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Bound Monoamine Oxidase: Ph and Temperature Dependences Inhibitory Effect of NaCI on Hog Kidney Mitochondrial Membrane- Bound Monoamine Oxidase: pH and Temperature Dependences Yoko Omura Department of Chemistry, Kanagawa Prefectural College of Nursing and Medical Technology, 50-1 Nakao-Cho, Yokohama 241, Japan Received April 12, 1995 Accepted September 5, 1995 ABSTRACT-For a further understanding of the inhibitory effect of NaCI on hog kidney mitochondrial monoamine oxidase (MAO), the activity for benzylamine as substrate was assayed spectrophotometrically in the absence and presence of NaCI for mitochondrial outer membrane preparations as well as whole mitochondria. The effect of CaC12 was also examined for comparison. The inhibition by NaCI but not CaC12 was strongly pH dependent. The pH dependence of the inhibitory effect of NaCI in phosphate buffer was parallel to the pH dependence of the MAO activity itself. The point at which the slope of the Arrhenius plot in the absence of NaCl decreases with increasing temperature was to be 32.31C at pH 7.0 and 30.41C at pH 7.5 in phosphate buffer, while the Arrhenius plot in the presence of NaCI exhibited discontinuities without change in the slope in small temperature ranges, 39.21C -40.01C and 33.0'C -34.21C. It was esti- mated that the inhibitory effect of NaCl was due to a pH and temperature sensitive cooperative state change involving MAO protein and boundary lipids, while the effect of CaC12 could be induced by specific Ca 21 binding to acidic phospholipids. Keywords: Hog kidney monoamine oxidase, Whole mitochondria, Mitochondrial outer membrane, Inhibitory effect of NaCl, Arrhenius plot Monoamine oxidase (MAO, EC 1. 4. 3. 4) is known as ney mitochondrial MAO to determine if membranous a mitochondrial outer membrane enzyme, which oxida- MAO is present in vivo, we found that (NH4)2SO4 and tively deaminates neurotransmitters such as catechol- NaCl markedly inhibited the MAO activity at fairly low amines and also exogeneous biogenic amines. At least two salt concentrations. We have reported the inhibitory types of MAO (MAO-A and MAO-B) have been iden- effect of NaCI on MAO in hog kidney whole mitochon- tified based on the differences in their substrate specific- dria (23). The inhibition was reversible and noncompeti- ities and inhibitor sensitivities (1, 2) (for a more recent tive. The decrease in the inhibition of the Triton X-100 review, see Ref. 3). While there was convincing ex- solubilized MAO suggested that the mitochondrial mem- perimental support for the hypothesis that the two types brane was at least in part responsible for the inhibition: of MAO were distinct enzyme proteins (4-7), it was sug- 70% inhibition at a NaCI concentration of 1070(0.17 M), gested by several workers that they might be the same 85070 at 2070, 92010 at 3070 and 95070 at 5010 for whole protein in different membrane lipid environments (8-10). mitochondria in phosphate buffer, pH 7.0 at 38C;°53010 Recently, cloning of the cDNAs for MAO-A and MAO-B at 1010,67010 at 2070,72% at 3% and 73010at 5070under the demonstrated that the two forms of the enzyme share same conditions for Triton X-100 solubilized MAO (23). about 70% sequence identity and were encoded by differ- Therefore, preceding the purification and reconstitu- ent genes derived from the same ancestral gene. Full tion of MAO for the study on the artificial model system, length cDNA clones for human (11-13), bovine (14) and we investigated the mitochondrial MAO from both en- rat (15) MAO-A and human (11, 13) and rat (16) MAO-B zymatic and spectroscopic aspects by using mitochondrial have been characterized. However, the in vivo presence of outer membrane preparations to which MAO is tightly membranous MAO-A and MAO-B and the nature of bound. These investigations are expected to provide their interaction with lipids are still unsolved biochemical information about the functional state of hog kidney questions (3, 17-22). Further investigations are needed. mitochondrial membrane-bound MAO. In the process of purifying and reconstituting hog kid- To investigate the effect of NaCI on the spectral characteristics of the mitochondria) outer membranes, we described below. studied the effect of NaCI on the near infrared excited The sub fractionation of mitochondria by digitonin Fourier transform Raman spectra of hog kidney treatment was carried out essentially according to the mitochondrial outer membrane preparations. We ob- method of Schnaitman et al. and Okamoto et al. (27 - served a spectral change in the phospholipid acyl chain 29). A 2% digitonin solution was prepared just prior to CC stretching region, indicating that the presence