The metabolic role of human ADH3 functioning as ethanol dehydrogenase

FEBS Letters

Yin, Shih-Jiun²  Lee, An-I¹  Lee, Shou-Lun²  Wang, Ming-Fang¹ 

[1] Department of Biochemistry, National Defense Medical Center, 161 Min-Chuan East Road Section 6, Taipei 114, Taiwan;Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 114, Taiwan

关键词: Alcohol dehydrogenase;    class III;    Formaldehyde dehydrogenase;    Ethanol dehydrogenase;    Kinetic cooperativity;    First-pass metabolism;    ADH;    alcohol dehydrogenase;    ADH3;    class III ADH;    HMGSH;    S-(hydroxymethyl)glutathione;    FPM;    first-pass metabolism;   

DOI  :  10.1016/S0014-5793(03)00492-7

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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 5.4×10⁶-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.

【 授权许可】

Unknown