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On the Effects of Urea on the Molecular Structure and Activity of Various The Journal of Biochemistry, Vol. 58, No. 1, 1965 Effects of Urea on the Activity and Structure of Yeast Alcohol Dehydrogenase By TAKAHISA OHTA* and YASUYUEI OGURA (From the Department of Biophysics and Biochemistry, Faculty of Science, University of Tokyo, Bunkyo-ku, Tokyo) (Received for publication, March 29, 1965) There have been many reports (1-8) on (9) and K lot z (10). However, to interprete the effects of urea on the molecular structure the mechanism of inhibition by urea on enzyme and activity of various enzymes. Most reactions, further investigations are necessary enzymes (1-4) are known to be inhibited by since few have covered both kinetics of the en low concentrations of urea which do not zymatic reaction and physicochemical analysis denature their protein. The mode of inhibi of the structural changes of the enzyme protein. tion of urea on various enzyme reactions has In this paper, the effects of urea upon yeast been studied kinetically by R a j a g o p a l a n, alcohol dehydrogenase [EC 1. 1. 1. 1, Alcohol: Fridovich and Handler (3) and also NAD oxidoreductase (yeast)] have been studi by Chase's group (6-8) using rather low ed, focusing attention on the relationship be concentrations of urea. The inhibition by tween the structure of the enzyme molecule urea of various enzymes, such as xanthine and its catalytic activity. oxidase [EC 1.2.3.2], muscle lactate dehydro EXPERIMENTAL genase [EC 1. 1. 1. 27] (3) and kidney aldose mutarotase [EC 5.1.3.3] (6) has been reported Materials-Yeast alcohol dehydrogenase was prepar to be reversible and competitive for the sub ed from fresh baker's yeast* by the following pro strate. However, the reactions of yeast and cedures which are essentially based upon the method liver alcohol dehydrogenases [EC 1. 1. 1. 1] (3), of R a c k e r (11). Eight pounds of fragmented fresh yeast were macerated with 450 ml. of ethyl acetate. yeast ji-fructofuranosidase [EC 3.2. 1.26, pre The mixture was left at room temperature for 40 viously known as invertase] (7) arid (3-amylase minutes and then centrifuged at 6,000Xg for 30 [EC 3.2.1.2] (8) were found to be noncompeti minutes. The resulting precipitate was suspended in tivelv inhibited by urea. 4 liters of 0.25 .44 Na2HPO4, and the suspension was In the presence of higher concentrations adjusted to pH 7.5 with NH4OH, and left at 4°C for of urea, however, Brand, E v e r s e and a week. At the end of this autolysis period, the yeast K a p l a n (4) found that yeast and liver residue was removed by centrifugation. To the alcohol dehydrogenases and various animal supernatant solution, solid ammonium sulfate was lactate dehydrogenases lost activity irrever added to 60% saturation. The mixture was left to stand for 30 minutes at room temperature and then sibly and in parallel with the changes in the precipitate was collected by centrifugation, dis their protein structure. On the other hand, solved in cold water and dialysed against 0.0211 Harris (5) reported that in the presence Na2HPO4 at 4°C overnight. The dialysed solution of 2.0-8.O M urea trypsin loses reversibly its was quickly brought to 50-55•Ž and maintained at activity in parallel with the unfolding of its this temperature for 15 minutes in a water bath. protein molecule. After cooling, the mixture was centrifuged and the The action of urea on the various protein Abbreviations used: NAD, nicotinamide adenine molecules has been explained by K a u z man n dinucleotide ; NADH,, reduced nicotinamide adenine * Present address : Department of Chemistry, dinucleotide ; EDTA, ethylenediamine tetraacetate. ** Baker's yeast was kindly supplied by Oriental College of General Education, University of Tokyo, Meguro-ku, Tokyo. Yeast Co., Tokyo. 73 74 T. OHTA and Y. OGuRA clear supernatant obtained was chilled in a salt-ice of the assay medium was 3.0 ml. The reaction was bath. One-half volume of acetone (-10°C) was added initiated by addition of 0.01 ml. of enzyme solution slowly to the supernatant with continuous stirring and in pyrophosphate buffer. Spectrophotometric readings the mixture was kept at -10°C for 1 hour. The were taken at 10 second intervals and the initial resulting precipitate was removed by centrifugation velocity was determined from the changes in optical at 6,000Xg for 10 minutes or by filtration. Then density observed during the first 30 seconds. The the supernatant was again chilled to -10°C, and velocity was expressed as moles of substrate oxidized mixed with an additional 0.55 volume of cold acetone. per second per enzyme unit, assuming that one native The resulting precipitate was collected by centrifuga enzyme molecule contains four enzyme units. tion or