Activity, regulation, copy number and function in the glyoxalase system
Activity, regulation, copy number and function in the glyoxalase system
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DOI：
10.1042/bst20140008
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发表时间：
2014-04-01
影响因子：
3.9
通讯作者：
Thornalley, Paul J.
中科院分区：
文献类型：
--
作者：
Rabbani, Naila;Xue, Mingzhan;Thornalley, Paul J.
许多物种的乙草酸酶途径酶的分子、催化和结构特性现已为人所知。目前的研究主要集中在6101(乙醛酸酶I)和Glo2(乙醛酸酶II)的活性和表达的调节以及它们在健康和疾病中的作用。人类6101具有金属反应元件、胰岛素反应元件、E2F4、AP-2α和抗氧化剂反应元件，是拷贝数变异的热点。人类6102基因，HAGH(羟酰基谷胱甘肽水解酶)，有一个调控的P53反应元件。Glo1与健康老龄化、肥胖、糖尿病和糖尿病并发症、慢性肾脏疾病、心血管疾病、其他疾病以及癌症化疗中的多药耐药有关。乙醛酶途径的数学模型预测，6101活性增加的药理水平显著减少细胞甲基乙醛和相关糖基化，而药理6101抑制显著增加细胞甲基乙醛和相关糖基化。Glo1诱导剂正在开发中，以维持健康的衰老，并用于治疗糖尿病和其他疾病的血管并发症，细胞透过性Glo1抑制剂正在开发中，用于治疗耐多药肿瘤、疟疾和潜在的致病细菌和真菌。
Molecular, catalytic and structural properties of glyoxalase pathway enzymes of many species are now known. Current research has focused on the regulation of activity and expression of 6101 (glyoxalase I) and Glo2 (glyoxalase II) and their role in health and disease. Human 6101 has MRE (metal-response element), IRE (insulin-response element), E2F4 (early gene 2 factor isoform 4), AP-2 alpha (activating enhancer-binding protein 2 alpha) and ARE (antioxidant response-element) regulatory elements and is a hotspot for copy number variation. The human 6102 gene, HAGH (hydroxyacylglutathione hydrolase), has a regulatory p53-response element. Glo1 is linked to healthy aging, obesity, diabetes and diabetic complications, chronic renal disease, cardiovascular disease, other disorders and multidrug resistance in cancer chemotherapy. Mathematical modelling of the glyoxalase pathway predicts that pharmacological levels of increased 6101 activity markedly decrease cellular methylglyoxal and related glycation, and pharmacological 6101 inhibition markedly increases cellular methylglyoxal and related glycation. Glo1 inducers are in development to sustain healthy aging and for treatment of vascular complications of diabetes and other disorders, and cell-permeant Glo1 inhibitors are in development for treatment of multidrug-resistant tumours, malaria and potentially pathogenic bacteria and fungi.