The Molecular Basis of Adaptive Variation in Ethanol Resistance in Drosophila melanogaster: Contribution of Aldehyde Dehydrogenase

乙醛是一种剧毒的中间体，由乙醇(乙醇)在酶作用下分解而成。经常消耗乙醇的物种，包括人类和常见的果蝇黑腹果蝇，都依赖乙醛脱氢酶(ALDH)来进行乙醛解毒。在这项拟议的工作中，将研究在一些种群中发现的ALDH的结构变化，这是一种以靠发酵高乙醇的水果而蓬勃发展的物种。初步结果表明，改变后的ALDH对乙醛的解毒能力高于原酶，但对其他醛的解毒能力低于原酶。因此，这种变化预计对以乙醇为食的果蝇是有益的，但在没有乙醇的情况下可能是有害的。为了验证这些预测，我们将在含有和不含乙醇的饮食中对含有和改变了ALDH的果蝇的存活和繁殖进行比较。此外，这两种ALDH变体的催化性能将在各种生物相关的醛底物上进行测量。通过利用果蝇可用的强大遗传工具，拟议的工作将为有机体适应其生态位的分子基础提供独特的见解。此外，由于ALDH在果蝇中具有与人类大致相似的结构和功能，因此该结果可能有助于阐明这种酶在人类健康和疾病中的作用。

Acetaldehyde is a highly toxic intermediate generated by the enzymatic breakdown of ethanol (ethyl alcohol). Species that regularly consume ethanol, including both humans and the common fruit fly Drosophila melanogaster, rely on the enzyme aldehyde dehydrogenase (ALDH) for acetaldehyde detoxification. In the proposed work, a structural change in ALDH found in some populations of D. melanogaster, a species notable for its ability to thrive on fermenting fruit high in ethanol, will be studied. Initial results indicate that the altered ALDH has higher ability to detoxify acetaldehyde, but lower ability to detoxify other aldehydes, than the original enzyme. Thus the change is predicted to be beneficial in flies feeding on ethanol, but may be detrimental in the absence of ethanol. To test these predictions, survival and reproduction of flies with the original and altered ALDH will be compared on diets both containing and lacking ethanol. In addition, the catalytic properties of the two ALDH variants will be measured with a variety of biologically relevant aldehyde substrates.By taking advantage of the powerful genetic tools available for Drosophila, the proposed work will give unique insight into the molecular basis of adaptation of an organism to its ecological niche. In addition, because ALDH has broadly similar structure and function in Drosophila as in humans, the results may shed light on the role of this enzyme in human health and disease.