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On the bases of the linear correlation existing for a training set of homomultisubstituted 4-aminodiphenyl sulfones between the computed (INDO) electronic net charges of the SO2 group and the enzymic inhibition data on dihydropteroate synthase from Escherichia coli, seven new heteromultisubstituted derivatives were designed, synthesized, and tested for their inhibition potencies. These compounds were found to be from 5-11 times more effective than 4,4'-diaminodiphenyl sulfone. The implications of the results in the drug design and in the model for the enzyme-inhibitors interaction are discussed.

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A set of 25 4'-, eight 2',4'-, and five 2',4',6'-substituted 4-aminodiphenyl sulfones were tested for their inhibitory activity on dihydropteroate synthase of Escherichia coli. Linear regression analysis shows that enzymic inhibition indices correlate well with both quantum chemical and spectroscopic descriptors of the electronic structure of the common moiety 4-NH2-C6H4-SO2 of the sulfones (the above descriptors being expressed in relation to the electronic structure of the enzyme substrate, p-aminobenzoate). Therefore, the biological activity of the sulfones can be related to the electronic structural resemblance between these inhibitors and the substrate of the target enzyme. Since a similar result was previously obtained for a wide series of sulfanilamides in their different (amidic, imidic, and anionic) forms, it appears possible to consider the antibacterial sulfones and sulfanilamides as a congeneric chemical series. On the basis of the present results, the classical theory of antimetabolites would appear to take on a quantitative and sound rationale.

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A set of 12 acidic, 5 imidic, and 5 amidic sulfanilamides (SA) were tested for their inhibitory activity on dihydropteroate synthase of Escherichia coli. The enzyme inhibition indexes (EII50) were compared with the growth inhibition indexes (GII50), and electronic structures of SA and cell permeability effects were discussed as possible determinant factors of the observed variation of the activity in the SA set. The results strongly support the following conclusion: (a) permeability factors are highly effective in depressing the activity of SA in growth inhibition with respect to enzyme inhibition, but they do not appear to contribute significantly to the activity variation; (b) the activities of the different SA, both in growth and enzyme inhibition experiments, are well accounted for by the electronic features of these compounds.

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The effect of the surgery on the TSH and on the extra thyroid T4 metabolism was studied in thirty euthyroid patients. The TSH showed a light increase thirty minutes after the skin cut. There were no remarkable changes of T4 serum levels, while the serum triiodothyronine concentration fell during and after the operation, with a concomitant rise in reverse triiodothyronine.

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The kinetic properties of the cytoplasmic and mitochondrial aconitate hydratases of rat liver have been studied by measuring the formation of the two products from each of the three tricarboxylic acids used as substrate. The kinetic properties of the two enzymes are very similar; the similarity of the Km values for each of the three substrates is particularly remarkable. The results are discussed with particular reference to a possible role of the cytoplasmic aconitate hydratase in the process of gluconeogenesis. With both aconitate hydratases, substrate activation by citrate and D-isocitrate has been observed.

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The developmental patterns of the activity of cytoplasmic and mitochondrial aconitate hydratses of rat liver have been studied. Both activities are low in foetal liver, with respect to adult levels, and begin to increase after birth. The activity of the mitochondrial enzyme reaches a maximum about two days after birth, then decreasing gradually to adult level. The activity of the cytoplasmic enzyme reaches its maximum level, nearly equal to adult level, about ten days after birth. The developmental pattern of the activity of the cytoplasmic aconitate hydratase may suggest a possible role of this enzyme in gluconeogenesis.

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The method of affinity chromatography has been used for studying the effects of some ligands of yeast NAD-specific isocitrate dehydrogenase on the affinity of the enzyme for NAD+ immobilized on Sepharose 4B. In absence of ligands, the enzyme is eluted from NAD+-Sepharose columns by 0.1 M phosphate buffer, pH 7.6, in a highly purified form. The elution of enzyme is accelerated by NAD+ and, more effectively, by AMP; and retarded by isocitrate and citrate. The elution patterns show a rather irregular shape, probably due to the occurrence of aggregation processes of the enzyme protein.

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The molecular weight of NAD-specific isocitrate dehydrogenase, purified from baker's yeast, has been studied by molecular sieve chromatography. By elution of the enzyme from columns of Sepharose 6B with 0.05 M phosphate buffer, pH 7.6, a mol. wt of 151,000 was measured. Higher values of the mol. wt were measured in presence of the following ligands (mol. wt in parentheses): the substrate, isocitrate (224,000); the activators, citrate (203,000) and AMP (275,000); the inhibitor, NaCl (360,000). A mol. wt of 337,000 was measured when AMP, which antagonizes the inhibition by chloride, was present together with NaCl. The results indicate the absence of a correlation between the aggregation form of the enzyme in presence of the ligands and the effects of these ligands on the enzyme activity.

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1. The sensitivity of the NAD(+)-specific isocitrate dehydrogenase from baker's yeast towards inhibition by anions decreases with decrease in pH. The patterns of the pH-dependence of the enzymic activity can be explained by this effect. 2. In the presence of a high isocitrate concentration, citrate, unlike AMP, has no antagonizing effect on the inhibition of the enzyme by anions. In the presence of AMP, citrate inhibits the enzyme at high isocitrate concentration and activates at low isocitrate concentration. 3. The effects on the enzymic activity of the previous incubation of the enzyme were studied in relation to the substrate concentration, the chloride concentration and the presence of citrate and AMP.

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