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Pathway and Regulation of Erythritol Formation In JOURNAL OF BACTERIOLOGY, JUly 1993, p. 3941-3948 Vol. 175, No. 13 0021-9193/93/133941-08$02.00/0 Copyright © 1993, American Society for Microbiology Pathway and Regulation of Erythritol Formation in Leuconostoc oenos MARIA VEIGA-DA-CUNHA,12,3t* HELENA SANTOS,3'4 AND EMILE VAN SCHAFTINGEN" 2 Laboratory ofPhysiological Chemistry, University of Louvain, 1 and International Institute of Cellular and Molecular Pathology, 2 Brussels, Belgium, and Centro de Tecnologia Quimica e Biol6gica/Instituto de Biologia Experimental e Tecnologica, Apartado 127, 2780 Oeiras,3 and Departamento de Quimica, Faculdade de Ciencias e Tecnologia, Universidade Nova de Lisboa, Quinta da Torre, 2825 Monte da Caparica, Portugal Received 16 February 1993/Accepted 25 April 1993 It was recently observed that Leuconostoc oenos GM, a wine lactic acid bacterium, produced erythritol anaerobically from glucose but not from fructose or ribose and that this production was almost absent in the presence of 02. In this study, the pathway of formation of erythritol from glucose in L. oenos was shown to involve the isomerization of glucose 6-phosphate to fructose 6-phosphate by a phosphoglucose isomerase, the cleavage of fructose 6-phosphate by a phosphoketolase, the reduction of erythrose 4-phosphate by an erythritol 4-phosphate dehydrogenase and, finally, the hydrolysis of erythritol 4-phosphate to erythritol by a phos- phatase. Fructose 6-phosphate phosphoketolase was copurified with xylulose 5-phosphate phosphoketolase, and the activity ofthe latter was competitively inhibited by fructose 6-phosphate, with a K1 of26 mM, corresponding to the Km offructose 6-phosphate phosphoketolase (22 mM). These results suggest that the two phosphoketolase activities are borne by a single enzyme. Extracts of L. oenos were also found to contain NAD(P)H oxidase, which must be largely responsible for the reoxidation of NADPH and NADH in cells incubated in the presence of 02. In cells incubated with glucose, the concentrations of glucose 6-phosphate and of fructose 6-phosphate were higher in the absence of 02 than in its presence, explaining the stimulation by anaerobiosis of erythritol production. The increase in the hexose 6-phosphate concentration is presumably the result of a functional inhibition of glucose 6-phosphate dehydrogenase because of a reduction in the availability of NADP. The metabolism of glucose in heterolactic acid bacteria is tion, erythritol was found to be derived from C-3 to C-6 of described as fermentation initiated by the oxidation of glu- glucose. These results therefore indicated that, in the ab- cose 6-phosphate to gluconate 6-phosphate (13, 31). Follow- sence of oxygen, the C6 molecule was cleaved between ing oxidative decarboxylation of the latter, ribulose 5-phos- carbons C-2 and C-3 as well as between carbons C-3 and C-4. phate is converted to xylulose 5-phosphate, which is then For explanation of the former type of cleavage, the existence split into acetyl phosphate and glyceraldehyde 3-phosphate of a fructose 6-phosphate phosphoketolase in L. oenos was by a pentose-phosphate phosphoketolase present in all het- suggested (33). erolactic acid bacteria (7). Subsequently, acetyl phosphate is The purposes of the present study were to establish the converted to ethanol and/or acetate, whereas glyceraldehyde enzymatic pathway involved in the formation of erythritol in 3-phosphate is metabolized to lactate via pyruvate. L. oenos and to explain the effect of oxygen on the regulation There are, however, considerable variations in the end of the production of this polyol from glucose. products obtained from the metabolism of glucose in the presence of 02 (3, 20, 23, 32) or other external electron acceptors (16, 19), indicating differences in the pathways MATERIALS AND METHODS and/or control of sugar metabolism among the heterolactic acid bacteria themselves. As confirmation of the extent of Materials. 3-(N-morpholino)propanesulfonic acid (MOPS), this diversity, it was observed that Leuconostoc oenos GM, N- (2- hydroxyethyl ) piperazine -N' -2- ethanesulfonic acid a wine lactic acid bacterium described as metabolizing and Tris were from Sigma (St. Louis, Mo.), as erythritol (HEPES), glucose heterofermentatively (7, 17), produced were the substrates for all enzyme activities measured. in addition to the end mentioned and glycerol products DEAE-Sepharose Fast Flow was from Pharmacia LKB it was found that the above (25, 28, 33). Moreover, produc- Biotechnology Inc. (Uppsala, Sweden). Auxiliary enzymes of occurred from but tion erythritol anaerobically glucose and the remaining biochemical agents were from Boehringer not fructose or ribose and that it was almost absent from (Mannheim, Germany). Chemicals were from Merck (Darm- conditions. '3C nuclear resonance under aerobic magnetic stadt, Germany) and were of analytical grade. as that L. oenos (NMR) experiments showed, expected, Commercial erythrose 4-phosphate was found to be con- formed ethanol and acetate from C-2 and C-3 of glucose taminated with approximately 10% glucose 6-phosphate, was in the presence of oxygen when this sugar metabolized which interfered in the assay of erythritol 4-phosphate of these but that substantial proportions glycolytic products dehydrogenase. This contaminant was eliminated as follows. came from C-1 or C-2 under anaerobic conditions. In addi- A 1-ml solution containing 20 mM erythrose 4-phosphate was incubated at 30°C in the presence of 50 mM HEPES, (pH 7.1)-5 mM MgCl2-10 mM NADP-10 U of yeast glucose * Corresponding author. 