Alcohol dehydrogenase (ADH) is the enzyme that is responsible for converting eth

Question

Alcohol dehydrogenase (ADH) is the enzyme that is responsible for converting ethanol to acetaldehyde (the reaction is shown in Figure 13.1). It is the enzyme responsible for the metabolism of ethanol in the alcoholic beverages we consume. Five different isozymes of ADH have been identified, and it has been shown that the enzyme has a rather broad substrate specificity and can oxidize aldehydes as well as primary and secondary alcohols. For example, ADH can also oxidize methanol (wood alcohol) and ethylene alcohol (antifreeze). The poisonous nature of these compounds results from the ADH-catalyzed conversion of these compounds to toxic products. For example, ADH converts methanol to formaldehyde, which is toxic to the optic nerve and can produce blindness. In high doses, formaldehyde may be fatal.

In this study, the authors investigated the ability of formamide compounds to inhibit alcohol dehydrogenase. Only a portion of their data is presented here. The authors were able to propose a mechanism for the inhibition from the extensive data they collected using a wide variety of formamide compounds. The mechanism is shown in Figure 13.2.

1) The authors of this study studied the ability of N-1,5-dimethylhexylformamide to inhibit mouse ADH1. The activity of the enzyme was measured in the absence of inhibitor, and in the presence of 1.0 mM inhibitor. The data are presented below.

a. What type of inhibitor is N-1,5-dimethylhexylformamide? Explain by calculating the Ki and/or Ki’ whichever is appropriate) for N-1,5-dimethylhexylformamide? Would N-1,5-dimethylhexylformamide be effective even if the concentrations of methanol or ethylene glycol were very high? (Hint: Compare the values of KI or KI’, whichever is appropriate, and KM).

Explanation / Answer

What type of inhibitor is N-1,5-dimethylhexylformamide?

Formamides are analogues of the carbonyl substrates, are bound preferentially to the enzyme-NADH complex, and are potent uncompetitive inhibitors against varied concentrations of alcohol

Explain by calculating the Ki and/or Ki’ whichever is appropriate) for N-1,5-dimethylhexylformamide?

N-1,5-dimethylhexylformamide are particularly potent inhibitors of the human and mouse enzymes, with Ki values less than 1 M. (Ki values are not easily calculated)

Would N-1,5-dimethylhexylformamide be effective even if the concentrations of methanol or ethylene glycol were very high?

Uncompetitive inhibitors could be especially useful for controlling alcohol metabolism since they are effective even when the concentrations of alcohol are saturating(very high concentrations).

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