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首页> 外文期刊>The FEBS journal >Enzymes of mannitol metabolism in the human pathogenic fungus Aspergillusfumigatus - kinetic properties of mannitol-1-phosphate 5-dehydrogenase and mannitol 2-dehydrogenase, and their physiological implications.
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Enzymes of mannitol metabolism in the human pathogenic fungus Aspergillusfumigatus - kinetic properties of mannitol-1-phosphate 5-dehydrogenase and mannitol 2-dehydrogenase, and their physiological implications.

机译：人病原性真菌曲霉中的甘露醇代谢酶-甘露醇-1-磷酸5-脱氢酶和甘露醇2-脱氢酶的动力学特性及其生理学意义。

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摘要

The human pathogenic fungus Aspergillus fumigatus accumulates large amounts of intracellular mannitol to enhance its resistance against defense strategies of the infected host. To explore their currently unknown roles in mannitol metabolism, we studied A. fumigatus mannitol-1-phosphate 5-dehydrogenase (AfM1PDH) and mannitol 2-dehydrogenase (AfM2DH), each recombinantly produced in Escherichiacoli, and performed a detailed steady-state kinetic characterization of the two enzymes at 25 degrees C and pH7.1. Primary kinetic isotope effects resulting from deuteration of alcohol substrate or NADH showed that, for AfM1PDH, binding of D-mannitol 1-phosphate and NAD+ is random, whereas D-fructose 6-phosphate binds only after NADH has bound to the enzyme. Binding of substrate and NAD(H) by AfM2DH is random for both D-mannitol oxidation and D-fructose reduction. Hydride transfer is rate-determining for D-mannitol 1-phosphate oxidation by AfM1PDH (kcat=10.6 s-1) as well as D-fructose reduction by AfM2DH (kcat=94 s-1). Product release steps control the maximum rates in the other direction of the two enzymatic reactions. Free energy profiles for the enzymatic reaction under physiological boundary conditions suggest that AfM1PDH primarily functions as a D-fructose-6-phosphate reductase, whereas AfM2DH acts in D-mannitol oxidation, thus establishing distinct routes for production and mobilization of mannitol in A. fumigatus. ATP, ADP and AMP do not affect the activity of AfM1PDH, suggesting the absence of flux control by cellular energy charge at the level of D-fructose 6-phosphate reduction. AfM1PDH is remarkably resistant to inactivation by heat (half-life at 40 degrees C of 20h), consistent with the idea that formation of mannitol is an essential component of the temperature stress response of A. fumigatus. Inhibition of AfM1PDH might be a useful target for therapy of A. fumigatus infections.
机译：人类病原性真菌烟曲霉会积累大量细胞内甘露醇，以增强其对感染宿主防御策略的抵抗力。为了探索它们目前在甘露醇代谢中的未知作用，我们研究了 A。烟曲霉甘露醇-1-磷酸5-脱氢酶（ M2DH），分别在埃希氏菌< ，并在25摄氏度和pH7.1下对这两种酶进行了详细的稳态动力学表征。乙醇底物或NADH氘化产生的主要动力学同位素效应表明，对于 Af M1PDH，D-甘露醇1-磷酸和NAD + 的结合是随机的，而D-果糖6-磷酸仅在NADH与酶结合后才能结合。 AfM2DH对底物和NAD（H）的结合对于D-甘露醇氧化和D-果糖还原都是随机的。氢化物转移速率决定了 Af M1PDH（ k cat = 10.6 s -1 < / sup>）和 Af M2DH（ k cat = 94 s -1 ）。产品释放步骤控制着两个酶促反应的另一个方向的最大速率。生理边界条件下酶促反应的自由能谱表明， Af M1PDH主要起D-果糖-6-磷酸还原酶的作用，而 Af M2DH在D-甘露醇中起作用氧化，从而建立了生产和动员A中甘露醇的独特途径。烟熏。 ATP，ADP和AMP不会影响 Af M1PDH的活性，这表明在D-果糖6-磷酸还原水平下，细胞能量电荷无法控制通量。 AfM1PDH对热灭活具有显着的抵抗力（在40摄氏度下的半衰期为20小时），这与甘露醇的形成是A的温度应激反应的重要组成部分这一想法相一致。 。烟熏。 Af M1PDH的抑制可能是治疗 A的有用靶标。烟熏感染。

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