Abstract
Squalene monooxygenase is a flavin adenine dinucleotide-containing, microsomal enzyme that catalyzes the second step in the committed pathway for cholesterol biosynthesis. Feeding weanling rats a diet containing 1% elemental tellurium causes a transient, peripheral demyelination due to the disruption of cholesterol synthesis in Schwann cells secondary to inhibition of squalene monooxygenase. The tellurium species responsible for the inhibition is unknown, as is the mechanism of inhibition. To study the potential mechanisms of tellurium toxicity in humans, three likely in vivo metabolites of tellurium (tellurite, dimethyltellurium dichloride, and dimethyltelluride) were tested as inhibitors of purified human squalene monooxygenase. All three inhibitors reacted with the enzyme slowly and the resulting interaction was not freely reversible. The 50% inhibitory concentration for the methyltellurium compounds (~100 nM) after a 30-min preincubation was 100-fold lower than that of tellurite, indicating a role for hydrophobicity in the enzyme-inhibitor interaction. The ability of glutathione and 2,3-dimercaptopropanol to prevent and reverse the inhibition indicated that the tellurium compounds were reacting with sulfhydryls on squalene monooxygenase, and the ability of phenylarsine oxide, which reacts specifically with vicinal sulfhydryls, to inhibit the enzyme indicated that these sulfhydryls are located proximal to one another on the enzyme. These results suggest that the unusual sensitivity of squalene monooxygenase to tellurium compounds is due to the binding of these compounds to vicinal cysteines, and that methylation of tellurium in vivo may enhance the toxicity of tellurium for this enzyme. —Laden, B. P., and T. D. Porter. Inhibition of human squalene monooxygenase by tellurium compounds: evidence of interaction with vicinal sulfhydryls.
Highlights
Squalene monooxygenase is a flavin adenine dinucleotide-containing, microsomal enzyme that catalyzes the second step in the committed pathway for cholesterol biosynthesis
Tellurium is methylated in the liver [9], and two methyltellurium compounds, dimethyltellurium dichloride [Te(CH3)2Cl2,; DMTDC] and dimethyltelluride [Te(CH3)2; DMT], inhibit squalene monooxygenase activity both in cultured Schwann cells and in weanling rats, whereas tellurite does not [10]
To determine which tellurium compounds inhibit the human enzyme we tested the ability of tellurite, DMT, and DMTDC to inhibit the human enzyme in Squalene monooxygenase catalyzes the second and potentially rate-limiting step in the committed pathway for cholesterol biosynthesis, yet little is known about the basic structure and biochemistry of the enzyme [1]
Summary
A purified system and investigated the mechanism of this inhibition. The present study provides evidence that the tellurium compounds react with vicinal cysteine sulfhydryl groups on squalene monooxygenase, and that methylation of this element, normally considered a detoxication reaction, may yield a more toxic metabolite for this enzyme. Selenium and arsenic share many similar chemical properties with tellurium and can produce a demyelination similar to that caused by tellurium; the molecular targets responsible for the arsenic and selenium-induced neuropathy are unknown, but the ability of phenylarsine oxide to inhibit squalene monooxygenase suggests that this enzyme may be one such target
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