Biochemical phenotype of a common disease-causing mutation and a possible therapeutic approach for the phosphomannomutase 2-associated disorder of glycosylation.
Biochemical phenotype of a common disease-causing mutation and a possible therapeutic approach for the phosphomannomutase 2-associated disorder of glycosylation.
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DOI：
10.1002/mgg3.3
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发表时间：
2013-05
影响因子：
2
通讯作者：
Cubellis, Maria Vittoria
中科院分区：
文献类型：
--
作者：
Andreotti, Giuseppina;Pedone, Emilia;Giordano, Assunta;Cubellis, Maria Vittoria
磷酸甘露糖变位酶 2 (PMM2) 缺陷是最常见的先天性糖基化疾病类型。对于这种疾病目前尚无治愈方法。磷酸甘露糖变位酶活性的完全丧失可能与生活不相容，受影响的人携带至少一种具有残留活性的等位基因。我们对野生型 PMM2 及其最常见的亚等位突变体 p.F119L 进行了表征，该突变体与该疾病的严重表型相关。我们证明活性物质是二聚酶，突变削弱了四级结构，同时影响酶的活性和稳定性。我们证明配体结合可以稳定野生型和 F119L-PMM2 两种蛋白质，并促进体外亚基关联。在钒酸盐存在下，1,6-二磷酸葡萄糖 (Glc-1,6-P2) 或单磷酸葡萄糖的效果最强。这一发现为治疗 PMM2 缺陷提供了一种新方法。我们建议通过作用于控制其合成和降解的代谢途径或利用能够跨膜的前药来提高 Glc-1,6-P2 浓度。
Phosphomannomutase 2 (PMM2) deficiency represents the most frequent type of congenital disorders of glycosylation. For this disease there is no cure at present. The complete loss of phosphomannomutase activity is probably not compatible with life and people affected carry at least one allele with residual activity. We characterized wild-type PMM2 and its most common hypomorphic mutant, p.F119L, which is associated with a severe phenotype of the disease. We demonstrated that active species is the dimeric enzyme and that the mutation weakens the quaternary structure and, at the same time, affects the activity and the stability of the enzyme. We demonstrated that ligand binding stabilizes both proteins, wild-type and F119L-PMM2, and promotes subunit association in vitro. The strongest effects are observed with glucose-1,6-bisphosphate (Glc-1,6-P2) or with monophosphate glucose in the presence of vanadate. This finding offers a new approach for the treatment of PMM2 deficiency. We propose to enhance Glc-1,6-P2 concentration either acting on the metabolic pathways that control its synthesis and degradation or exploiting prodrugs that are able to cross membranes.