Functionally active cross-linked protein oligomers formed by homocysteine thiolactone.

Deposition of high-order protein oligomers is a common hallmark of a large number of human diseases and therefore, has been of immense medical interest. From the past several decades, efforts are being made to characterize protein oligomers and explore how they are linked with the disease pathologies. In general, oligomers are non-functional, rather cytotoxic in nature while the functional (non-cytotoxic) oligomers are quite rare. In the present study, we identified new protein oligomers of Ribonuclease-A and Lysozyme that contain functionally active fractions. These functional oligomers are disulfide cross-linked, native-like, and obtained as a result of the covalent modification of the proteins by the toxic metabolite, homocysteine thiolactone accumulated under hyperhomocysteinemia (a condition responsible for cardiovascular complications including atherosclerosis). These results have been obtained from the extensive analysis of the nature of oligomers, functional status, and structural integrity of the proteins using orthogonal techniques. The study implicates the existence of such oligomers as protein sinks that may sequester toxic homocysteines in humans.

TMAO to the rescue of pathogenic protein variants.

Trimethylamine N-oxide (TMAO) is a chemical chaperone found in various organisms including humans. Various studies unveiled that it is an excellent protein-stabilizing agent, and induces folding of unstructured proteins. It is also well established that it can counteract the deleterious effects of urea, salt, and hydrostatic pressure on macromolecular integrity. There is also existence of large body of data regarding its ability to restore functional deficiency of various mutant proteins or pathogenic variants by correcting misfolding defects and inhibiting the formation of high-order toxic protein oligomers. Since an important class of human disease called "protein conformational disorders" is due to protein misfolding and/or formation of high-order oligomers, TMAO stands as a promising molecule for the therapeutic intervention of such diseases. The present review has been designed to gather a comprehensive knowledge of the TMAO's effect on the functional restoration of various mutants, identify its shortcomings and explore its potentiality as a lead molecule. Future prospects have also been suitably incorporated.