The Human Hydroxyacylglutathione Hydrolase (HAGH) Gene Encodes Both Cytosolic and Mitochondrial Forms of Glyoxalase II

Abstract

In yeast and higher plants, separate genes encode the cytosolic and mitochondrial forms of glyoxalase II. In contrast, although glyoxalase II activity has been detected both in the cytosol and mitochondria of mammals, only a single gene encoding glyoxalase II has been identified. Previously it was thought that this gene (the hydroxyacylglutathione hydrolase gene), comprised 8 exons that are transcribed into mRNA and that the resulting mRNA species encoded a single cytosolic form of glyoxalase II. Here we show that this gene gives rise to two distinct mRNA species transcribed from 9 and 10 exons, respectively. The 9-exon-derived transcript encodes two protein species: mitochondrially targeted glyoxylase II, which is initiated from an AUG codon in a previously uncharacterized part of the mRNA sequence, and cytosolic glyoxalase II, which is initiated by internal ribosome entry at a downstream AUG codon. The transcript deriving from 10 exons has an in-frame termination codon between the two initiating AUG codons and hence only encodes the cytosolic form of the protein. Confocal fluorescence microscopy indicates that the mitochondrially targeted form of glyoxalase II is directed to the mitochondrial matrix. Analysis of glyoxalase II mRNA sequences from a number of species indicates that dual initiation from alternative AUG codons is conserved throughout vertebrates.

The Global Transcriptional Responses of Bacillus anthracis Sterne (34F 2 ) and a Δ sodA1 Mutant to Paraquat Reveal Metal Ion Homeostasis Imbalances during Endogenous Superoxide Stress

“…Notably, the expression of three separate putative glyoxalase family genes is greatly increased in both Sterne and the ⌬sodA1 mutant upon treatment with paraquat at both doses (increases of 37-to 85-fold for GBAA1653, 3-to 28-fold for GBAA3339, and 4-to 18-fold for GBAA3878 [ Table 3]). The glyoxalase cycle is highly conserved in eukaryotes and prokaryotes, is important in certain types of cellular detoxification (16), and has been linked to potassium efflux in E. coli (51). The nucleophile methylglyoxal is a toxic but naturally occurring metabolite that can accumulate in cells as a result of various metabolic processes (9,27), and the glyoxalase system has evolved as a protective mechanism.…”

Structural Studies on a Mitochondrial Glyoxalase II

“…In contrast to GLX1, which is found as a single isozyme, GLX2 exists as multiple isozymes in many organisms, including yeast, plants, and animals. GLX2 activity has been found in both the cytosol and mitochondria (21)(22)(23). Furthermore, GLX2 isozymes were found in both the matrix and inter-membrane space of rat liver mitochondria (24,25).…”

“…In most cases, separate genes encode the cytosolic and mitochondrial isozymes. However, in humans a single gene produces both cytosolic and mitochondrial GLX2 (21). Therefore, the physiological role(s) of GLX2 may be more complex than GLX1.…”

Glyoxalase I in Tumor Cell Proliferation and Survival and as a Potential Target for Anticancer Therapy

“…This gene is composed of 10 exons and is transcribed to 2 different mRNAs, encoding the mitochondrial and cytosolic GLO2, respectively. Mitochondrial GLO2, with a molecular mass of 33.9 kDa and an isoelectric point of 8.3, is directed to the mitochondrial matrix, and cytosolic GLO2, with a molecular mass of 28.8 kDa and isoelectric point of 8.3, is mainly involved in detoxification [5,6,12]. Intron 1 of GLO2 contains a specific responsive element, which can be bound and activated by transcription factors p63 and p73, thereby up-regulating GLO2 expression [13].…”