Methylglyoxal-Scavenging Enzyme Activities Trigger Erythroascorbate Peroxidase and Cytochrome c Peroxidase in Glutathione-Depleted Candida albicans

Abstract

Methylglyoxal (MG, CH 3 COCHO) reacts with nucleic acids and proteins, causing to cellular damage [1], and also inhibits cell division in eukaryotes [2]. MG non-specifically binds to amines, amino acids, and proteins and produces biologically active free radicals [3-5]. Advanced glycation end-products are derived from MG, leading to hyperglycemic damage in cells [1, 6]. This highly reactive α-ketoaldehyde inhibits human leukemia 60 cells, resulting in apoptosis [7]. In the fission yeast Schizosaccharomyces pombe, MG can activate stress-activated protein kinase signaling cascade [8]. As demonstrated in our previous studies at the microbial level, MG accumulation in cells results in the defective growth and the arrest of the G1-phase specific cell cycle in γ-glutamyl cysteinyl synthetase (GCS)-deficient gcsof Dictyostelium discoideum [9]. Glutathione (GSH)-depleted strains provide a working concept for cellular accumulation of MG via the inactive GSH-required glyoxalase system [9]. Investigations have focused on a number of MG scavengers, including aldehyde dehydrogenase, aldehyde reductase, aldose reductase, and αketoaldehyde dehydrogenase. These enzymes commonly catalyze the oxidation or reduction of MG into pyruvate or acetol [10]. Inspired by these findings, in Candida albicans, we previously purified and characterized two predominant MG-scavenging enzymes, NAD(H)-linked alcohol dehydrogenase 1 (CaO19.3997; Adh1) [11] and NAD(H)-linked MG oxidoreductase (CaO19.4309; Mgd1) [12]. The Mgd protein, Mgd1, has been revealed to be γ-Glutamylcysteine synthetase (Gcs1) and glutathione reductase (Glr1) activity maintains minimal levels of cellular methylglyoxal in Candida albicans. In glutathione-depleted Δgcs1, we previously saw that NAD(H)-linked methylglyoxal oxidoreductase (Mgd1) and alcohol dehydrogenase (Adh1) are the most active methylglyoxal scavengers. With methylglyoxal accumulation, disruptants lacking MGD1 or ADH1 exhibit a poor redox state. However, there is little convincing evidence for a reciprocal relationship between methylglyoxal scavenger genes-disrupted mutants and changes in glutathione-(in)dependent redox regulation. Herein, we attempt to demonstrate a functional role for methylglyoxal scavengers, modeled on a triple disruptant (Δmgd1/Δadh1/Δgcs1), to link between antioxidative enzyme activities and their metabolites in glutathione-depleted conditions. Despite seeing elevated methylglyoxal in all of the disruptants, the result saw a decrease in pyruvate content in Δmgd1/Δadh1/Δgcs1 which was not observed in double gene-disrupted strains such as Δmgd1/Δgcs1 and Δadh1/Δgcs1. Interestingly, Δmgd1/Δadh1/Δgcs1 exhibited a significantly decrease in H 2 O 2 and superoxide which was also unobserved in Δmgd1/Δgcs1 and Δadh1/Δgcs1. The activities of the antioxidative enzymes erythroascorbate peroxidase and cytochrome c peroxidase were noticeably higher in Δmgd1/Δadh1/Δgcs1 than in the other disruptants. Meanwhile, Glr1 activity severely diminished in Δmgd1/Δadh1/Δgcs1. Monitoring complementary gene transcrip...

Redox dyshomeostasis strategy for tumor therapy based on nanomaterials chemistry

“…Therefore, g-GCS is used as a more popular target for the regulation of GSH synthesis. 45,46 The g-GCS inhibitor L-buthionine-(S,R)-sulfoximine (BSO) is the most widely used chemical compound for the inhibition of GSH biosynthesis. 47 Xiaolin Wang et al developed near-infrared photothermal liposomal nano-antagonists (PLANs) containing a photosensitizer indocyanine (ICG) and BSO.…”