Mammalian Phosphomannomutase PMM1 Is the Brain IMP-sensitive Glucose-1,6-bisphosphatase*
Mammalian Phosphomannomutase PMM1 Is the Brain IMP-sensitive Glucose-1,6-bisphosphatase*
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哺乳动物磷酸甘露糖变位酶 PMM1 是大脑 IMP 敏感的葡萄糖 1,6-二磷酸酶*
DOI：
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发表时间：
2008
影响因子：
4.8
通讯作者：
E. Van Schaftingen
中科院分区：
文献类型：
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作者：
M. Veiga;W. Vleugels;Pushpa Maliekal;G. Matthijs;E. Van Schaftingen
脑中的葡萄糖1，6-二磷酸（Glc-1，6-P2）浓度远高于磷酸葡萄糖变位酶发挥功能所需的浓度，表明该化合物具有磷酸变位酶辅因子以外的作用。在无细胞系统中，Glc-1，6-P2由1，3-二磷酸甘油酸和Glc-6-P通过两种相关的酶形成：PGM 2L 1（磷酸葡萄糖变位酶2样1）和较小程度的PGM 2（磷酸葡萄糖变位酶2）。它被IMP刺激的脑Glc-1，6-二磷酸酶水解，其身份仍未知。我们的目的是测试葡萄糖-1，6-二磷酸酶是否对应于磷酸甘露糖变位酶PMM 1，一种具有神秘生理功能的酶，与葡萄糖-1，6-二磷酸酶共享几个特性。我们发现，IMP，而不是其他核苷酸，刺激>100倍（Ka <20 μm）的重组PMM 1的内在葡萄糖-1，6-二磷酸酶活性，同时抑制其磷酸葡萄糖变位酶活性。PMM 2没有观察到这种效应，PMM 2是一种与PMM 1类似的酶，在哺乳动物中生理上充当磷酸甘露糖变位酶。用PGM 2L 1（而不是相关酶PGM 2）转染HEK 293 T细胞，导致Glc-1，6-P2浓度增加约20倍。PMM 1的转染引起了与PGM 2L 1共转染或未共转染的细胞中Glc-1，6-P2的显著降低（>5倍）。此外，野生型小鼠脑中Glc-1，6-P2的浓度随着缺血后时间的推移而降低，而PMM 1缺陷型小鼠脑中Glc-1，6-P2的浓度没有变化。总之，这些数据表明，PMM 1对应于IMP刺激的Glc-1，6-二磷酸酶，并且该酶负责脑中Glc-1，6-P2的降解。此外，建立了PGM 2L 1作为负责合成脑中升高浓度的Glc-1，6-P2的酶的作用。
Glucose 1,6-bisphosphate (Glc-1,6-P2) concentration in brain is much higher than what is required for the functioning of phosphoglucomutase, suggesting that this compound has a role other than as a cofactor of phosphomutases. In cell-free systems, Glc-1,6-P2 is formed from 1,3-bisphosphoglycerate and Glc-6-P by two related enzymes: PGM2L1 (phosphoglucomutase 2-like 1) and, to a lesser extent, PGM2 (phosphoglucomutase 2). It is hydrolyzed by the IMP-stimulated brain Glc-1,6-bisphosphatase of still unknown identity. Our aim was to test whether Glc-1,6-bisphosphatase corresponds to the phosphomannomutase PMM1, an enzyme of mysterious physiological function sharing several properties with Glc-1,6-bisphosphatase. We show that IMP, but not other nucleotides, stimulated by >100-fold (Ka ≈ 20 μm) the intrinsic Glc-1,6-bisphosphatase activity of recombinant PMM1 while inhibiting its phosphoglucomutase activity. No such effects were observed with PMM2, an enzyme paralogous to PMM1 that physiologically acts as a phosphomannomutase in mammals. Transfection of HEK293T cells with PGM2L1, but not the related enzyme PGM2, caused an ≈20-fold increase in the concentration of Glc-1,6-P2. Transfection with PMM1 caused a profound decrease (>5-fold) in Glc-1,6-P2 in cells that were or were not cotransfected with PGM2L1. Furthermore, the concentration of Glc-1,6-P2 in wild-type mouse brain decreased with time after ischemia, whereas it did not change in PMM1-deficient mouse brain. Taken together, these data show that PMM1 corresponds to the IMP-stimulated Glc-1,6-bisphosphatase and that this enzyme is responsible for the degradation of Glc-1,6-P2 in brain. In addition, the role of PGM2L1 as the enzyme responsible for the synthesis of the elevated concentrations of Glc-1,6-P2 in brain is established.