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(19) & (11) EP 2 308 965 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 13.04.2011 Bulletin 2011/15 C12N 9/04 (2006.01) C12P 7/60 (2006.01) C12P 17/04 (2006.01) (21) Application number: 10183907.4 (22) Date of filing: 10.02.2006 (84) Designated Contracting States: (71) Applicant: DSM IP Assets B.V. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 6411 TE Heerlen (NL) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR (72) Inventors: • Beuzelin Ollivier, Marie-Gabrielle (30) Priority: 11.02.2005 EP 05405066 1131 Tolochenaz (CH) 11.02.2005 EP 05405067 • Chevreux, Bastien 11.02.2005 EP 05405072 79618, Rheinfelden (DE) 11.02.2005 EP 05405073 • Dalluegge, Manuela 11.02.2005 EP 05405081 79618, Rheinfelden (DE) 11.02.2005 EP 05405082 • Gelder Van, Marina 11.02.2005 EP 05405083 3205, TG Spijkenisse (NL) 11.02.2005 EP 05405084 • Goese, Markus G. 11.02.2005 EP 05405087 4054, Basel (CH) 11.02.2005 EP 05405088 • Hauk, Corina 11.02.2005 EP 05405089 79576 Weil am Rhein (DE) 11.02.2005 EP 05405090 • Koekman, Bertus Pieter 11.02.2005 EP 05405091 2636 BG Schipluiden (NL) 11.02.2005 EP 05405093 • Meury Bechtel, Anja 11.02.2005 EP 05405094 8032 Zürich (CH) 11.02.2005 EP 05405109 • Mouncey, Nigel John 11.02.2005 EP 05405110 Indiananpolis, IN 46220 (US) 11.02.2005 EP 05405111 • Mayer, Anne Françoise 11.02.2005 EP 05405112 4052 Basel (CH) 11.02.2005 EP 05405119 • Schipper, Dick 11.02.2005 EP 05405120 2612 HL Delft (NL) 11.02.2005 EP 05405121 • Toepfer, Christine 11.02.2005 EP 05405139 79630 Murg (DE) 11.02.2005 EP 05405140 • Vollebregt, Adrianus Wilhelmus Hermanus 11.02.2005 EP 05405146 2673 BB Naaldwijk (NL) 11.02.2005 EP 05405147 • Lee, Connie 11.02.2005 EP 05405148 107 Reykjavik (IS) 11.02.2005 EP 05405149 • Shinjoh, Masako 11.02.2005 EP 05405150 Kamakura Kanagawa 248-0017 (JP) 11.02.2005 EP 05405151 11.02.2005 EP 05405152 (74) Representative: Seibel-Thomsen, Nadja 11.02.2005 EP 05405153 DSM Nutritional Products Ltd 11.02.2005 EP 05405166 Patent Department 11.02.2005 EP 05405167 Wurmisweg 576 11.02.2005 EP 05405168 4303 Kaiseraugst (CH) 11.02.2005 EP 05405169 11.02.2005 EP 05405170 Remarks: This application was filed on 30-09-2010 as a (62) Document number(s) of the earlier application(s) in divisional application to the application mentioned accordance with Art. 76 EPC: under INID code 62. 06706841.1 / 1 846 554 EP 2 308 965 A1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 308 965 A1 (54) Fermentative vitamin C production (57) The present invention relates to newly identified pact on yield, production, and/or efficiency of production microorganisms capable of direct production of L- ascor- of the fermentation product in said microorganism. Also bic acid (hereinafter also referred to as Vitamin C). The included are methods/processes of using the polynucle- invention also relates to polynucleotide sequences com- otides and modified polynucleotide sequences to trans- prising genes that encode proteins which are involved in form host microorganisms. The invention also relates to the synthesis of Vitamin C. The invention also features genetically engineered microorganisms and their use for polynucleotides comprising the full length polynucleotide the direct production of Vitamin C. sequences of the novel genes and fragments thereof, the novel polypeptides encoded by the polynucleotides and fragments thereof, as well as their functional equiv- alents. The present invention also relates to the use of said polynucleotides and polypeptides as biotechnolog- ical tools in the production of Vitamin C from microorgan- isms, whereby a modification of said polynucleotides and/or encoded polypeptides has a direct or indirect im- 2 EP 2 308 965 A1 Description [0001] The present invention relates to the use of polynucleotides and polypeptides as biotechnological tools in the production of Vitamin C from microorganisms, whereby said polynucleotides and/or encoded polypeptides have a direct 5 