This systematic review describes how the glyoxalase system detoxifies methylglyoxal into D-lactate, its links to glycation-related diseases, and the small-molecule GLO1 activators and inhibitors and screening assays reported to date.
Authors
- He Y, Zhou C, Huang M, Tang C, Liu X, Yue Y, Diao Q, Zheng Z, Liu D. , Biomedicine & Pharmacotherapy. 2020
What was reviewed
This systematic review examines the glyoxalase system, a ubiquitous enzymatic network made up of glyoxalase 1 (GLO1), glyoxalase 2 (GLO2) and reduced glutathione (GSH). Together these convert methylglyoxal (MG), a reactive by-product of metabolism, and other harmful endogenous metabolites into non-toxic D-lactate. The review describes how GLO1 is regulated in different disease states, and it surveys the small molecules discovered so far that activate or inhibit GLO1, including their chemical classes, structures and structure–activity relationships. It also describes the laboratory assays used to screen for new glyoxalase regulators.
Who was reviewed
The review draws on published biochemical, cellular, animal and human research on the glyoxalase system and on the chemistry of compounds that modulate GLO1. It is written for researchers designing new GLO1 regulators and is not a study of a specific population or of an exposure.
Most important findings
| Critical Points | Details |
|---|---|
| 1. Role in detoxification | The glyoxalase system (GLO1, GLO2 and GSH) detoxifies methylglyoxal and other harmful endogenous metabolites into non-toxic D-lactate, an essential metabolic function in cells. |
| 2. Anti-glycation defence | GLO1 is the key rate-limiting enzyme in the cell's defence against glycation. Methylglyoxal and the advanced glycation end-products (AGEs) derived from it are associated with diabetes, cardiovascular disease, neurodegenerative disorders and cancer. |
| 3. A drug target | Because GLO1 activity and expression are abnormal in various diseases, the authors consider the enzyme a promising target for drug design and development. |
| 4. Activators and inhibitors | The review catalogues GLO1 activators and inhibitors reported since their discovery, grouped by chemical class, with their structures and structure–activity relationships. |
| 5. Screening methods | Compared with spectrophotometer-based assays, microplate-based assays are a simpler, faster and quantitative high-throughput way to screen for small-molecule regulators of the glyoxalase system. |
Key implications
The review is a reference for researchers developing GLO1-targeted compounds, and it summarises the glyoxalase system's role in protecting cells from methylglyoxal and glycation damage. It does not specifically study heavy metals. Its relevance to heavy metal research is background: glutathione-dependent detoxification and the control of reactive by-products are among the cellular defences that come under strain during toxic and oxidative stress. The review does not establish glyoxalase activity or methylglyoxal levels as biomarkers of heavy metal exposure.
Citation
He Y, Zhou C, Huang M, Tang C, Liu X, Yue Y, Diao Q, Zheng Z, Liu D. Glyoxalase system: A systematic review of its biological activity, related-diseases, screening methods and small molecule regulators. Biomedicine & Pharmacotherapy. 2020;131:110663. doi:10.1016/j.biopha.2020.110663