between the carbon atom of the oxo (i.e. the C=O) 0009. The present invention meets this demand for an group of acetone and the methyl group of the compound alternative process for the production of 3-hydroxy-3-meth which provides an activated acetyl group. Preferably, the ylbutyrate and provides a method which is based on biologi enzyme employed in the process is an enzyme with the activ cal resources and allows to produce 3-hydroxy-3-methylbu ity of a HMG CoA synthase (EC 2.3.3.10) and/or a PksG tyrate in vitro or in vivo in a microorganism and other species. protein and/or an enzyme with the activity of a C-C bond cleavage/condensation lyase, such as HMG CoA lyase (EC DETAILED DESCRIPTION OF THE INVENTION 4.1.3.4). The present invention also relates to organisms able to produce 3-hydroxy-3-methylbutyric acid from acetone and (0010 Method for the Production of 3-hydroxy-3-methyl a compound which provides an activated acetyl group and to butyric Acid the use of the above-mentioned enzymes and organisms for 0011. In particular, the present invention relates to a the production of 3-hydroxy-3-methylbutyric acid. Finally, method for the production of 3-hydroxy-3-methylbutyric the present invention relates to the use of acetone for the acid (also referred to as beta-hydroxyisovalerate or HIV) production of 3-hydroxy-3-methylbutyric acid. from acetone and a compound which provides an activated acetyl group comprising the enzymatic conversion of acetone BACKGROUND OF THE INVENTION and a compound which provides an activated acetyl group 0003 3-hydroxy-3-methylbutyric acid (also referred to as into 3-hydroxy-3-methylbutyric acid. beta-hydroxyisovalerate or HIV: see FIG. 1) is a metabolite of 0012 Acetone is represented by the following formula: the essential amino acid leucine and is synthesized in the CH (C=O)—CH. In a preferred embodiment the com human body. It can be found in Small quantities in grapefruit, pound which provides an activated acetyl group is character alfalfa and catfish. It is also known to occur in Some metabolic ized by the following formula (I): disorders of leucine catabolism, i.e. hypoValeric acidemia. It has been shown that 3-hydroxy-3-methylbutyric acid may have an effect on increasing muscle weight and strength (Nis sen et al., J. Appl. Physiol. 81 (1996), 2095-2104). Wilson et al. (Nutrition & Metabolism 5 (2008)) proposes as the mecha nisms of action the following: 0004 increased sarcolemmal integrity via conversion by HMG CoA reductase 0005 enhanced protein synthesis via the mTOR path 0013 , wherein X is selected from the group consisting of way S CH2-CH2-NH CO CH2-CH2-NH CO CH 0006 depression of protein degradation through inhibi (OH) C(CH3)2-CH2-O-PO2H C10H13N5O7P (coen tion of the ubiquitin pathway. Zyme A), S CH2-CH2-NH CO-CH2-CH2-NH CO 0007 3-hydroxy-3-methylbutyric acid is supposed to help CH(OH)–C(CH3)2-CH2-O-PO2H-polypeptide (acyl muscles combat protein breakdown, assist in muscle repair carrier protein), S CH2-CH2-NH CO-CH2-CH2 and Support increased endurance. It has been described to NH CO-CH(OH)–C(CH3)2-CH2-OH (pantetheine), help patients with chronic obstructive pulmonary disease in S CH-CH NH CO-CH (N-acetyl-cysteamine), hospital intensive care units, muscle wasting associated with S-CH (methane thiol), S CH2-CH(NH2)-CO2H (cys US 2015/0240271 A1 Aug. 27, 2015 teine), S CH2-CH2-CH(NH2)-CO2H (homocysteine), the PksG protein. The PksG protein is one of the proteins S CH2-CH(NH C5H8NO3)-CO.
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