or indirect impact on yield, production, and/or efficiency of production of the fermentation product. The invention also relates to genetically engineered microorganisms and their use for the direct production of Vitamin C. [0002] Vitamin C is one of very important and indispensable nutrient factors for human beings. Vitamin C is also used in animal feed even though some farm animals can synthesize it in their own body. [0003] For the past 70 years, Vitamin C has been produced industrially from D- glucose by the well-known Reichstein 10 method. All steps in this process are chemical except for one (the conversion of D- sorbitol to L-sorbose), which is carried out by microbial conversion. Since its initial implementation for industrial production of Vitamin C, several chemical and technical modifications have been used to improve the efficiency of the Reichstein method. Recent developments of Vitamin C production are summarized in Ullmann’s Encyclopedia of Industrial Chemistry, 5th Edition, Vol. A27 (1996), pp. 547ff. 15 [0004] Different intermediate steps of Vitamin C production have been performed with the help of microorganisms or enzymes isolated therefrom. Thus, 2-keto-L-gulonic acid (2-KGA), an intermediate compound that can be chemically converted into Vitamin C by means of an alkaline rearrangement reaction, may be produced by a fermentation process starting from L-sorbose, by means of strains belonging e.g. to the Ketogulonicigenium or Gluconobacter genera, or by an alternative fermentation process starting from D-glucose, by means of recombinant strains belonging to the Glucono- 20 bacter or Pantoea genera. [0005] Current chemical production methods for Vitamin C have some undesirable characteristics such as high- energy consumption and use of large quantities of organic and inorganic solvents. Therefore, over the past decades, other approaches to manufacture Vitamin C using microbial conversions, which would be more economical as well as eco- logical, have been investigated. 25 [0006] Fermentative Vitamin C production from a number of substrates including D- sorbitol,L- sorbose and L- sorbosone has been reported in several microorganisms, such as algae and yeast, using different cultivation methods. The disad- vantage of using these microorganisms, however, is the low yield of Vitamin C produced since thes organisms are known to be capable of the production of both 2-keto-L-gulonic acid and Vitamin C, the yield of microbiologically produced Vitamin C is then limited by the relatively high production of 2-KGA which is more readily synthesized by said microor- 30 ganism, leading, for instance, to ratios between the concentration of Vitamin C and 2-KGA which are less than 0.1. [0007] Therefore it is desirable to develop production systems which have better industrial applicability, e.g. can be manipulated for increased titers and/or which have reduced fermentation times. One particularly useful system employs genes encoding membrane-bound L-sorbosone dehydrogenases or membrane-bound PQQ bound D- sorbitol dehydro- genases. An example of such a system uses a gene from Gluconobacter oxydans N44-1 encoding L-sorbosone dehy- 35 drogenase (hereafter called SNDHai) which converts L- sorbosone to L- ascorbic acid. This gene and homologous thereof have already been described in WO 2005/017159 which are incorporated herein. [0008] There is a continuing need in even more optimized fermentation systems for the microbial production of Vitamin C to get higher yields as with the systems described above. [0009] Surprisingly, it has now been found that under suitable culture conditions host cells expressing SNDHai can 40 be used for further optimizing the direct production of Vitamin C. [0010] This may be achieved by concurrent manipulation of a specific set of genes as further described herein. Such genes may be selected from the group consisting of RCS or SMS genes. This group of genes/proteins and the manip- ulation of each set is further