6-phosphate dehydrogenase. For removal of the nucleotides, t Present address: Universit6 Catholique de Louvain, 7539, activated charcoal was added to a final concentration of 2% Avenue Hippocrate 75, B-1200 Brussels, Belgium. (wt/vol) after 90 min; these preparations were then incubated 3941 3942 VEIGA-DA-CUNHA ET AL. J. BACTE RIOL. for 20 min at 30'C and centrifuged twice at 10,000 x g for 5 ing 5% (vol/vol) 2H20, and centrifuged to remove the pre- min to remove the charcoal. cipitated KCl04. The supernatant was removed, and EDTA Organisms and growth conditions. L. oenos GM was was added to a final concentration of 4 mM to chelate any obtained from Microlife Techniques, Sarasota, Fla., and L. paramagnetic ions. The pH was adjusted to exactly 8.0, and oenos ATCC 23277 was obtained from the American Type the extract was analyzed by 31P NMR. The same extract was Culture Collection, Rockville, Md. L. oenos 8A and L. also used for the enzymatic quantification of intermediary oenos CTQB M3 were isolated from Portuguese table wines; metabolites. Approximately 1.0 g (dry weight) of cells was the former was supplied by A. Mendes Faia (Universidade used per extract. de Vila Real e Tras-os-Montes, Vila Real, Portugal), and the NMR spectroscopy. 13C NMR spectra of the supernatant latter was supplied by V. San Romdo (Centro de Tecnologia were recorded at 30'C in a Bruker AMX-300 spectrometer Quimica e Biologica, Oeiras, Portugal). Leuconostoc lactis operating at 75.47 MHz. They were run with a 450 pulse, a NCW1 was received from T. Cogan (National Dairy Prod- 13-s repetition time, and 32,000 acquisition datum points; a ucts Research Center, Fermoy, Ireland). Lactobacillus 10-mm broad-band probe was used. Proton broad-band buchnen B190 and Lactobacillus brevis B22 were both decoupling was applied during the acquisition time only. 1H received from F. Radler (Institut fur Mikrobiologie und NMR spectra were recorded at 250C in a Bruker AMX-500 Weinforschung der Johannes Guttenberg, University of spectrometer operating at 500.13 MHz, with H20 presatura- Mainz, Mainz, Germany). tion, a 450 pulse, and a repetion time of 9.5 s. 1P NMR All strains were grown at 30'C in static 2-liter glass bottles. spectra were acquired at 30'C in the same spectrometer with L. oenos strains were grown in modified (33) FT 80 medium a 45° pulse, a repetition time of 8.8 s, and proton broad-band (2), (pH 5.0). L. lactis NCW1 was grown under the same decoupling during the acquisition time (0.8 s). conditions but without malic acid. L. brevis B22 and L. Enzyme assays. L. oenos GM cells were collected as buchneri B190 were grown in a similar way with a complex described above from 3- to 4-liter cultures, washed twice medium containing yeast extract (15.0 g* liter-1), triammo- with 100 mM MOPS (pH 6.5), and kept at -70'C until used. nium citrate (4.8 g liter-1), and MgSO4. 7H20 (0.1 For preparation of the extract, the pellet was resuspended in g liter-') in 0.1 M potassium phosphate buffer (pH 6.5). the same buffer at a concentration of approximately 0.06 g Glucose (10 g liter- ) was autoclaved separately and added (dry weight) ml-'. The cells were disrupted by ultrasoni- to the above-mentioned medium before inoculation. cation, and debris was removed by centrifugation before the MnSO4- 4H20 was added to the growth medium for the enzymes in the extract were assayed. cultures grown for the 13C NMR experiments and for the Enzyme activities were measured spectrophotometrically enzyme assays at concentrations of 1.0 and 3.0 mg. liter-', at 30'C in the presence of 25 mM HEPES (pH 7.1) with 3 respectively. The cells used for 31P NMR analysis were mM MgCl2. Unless otherwise stated, the concentrations of grown without added manganese. substrate and, if required, of auxiliary enzymes were as Preparation of culture supernatants for the quantification of follows: for glucose 6-phosphate dehydrogenase, 5 mM erythritol, glycerol, and ethanol by 13C NMR analysis. Fresh glucose 6-phosphate and 1 mM NAD(P); for 6-phosphoglu- cell suspensions were prepared for each experiment. Cul- conate dehydrogenase, 5 mM 6-phosphogluconate and 1 mM tures in the mid-logarithmic phase (three 2-liter cultures) NAD(P); for phosphoglucose isomerase, 0.01 to 0.2 mM were harvested by centrifugation (20 min at 3,000 x g) at fructose 6-phosphate, 2 U of yeast glucose 6-phosphate 4°C, and the pellet was washed twice with 0.2 M potassium dehydrogenase, and 1 mM NADP; for triose phosphate phosphate (pH 5.0) and suspended in the same buffer to a isomerase, 0.05 to 0.8 mM glyceraldehyde 3-phosphate, 2 U final volume of approximately 8 ml.
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