Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Biochem J. 2011 Jul 1;437(1):109-15. doi: 10.1042/BJ20102069.
With the exception of the oxidation of G6P (glucose 6-phosphate) by H6PDH (hexose-6-phosphate dehydrogenase), scant information is available about other endogenous substrates affecting the redox state or the regulation of key enzymes which govern the ratio of the pyridine nucleotide NADPH/NADP. In isolated rat liver microsomes, NADPH production was increased, as anticipated, by G6P; however, this was strikingly amplified by palmitoylcarnitine. Subsequent experiments revealed that the latter compound, well within its physiological concentration range, inhibited 11β-HSD1 (11β-hydroxysteroid dehydrogenase 1), the bidirectional enzyme which interconnects inactive 11-oxo steroids and their active 11-hydroxy derivatives. Notably, palmitoylcarnitine also stimulated the antithetical direction of 11β-HSD1 reductase, namely dehydrogenase. This stimulation of H6PDH may have likewise contributed to the NADPH accretion. All told, the result of these enzyme modifications is, in a conjoint fashion, a sharp amplification of microsomal NADPH production. Neither the purified 11β-HSD1 nor that obtained following microsomal sonification were sensitive to palmitoylcarnitine inhibition. This suggests that the long-chain amphipathic acylcarnitines, given their favourable partitioning into the membrane lipid bilayer, disrupt the proficient kinetic and physical interplay between 11β-HSD1 and H6PDH. Finally, although IDH (isocitrate dehydrogenase) and malic enzyme are present in microsomes and increase NADPH concentration akin to that of G6P, neither had an effect on 11β-HSD1 reductase, evidence that the NADPH pool in the endoplasmic reticulum shared by the H6PDH/11β-HSD1 alliance is uncoupled from that governed by IDH and malic enzyme.
除了 H6PDH（己糖-6-磷酸脱氢酶）氧化 G6P（葡萄糖 6-磷酸）之外，关于其他内源性底物如何影响氧化还原状态或调节控制吡啶核苷酸 NADPH/NADP 比值的关键酶的信息很少。在分离的大鼠肝微粒体中，正如预期的那样，NADPH 的产生增加了 G6P；然而，棕榈酰肉碱却显著放大了这种作用。随后的实验表明，后一种化合物在其生理浓度范围内，抑制了 11β-HSD1（11β-羟甾脱氢酶 1），这是一种连接无活性 11-酮类固醇及其活性 11-羟基衍生物的双向酶。值得注意的是，棕榈酰肉碱还刺激了 11β-HSD1 还原酶（即脱氢酶）的相反方向。这种 H6PDH 的刺激同样有助于 NADPH 的积累。总而言之，这些酶修饰的结果是，微粒体 NADPH 的产生急剧增加。既没有纯化的 11β-HSD1，也没有通过微粒体超声获得的 11β-HSD1 对棕榈酰肉碱抑制敏感。这表明长链两亲性酰基肉碱由于其有利于分配到膜脂质双层中，破坏了 11β-HSD1 和 H6PDH 之间有效的动力学和物理相互作用。最后，尽管 IDH（异柠檬酸脱氢酶）和苹果酸酶存在于微粒体中，并且类似于 G6P 增加 NADPH 浓度，但它们都没有对 11β-HSD1 还原酶产生影响，这表明内质网中 H6PDH/11β-HSD1 联盟共享的 NADPH 池与由 IDH 和苹果酸酶控制的 NADPH 池是解偶联的。
