Palmitoylation inhibitors in the prevention of major disorders

Sayak Banerjee, Amity University Kolkata

Palmitoylation and PATs:

Several proteins undergo post-translational modification via the addition of a lipid molecule on the amino acid cysteine through a thioester bond. This modification is termed palmitoylation and owing to the incorporation of variable lengths of lipid chains, it is also called S-acylation. Being a reversible lipid modification, protein S-acylation has the potential to exert regulatory roles. Many peripheral proteins like G protein or Ras protein are palmitoylated together with prenylation, thus getting recruited to membranes. Proteins with transmembrane domains (TMDs) are also subjected to palmitoylation. The function of palmitoylation is essential in various processes like signal transduction, visual cycle, protein trafficking, and synaptic transmission. This makes it the most prevalent post-translational modification with over 12% of the human proteome being considered to be S-acylated. 

Generally, a family of proteins comprising 50 amino acid domains, loaded with cysteines, known as DHHC-CRD (Asp-His-His-Cys-Cysteine-Rich-Domain), is responsible for S-acylation. These proteins were first detected in the yeast Saccharomyces cerevisiae, consisting of seven members of this protein family in its genome. Out of 50, 23 members of the DHHC family proteins, also known as palmitoyltransferases (PATs), are present in the human genome. Mutations in PATs often lead to schizophrenia, mental retardation, and other disorders of the central nervous system. 

Effects of PAT:

Since S-acylation of proteins is involved in signal transduction cascades, it is associated with various types of cancers. Some PATs have their action as tumor suppressors and some are illustrated as oncoproteins. Overexpression of the DHHC21 gene is significantly observed in human breast cancer. Hence, this gene could be targeted for the treatment of breast cancer. In addition to this, DHHC21 along with DHHC7 is also responsible for the modification of the amyloid precursor protein (APP). Therefore, certain inhibitors are required to be developed for the prevention of Alzheimer’s disease. 

Researchers from the Center for Research in Biological Chemistry of Córdoba have created an approach for the determination of palmitoylation inhibitors. This strategy was based on the yeast strains which carried a reporter gene controlled by an artificial transcription factor Tf that is fused to a palmitoylation substrate. The yeast protein Yck2 was the chosen substrate that was palmitoylated by the PAT Akr1. They had tested a PAT strain g16733 from the parasite G. lambia and demonstrated that the system could be used for isolating the PAT inhibitor. It was observed in yeast that although some PATs inherited overlapping specificities, others appeared very specific for a particular type of substrate.

Findings from the screening:

The scientists hypothesized a few compounds that were expected to be found. It could be the molecules that exclusively inhibit the PAT that was used in the screen. It could be the molecules that might inhibit all or quite a lot of PATs by affecting the mechanism of S-acylation in all PATs. This type of inhibitor could be studied in further researches as they do not affect the other cellular pathways, thus keeping the S. cerevisiae alive. They found certain inhibitors which could affect S-acylation indirectly and simultaneously reveal the mechanism for the modulation of S-acylation. They found some compounds which could interrupt the expression level of PATs, making the decrease in expression seem to be an inhibition mechanism. 

Out of all these, the most abundant outcomes in their proof-of-concept screen were the ones that permitted growth in the absence of histidine. It was a false positive that was effectively ruled out on counter-screening of the JVY104 strain. They had identified only one compound having a histidine in its structure (P1E4) but were uncertain why the other compounds enabled the growth of histidine. After several validations, they obtained a compound that exhibited a dose-response in the micro-molar range.

Palmitoylation inhibitors and therapeutic opportunities:

Further research is being conducted for understanding the specificity and mechanism of action of the compound. The researchers said that this finding could yield specific palmitoylation inhibitors which are much required for the advancement in the field of protein palmitoylation. It would give therapeutic opportunities that might arise from inhibition of protein palmitoylation.

Also read: Micro-electrode arrays: a tool for studying disease-specific genotype-phenotype correlations

Reference:

1. Coronel Arrechea, C., Giolito, M. L., García, I. A., Soria, G., & Valdez Taubas, J. (2021). A novel yeast-based high-throughput method for the identification of protein palmitoylation inhibitors. Open Biology, 11(8), 200415. https://doi.org/10.1098/rsob.200415

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Author info:

Sayak Banerjee is a 3^rd-year Biotechnology Engineering Student with a great interest in Immunology and Molecular genetics. He is a creative scientific writer in Bioxone with an inclination towards gaining knowledge regarding vast sections of Biotechnology and emphasizing himself in various wet lab skills.

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