Gale Christopher P, Grant Peter J
Academic Unit of Molecular Vascular Medicine, The General Infirmary at Leeds, Research School of Medicine, University of Leeds, G Floor, Martin Wing, Great George Street, Leeds LS1 3EX, United Kingdom.
Gene. 2004 Oct 13;340(2):251-60. doi: 10.1016/j.gene.2004.07.009.
Methylglyoxal (MG), which forms MG-derived AGE, is elevated in diabetic subjects with vascular disease. Detoxification of MG occurs through the glyoxalase system incorporating glyoxalase-1 (GLO1) and glyoxalase-2. Perturbations of the glyoxalase-1 gene (GLO1) may result in vulnerability to vascular complications through alterations in AGE interactions. We used bioinformatics to predict the structure, function and genetic variation of GLO1. We identified a previously unreported exon. Seventy single nucleotide polymorphisms (SNPs) were identified bioinformatically. The amino acid substitution Ala 111 Glu was confirmed and predicted to be tolerant. Though no alternative splice variants were identified, novel multiple alternative transcription start sites and alternative 3' UTRs were demonstrated. Ubiquitous expression of GLO1 was confirmed. Conserved regulatory regions were predicted 5' to the transcription start site and in the distal promoter, and several predicted conserved transcription regulatory elements were suggested in the 5' UTR. This study of GLO1 demonstrates multiple sequence variants at DNA and mRNA levels, areas of sequence conservation and SNPs that are predicted to affect function. A differential ability of glyoxalase-1 to reduce the formation and subsequent interaction of AGEs may have a role in the structural and functional manifestations of diabetic vascular disease.
甲基乙二醛（MG）可形成源自MG的晚期糖基化终产物（AGE），在患有血管疾病的糖尿病患者中其水平会升高。MG的解毒过程通过包含乙二醛酶-1（GLO1）和乙二醛酶-2的乙二醛酶系统进行。乙二醛酶-1基因（GLO1）的扰动可能通过AGE相互作用的改变导致易患血管并发症。我们使用生物信息学来预测GLO1的结构、功能和基因变异。我们鉴定出一个先前未报道的外显子。通过生物信息学鉴定出70个单核苷酸多态性（SNP）。氨基酸替换Ala 111 Glu得到确认，并预测为可耐受的。虽然未鉴定出可变剪接变体，但证实了存在新的多个可变转录起始位点和可变3'非翻译区（UTR）。确认了GLO1的广泛表达。在转录起始位点5'端和远端启动子中预测到保守调控区域，并且在5'UTR中提示了几个预测的保守转录调控元件。这项对GLO1的研究展示了DNA和mRNA水平上的多个序列变体、序列保守区域以及预测会影响功能的SNP。乙二醛酶-1减少AGE形成及后续相互作用的不同能力可能在糖尿病血管疾病的结构和功能表现中起作用。
