The Relation of Copper and Iron to Production of Toxin and Enzyme Action

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Abstract
Produc-tion of diphtheria toxin in proteose broth is inhibited by substances that diminish the available Cu in the medium or augment its available Fe. Additions of cysteine, K ferrocyanide, or ferric citrate in concentrations sufficient to alter the Cu/Fe ratio of the medium from the normal value of 10:1-20:1 to the low value of 1:1 depress the level of toxin production from the normal value of 600 minimal lethal doses per cc. to the low value of less than 20 minimal lethal doses per cc. Broth in which the available Cu has been markedly reduced following the action of cysteine, produces a normal amount of diphtheria toxin on reenrichment with cupric ion. Additions of Fe and Mn compounds to cysteine-treatod broth are followed by still greater depression of toxin production than that due to cysteine alone. Additions of a Zn com-pound are without appreciable effect. Broth treated with H2S and carefully freed from an excess of that reagent behaves similarly to cysteine-treated broth. Production of neurotoxin by the tetanus bacillus is partially inhibited in the presence of cysteine. The toxicity of sterile diphtheria and tetanus neurotoxin filtrates is partially neutralized by cysteine. The hemotoxin of the tetanus bacillus is not inactivated by that reagent. Production of the hemotoxin of Cl. welchii is unaffected by cysteine, cyanide or ferrocyanide, inhibited by fer-ricyanide and stimulated by ferrous Fe. The hemolytic titer of sterile filtrates of Cl. welchii hemotoxin is not depressed by cysteine or cyanide, but is depressed following contact with cupric ion. The inactivating effect of the cupric ion is reversible, the original titer of the lysin being restored following subsequent removal of the in-activating ion with cysteine or Na hydrosulphite. The neurotoxins appear to be dispersions of bacterial protoplasm containing deeply embedded fragments of a posi-tively charged (cationic) respiratory substance having Cu as the predominant catalyst. They resemble the respiratory enzymes of the oxidase type and the proteases of the pH 8 erepsin type in being inactivated by NaCN and cysteine. The hemotoxins appear to contain fragments of negatively charged (anionic) respiratory substance having ferrous Fe as the predominant catalyst. They resemble the respiratory enzymes of the dehydro-genase type and the proteases of the pH 4 papain type, which are not inactivated by NaCN or cysteine, but are (with the possible exception of dehydrogenase) inacti-vated by the cupric ion.

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