of use by adding digitonin (biochemical use; Wako Chemi- NaCI decreases the gauche character of the phospholipid cals Ltd., Osaka) to the warm 0.25 M sucrose solution in acyl chains (24). The observed spectral change was differ- a boiling water bath. The cold 2% digitonin solution was ent from that in an aqueous dispersion of phosphatidyl- added to the mitochondrial fraction in the ice bath with choline, for which it has been reported that monovalent continuous stirring for 15 min so that the relative weight ions such as Na+ do not appreciably affect the I,,,,/ of digitonin to 10 mg mitochondrial protein was 1.2-1.5 'gaucheratio (25, 26). It was suggested that the presence of mg. The suspension was diluted by 34 ml of 0.25 M su- membrane proteins was required for this membrane con- crose and was further stirred for 1-2 min at 0'C. The densation effect by NaCI (24). It was also estimated that diluted suspension was centrifuged at 9,500 x g for 10 min the presence of NaCI might increase the amount of im- at 4C. The first 9,500 x g pellet (inner membrane and mobilized boundary lipid (24). matrix fractions) was suspended in 34 ml of 0.25 M su- In the present study, to elucidate the cause of the crose, and the suspension was recentrifuged at 9,500 x g inhibitory effect of NaCI on hog kidney mitochondrial for 10 min. The resulting pale yellow supernatant was MAO, measurements of the inhibitory effect of NaCI on combined with the first 9,500 x g supernatant. The com- mitochondrial outer membrane preparations as well as bined supernatant was centrifuged at 105,000 x g for 90 whole mitochondria were performed at various concen- min at 4 C by a Beckman L5-65 ultracentrifuge with a trations of NaCl and pH values. Furthermore, the inhibi- Type 65 rotor (Beckman, Palo Alto, CA, USA). tory effects of 0.1 M NaCI were measured in phosphate The 105,000 x g pellet is the outer membrane fraction. buffer, pH 6.0, 6.5, 7.0 and 7.5 at 29°C and 8.0 at 38C, The activity of MAO, which is a marker enzyme of the for mitochondrial outer membrane preparations and mitochondrial outer membrane, was assayed for the whole mitochondria. To evaluate the thermal properties 105,000 x g pellet at 29C in phosphate buffer, pH 7.5. of the effect of NaCI, I measured the MAO activity in hog The pellet was stored at -201C just until used. kidney mitochondrial outer membrane preparations for oxidative deamination of benzylamine as a substrate at Determination of protein concentration various temperatures in the absence and presence of The concentration of mitochondrial protein was rapid- NaCI, and Arrhenius plots were made from the data. The ly determined spectrophotometrically by the Coomasie results are reported and discussed in this article in terms blue G dye-binding assay (30) preceding the procedure of of a cooperative change of state involving membrane digitonin treatment. Bovine serum albumin was used for proteins as well as phospholipid acyl chains. the standard protein. MATERIALS AND METHODS Standard assay of MAO activity The MAO activity was assayed spectrophotometrically Preparation of mitochondrial outer membranes on the basis of the method of Tabor et al. (31) by record- Hog kidney mitochondrial outer membranes were ing the absorbance at 250 nm due to benzaldehyde at 29C prepared as described in our previous paper (24). Briefly, in a standard assay system containing 0.1 ml of 0.1 M 50 g of hog kidney cortex was cut into small pieces and benzylamine hydrochloride as substrate, 1.0 ml of 0.2 M homogenized with a teflon homogenizer in 450 ml of 10 Na-K phosphate buffer adjusted to the appropriate pH by mM Na-K phosphate buffer, pH 7.5 containing 0.25 M mixing 0.2 M Na2HPO4 and KH2PO4 solution at the same sucrose (1 : 9 w/v). The homogenate was centrifuged at concentration and 0.5 ml of enzyme solution for the 3.0- 600 x g for 10 min at 4 °C, and the supernatant was recen- ml final volume of reaction mixture in the quartz cell of trifuged at 5,000 x g for 10 min. The resulting precipitate 10-mm path length. The final concentrations of phos- (crude mitochondrial fraction) was suspended in 200 ml phate buffer and substrate were 0.067 M and 3.33 x 10-3 of the same buffer (1 : 4 w/v) and centrifuged at 5,000 x g M, respectively. A blank cell was set up similarly in the for 10 min (mitochondrial fraction, 9-10 ml). One por- reference side except for omission of substrate, i.e., 0.1 tion of the mitochondrial fraction was diluted to 1/100 in ml of H20 was added instead of the same volume of sub- concentration by 0.25 M sucrose, and this was used to strate solution. The initial velocity 4A250/min was regard- determine the protein concentration.
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