Researchers from the Universities of Sao Paulo and California have succeeded in reproducing the in vivo performance of phosphatase in the laboratory, paving the way for the study of more effective drugs
FAPESP AGENCY – Involved in a number of biological processes, the enzymes Phosphatases are directly related to several diseases. One protein of this class, known as PTPN2 (non-receptor protein tyrosin phosphatase type 2), is highly expressed in T lymphocytes (lymphocytes) of the immune system (hence it is also known as T cell protein tyrosin phosphatase or, simply, TCPTP ) and its deficiency stimulates inflammatory responses such as those that occur in cases of diabetes type 1, rheumatoid arthritis, arthrosis, lupus and some types of tumors. Understanding his molecular mechanism in the laboratory, however, was a complex task, as his behavior was different in the organism.
Researchers from the University of Sao Paulo and the University of California in San Diego (USA) were able to reproduce the enzyme’s performance in the laboratory in vivo and understand how it works, opening the door to finding effective drugs against it . The results of the study were published in Journal of Biological Chemistry.
Supported by Fapesp, the investigation began with an extensive search of the scientific literature so that the authors could think of strategies to be applied in in vitro assays to mimic the intracellular environment. This was achieved after numerous unsuccessful experimental trials.
“We found that PTPN2 aggregates naturally within different human cells, reducing its enzymatic action, and then, in the laboratory, we made use of drugs called crowding agents, which promote this aggregation without affecting the activity of the enzyme.” ‘enzyme,’ explains Fábio Luis Forti, professor in the Department of Biochemistry at the USP Institute of Chemistry (IQ-USP) and co-author of the study.
The researchers believe that this factor may explain why such a relevant enzyme is still poorly understood at the molecular level in vivo, despite being extensively studied. From now on, according to them, new studies should emerge. “We were able to reproduce the same findings from PTPN2 activity, including targets that are directly involved in immune responses.”
The enzyme acts directly, for example, in the JAK-STAT signaling pathway, the main one involved in gene expression aimed at immune responses. “Any chemical, physical or biological mechanism that triggers an immune response in our cells is normally mediated through this pathway,” says Forti.
Different drugs
Unlike many enzymes involved in cancer and other pathologies, which are very present or have mutations that make them very active, requiring the action of drugs that block their functioning (most drugs act in this sense), the PTPN2 gene has polymorphisms (alternative forms of the gene) that lead to the loss of their protein function – and this is related to the fact that they cluster naturally. That is, it is its enzyme deficiency or ineffectiveness that causes the patient to have exacerbated inflammation and an autoimmune reaction.
“Knowing this, we can better research existing oral, nasal, or injectable drugs that can act directly on activating this enzyme where it is naturally inactive, as occurs in lupus, rheumatoid arthritis, type 1 diabetes, some lymphomas, in breast cancer and in glioblastoma (malignant tumor that affects the brain and spine),” says Forti.
“Furthermore, our work opens an interesting window of exploration for the development of new drugs that have these functions, which is what we intend to do next by screening libraries of synthetic and/or natural compounds by appropriate technologies based on the assays we have developed with this study,” he adds.
To contribute to the mission, the US research team maintains partnerships with biotech startups and other pharmaceutical companies who are aware of the latest discoveries related to phosphatases, which are still underexplored drug targets.
The article Macromolecular crowding amplifies allosteric regulation of T-cell protein tyrosine phosphatase can be read at: www.sciencedirect.com/science/article/pii/S0021925822010985?via%3Dihub.
Source: Terra
Ben Stock is a lifestyle journalist and author at Gossipify. He writes about topics such as health, wellness, travel, food and home decor. He provides practical advice and inspiration to improve well-being, keeps readers up to date with latest lifestyle news and trends, known for his engaging writing style, in-depth analysis and unique perspectives.
