Biology subjects

Termini, J.

Publications and source records attributed to Termini, J..

3 recordsLinked to original sources

bioRxiv2025

Mechanistic Link Between Glyoxalase 1 Expression and Methylglyoxal-Induced Oncogenic Stress in Prostate Cancer

Prostate cancer (PCa) is the second leading cause of cancer-related death in American men, with African American/Black (AA/B) men experiencing higher incidence and mortality than European American (EA) men. Obesity, which disproportionately affects AA/B men, is linked to increased PCa mortality, potentially through metabolic dysregulation. We hypothesize that methylglyoxal (MG), a reactive byproduct of glucose, lipid, and protein metabolism that is elevated in obesity, contributes to PCa progression. MG forms covalent adducts on DNA, RNA, and protein. We found that MG-adducts are elevated in AA/B men with PCa compared to EA men with PCa, as well as men without PCa. AA/B men with PCa had a higher frequency of SNP rs1049346 in glyoxalase 1 (GLO1), the primary MG detoxification enzyme. PCa cell lines from EA (C4-2) and AA/B (MDA-PCa-2b) men showed differential rs1049346 status, with C4-2 cells heterozygous and MDA-PCa-2b cells homozygous for the variant. This was associated with altered GLO1 expression and activity, with MDA-PCa-2b cells exhibiting reduced GLO1 function and increased MG-adducts compared to C4-2 cells. MG altered DNA repair and RNA processing pathways and induced distinct metabolic shifts in MDA-PCa-2b compared to C4-2 cells, including increased glycolysis and reduced oxidative phosphorylation. Transcriptomic analysis revealed unique MG-induced stress responses including a tenfold higher induction of TXNIP in MDA-PCa-2b vs. C4-2 cells, a gene inversely linked to GLO1 expression and activity. These findings suggest that MG stress may contribute to PCa progression in AA/B men through metabolic reprogramming and impaired detoxification, offering insight into potential precision medicine applications. Statement of SignificancePatients with obesity and diabetes have an elevated risk of cancer mortality. Defining how metabolic alterations contribute to this link is critical to understanding disease progression and identifying strategies to improve outcomes.

cancer biology↗

bioRxiv2024

Resolving DJ-1 Glyoxalase Catalysis Using Mix-and-Inject Serial Crystallography at a Synchrotron

DJ-1 (PARK7) is an intensively studied protein whose cytoprotective activities are dysregulated in multiple diseases. DJ-1 has been reported as having two distinct enzymatic activities in defense against reactive carbonyl species that are difficult to distinguish in conventional biochemical experiments. Here, we establish the mechanism of DJ-1 using a synchrotron-compatible version of mix-and-inject-serial crystallography (MISC), which was previously performed only at XFELs, to directly observe DJ-1 catalysis. We designed and used new diffusive mixers to collect time-resolved Laue diffraction data of DJ-1 catalysis at a pink beam synchrotron beamline. Analysis of structurally similar methylglyoxal-derived intermediates formed through the DJ-1 catalytic cycle shows that the enzyme catalyzes nearly two turnovers in the crystal and defines key aspects of its glyoxalase mechanism. In addition, DJ-1 shows allosteric communication between a distal site at the dimer interface and the active site that changes during catalysis. Our results rule out the widely cited deglycase mechanism for DJ-1 action and provide an explanation for how DJ-1 produces L-lactate with high chiral purity.

biochemistry↗

bioRxiv2022

DJ-1 glyoxalase activity makes a modest contribution to cellular defense against methylglyoxal damage in neurons

Human DJ-1 is a cytoprotective protein whose absence causes Parkinsons disease and is also associated with other diseases. DJ-1 has an established role as a redox-regulated protein that defends against oxidative stress and mitochondrial dysfunction. Multiple studies have suggested that DJ-1 is also a protein/nucleic acid deglycase that plays a key role in the repair of glycation damage caused by methylglyoxal (MG), a reactive -keto aldehyde formed by central metabolism. Contradictory reports suggest that DJ-1 is a glyoxalase but not a deglycase and does not play a major role in glycation defense. Resolving this issue is important for understanding how DJ-1 protects cells against insults that can cause disease. We find that DJ-1 reduces levels of reversible adducts of MG with guanine and cysteine in vitro. The steady-state kinetics of DJ-1 acting on reversible hemithioacetal substrates are fitted adequately with a computational kinetic model that requires only a DJ-1 glyoxalase activity, supporting the conclusion that deglycation is an apparent rather than a true activity of DJ-1. Sensitive and quantitative isotope-dilution mass spectrometry shows that DJ-1 modestly reduces the levels of some irreversible guanine and lysine glycation products in primary and cultured neuronal cell lines and whole mouse brain, consistent with a small but measurable effect on total neuronal glycation burden. However, DJ-1 does not improve cultured cell viability in exogenous MG. In total, our results suggest that DJ-1 is not a deglycase and has only a minor role in protecting neurons against methylglyoxal toxicity.

biochemistry↗