filtration, dissolved in 0.01 M phosphate Fluorometry-Fluorometric measurements were buffer, pH 6.5, and dialysed against the same buffer made with a Hitachi EPU-2A spectrophotometer overnight at 4°C. Then the precipitate was removed equipped with a Hitachi G-1 spectrofluorometric by centrifugation and the supernatant was passed attachment which consisted of a grating monochro through a DEAE-cellulose column previously equili meter and a 500 W high pressure xenon arclamp. brated with 0.01 M phosphate buffer, pH 6.5, and The simple was placed in a 1 em.2 quartz cell with washed with an equal volume of the same buffer. low fluorescence and was illuminated with monochro By this treatment nucleic acid, which disturbed the matic light. The fluorescence emission was measured crystallization of the enzyme, could be completely at right angles to the exciting light beam. Emitted removed. The eluate was then put into cellulose energy was measured by comparison of the observed tubing and left for several hours in 0.35 saturated value with the fluorescence excitation spectrum and ammonium sulfate solution, adjusted to pH 7.5. the absorption spectrum of a dilute solution of fluore Crystals which formed were collected by centrifuga seein in 0.1 N NaOH. The intensity of fluorescence tion and dissolved in 0.01 M phosphate buffer, pH 7.5. was expressed by the quantity F : After four recrystallizations, 200 to 400 mg. of crys talline yeast alcohol dehydrogenase were obtained from 8 1 b of fresh yeast. This enzyme preparation was , where q is proportional to the number of quanta found to be homogeneous by electrophoresis and emitted and T is the transmittancy to the test solution analytical centrifugation, though it was reported by at the wave length of the exciting light. The fluores H a y e s and V e l i c k (13) that two electrophoretically cence emission spectrum of the enzyme was measured different components of yeast alcohol dehydrogenase, using diluted enzyme solution with an optical density; that is, an active component and an inactive de less than 0.2 at 280 mp. naturation product, were present even after recrystalli Ultraviolet Difference Spectrum-The ultraviolet zation. Negligible amount of the denatured component difference spectrum was measured with a Hitachi seems to have been present in our preparation. EPU-2A spectrophotometer. The width of the slit was fixed during any one series of experiments and Urea was purified by the method of B e n e s c h, the same pipettes were employed to reduce pipetting Lard y and Ben e s c h (12), that is, a concentrated errors. The value of the difference in optical density solution of urea was treated with Amberlite MB-1 cation and anion exchange resin at 50-55°C, filtered at any given wave length thus obtained was expressed through a glass filter and crystallized. The NAD by dividing it by that of the reference solution at used was purchased from Sigma Chemicals. NADH2 280 my. was prepared by reduction of the NAD, with yeast Viscometry -Viscosity was measured with an alcohol dehydrogenase and ethanol in the presence of Ostwald type viscometer of spiral form. The outflow time for water was 80-100 seconds at 20.0°C. Measure semicarbazide and EDTA, and was purified by ments were carried out in a thermostat maintained repeated alcohol fractionation and washing with ether. at 20.0°C. The reduced viscosity was defined as follows : The enzyme concentration was determined by measuring the optical density at 280 my, assuming an extinction coefficient of 1.89 X 105 cm.2 mole-1 based were r and ƒÅƒÍ are the viscosity of the test solution on a molecular weight of 150,000 (13 ). and the solvent, and c is the concentration of protein Activity Measurements-Enzymatic activity was de in g. per 100 ml. termined by measuring the increase in optical density Sedimentation Analysis-Sedimentation measurments at 340 my due to formation of NADH,. The measure were carried out with a Spinco model E analytical ments were made at pH 8.5 and 20°C using a ultracentrifuge. The sedimentation patterns were Hitachi EPU-2A spectrophotometer. The total volume obtained by schlieren optics at a rotor speed of 59,780 Effects of Urea on Yeast Alcohol Dehydrogenase 75 r.pm, and temperatures between 10° and 28°C re urea, but the rate of the reaction decreased gulated by the automatic temperature control unit. with increase in the concentration of urea. The molecular weight of the enzyme was de The enzyme was not preincubated with urea, termined with an ultracentrifuge by Y p h a n t i s' but there was no lag in the inhibition. This procedure (14). 'Experiments were carried out using shows that the inhibitory effect of urea is a cell with seven observation channels at a rotor instantaneous.
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