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The metabolic role of human ADH3 functioning as ethanol dehydrogenase
Author(s) -
Lee Shou-Lun,
Wang Ming-Fang,
Lee An-I,
Yin Shih-Jiun
Publication year - 2003
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(03)00492-7
Subject(s) - cooperativity , alcohol dehydrogenase , chemistry , ethanol , glutathione , formaldehyde dehydrogenase , enzyme , dehydrogenase , enzyme kinetics , substrate (aquarium) , biochemistry , cooperative binding , kinetics , biophysics , active site , biology , ecology , physics , quantum mechanics
Human class III alcohol dehydrogenase (ADH3), also known as glutathione‐dependent formaldehyde dehydrogenase, exhibited non‐hyperbolic kinetics with ethanol at a near physiological pH 7.5. The S 0.5 and k cat were determined to be 3.4±0.3 M and 33±3 min −1 , and the Hill coefficient ( h ) 2.21±0.09, indicating positive cooperativity. Strikingly, the S 0.5 for ethanol was found to be 5.4×10 6 ‐fold higher than the K m for S ‐(hydroxymethyl)glutathione, a classic substrate for the enzyme, whereas the k cat for the former was 41% lower than that for the latter. Isotope effects on enzyme activity suggest that hydride transfer may be rate‐limiting in the oxidation of ethanol. Kinetic simulations using the experimentally determined Hill constant suggest that gastric ADH3 may highly effectively contribute to the first‐pass metabolism at 0.5–3 M ethanol, an attainable range in the gastric lumen during alcohol consumption. The positive cooperativity mainly accounts for this metabolic role of ADH3.