described and exemplified herein. [0011] The term "direct fermentation", "direct production", "direct conversion" and the like is intended to mean that a 45 microorganism is capable of the conversion of a certain substrate into the specified product by means of one or more biological conversion steps, without the need of any additional chemical conversion step. For instance, the term "direct conversion of D-sorbitol into Vitamin C" is intended to describe a process wherein a microorganism is producing Vitamin C and wherein D-sorbitol is offered as a carbon source without the need of an intermediate chemical conversion step. A single microorganism capable of directly fermenting Vitamin C is preferred. 50 [0012] As used herein, "improved" or "improved yield of Vitamin C" caused by a genetic alteration means an increase of at least 5%, 10%, 25%, 30%, 40%, 50%, 75%, 100%, 200% or even more than 500%, compared to a cell which is not genetically altered. Such unaltered cells are also often referred to as wild type cells [0013] Therefore, it is in the first instance an object of the present invention to provide a process for the direct fermen- tative production of Vitamin C by cultering under suitable culture conditions a host cell which genome is genetically 55 engineered by DNA sequences comprising the following polynucleotides a) a polynucleotide encoding L-sorbosone dehydrogenase according to SEQ ID NO: 2 or an active fragment or derivative thereof, and 3 EP 2 308 965 A1 b) at least one polynucleotide encoding a protein selected from the group consisting of 1) proteins which are involved in the Sorbitol/Sorbose Metabolization System (SMS); and 2) proteins which are involved in the Respiratory Chain System (RCS); 5 and by isolation of Vitamin C from such cells or the culture medium.
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  • Comprehensive Metabolomic Study of the Response of HK-2 Cells to Hyperglycemic, Hypoxic Diabetic-Like Milieu Has Never Been Performed

    Comprehensive Metabolomic Study of the Response of HK-2 Cells to Hyperglycemic, Hypoxic Diabetic-Like Milieu Has Never Been Performed

    www.nature.com/scientificreports OPEN Comprehensive metabolomic study of the response of HK‑2 cells to hyperglycemic hypoxic diabetic‑like milieu Alberto Valdés 1,2*, Francisco J. Lucio‑Cazaña3, María Castro‑Puyana1,4, Coral García‑Pastor3, Oliver Fiehn2 & María Luisa Marina 1,4* Diabetic nephropathy (DN) is the leading cause of chronic kidney disease. Although hyperglycaemia has been determined as the most important risk factor, hypoxia also plays a relevant role in the development of this disease. In this work, a comprehensive metabolomic study of the response of HK‑2 cells, a human cell line derived from normal proximal tubular epithelial cells, to hyperglycemic, hypoxic diabetic‑like milieu has been performed. Cells simultaneously exposed to high glucose (25 mM) and hypoxia (1% O2) were compared to cells in control conditions (5.5 mM glucose/18.6% O2) at 48 h. The combination of advanced metabolomic platforms (GC‑TOF MS, HILIC‑ and CSH‑ QExactive MS/MS), freely available metabolite annotation tools, novel databases and libraries, and stringent cut‑of flters allowed the annotation of 733 metabolites intracellularly and 290 compounds in the extracellular medium. Advanced bioinformatics and statistical tools demonstrated that several pathways were signifcantly altered, including carbohydrate and pentose phosphate pathways, as well as arginine and proline metabolism. Other afected metabolites were found in purine and lipid metabolism, the protection against the osmotic stress and the prevention of the activation of the β‑oxidation pathway. Overall, the efects of the combined exposure of HK‑cells to high glucose and hypoxia are reasonably compatible with previous in vivo works. Diabetic nephropathy (DN) is the leading cause of chronic kidney disease and if afects approximately 25–40% of type 1 and type 2 diabetic patients 1,2.