The characterisation and functional analysis of the human glyoxalase-1 gene using methods of bioinformatics.
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.
Gale
Christopher P
CP
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. medcpg@leeds.ac.uk
Grant
Peter J
PJ
D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D019295:Computational Biology / Q000379:methods*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D030561:Databases, Nucleic Acid; D023281:Genomics / Q000379:methods; D006801:Humans; D007791:Lactoylglutathione Lyase / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional; D014157:Transcription Factors / Q000378:metabolism; D024363:Transcription Initiation Site; D014158:Transcription, Genetic
D018076:DNA, Complementary; D014157:Transcription Factors; D004247:DNA; D007791:Lactoylglutathione Lyase