Tyrosine hydroxylase (TH) is an enzyme that converts the amino acid L-tyrosine into the neurotrasmitter L-DOPA, fundamental for the normal functioning of the nervous system. Mutations in the gene that codes for TH cause a reduction in enzyme activity and are associated to disorders like tyrosine hydroxylase deficiency (THD), Parkinson’s disease and Alzheimer’s disease. For these reasons, researchers are trying to identify new therapeutic strategies aimed to stabilize TH activity, including the administration of pharmacological chaperones.

Chaperones are very small compounds that exist in nature and whose function is to facilitate the correct conformation for newly synthesized proteins, thus favoring their transport and increasing their cellular levels and activity. The use of these molecules in the treatment of rare genetic disorders caused by misfolding or instability of one enzyme, is based on the concept that they may be able to improve enzyme activity and restore their metabolic functions. In THD, patients present decreased TH and dopamine levels that lead to movement and cognitive problems within the first year of life. Patients can be classified in two groups: type A patients,  which usually respond to treatment with L-DOPA, and type B patients who respond poorly or not at all to treatment, for which the prognosis is more severe and new treatments are needed. Researchers from Norway and Spain identified five compounds that bind TH enzyme and could function as pharmacological chaperones, whose characteristics have been published in the journal Biochimica et Biophysica Acta.

For people who do not have much affinity for biochemistry, it might seem like looking for a needle in a haystack, but complex techniques named differential scanning fluorimetry, electron paramagnetic resonance and  scanning electron microscopy, among others, returned to the authors five interesting molecules of the 10,000 tested. They called this entities compound 1,2,3,4,5.

How did they arrive to these few molecules? Firstly, they excluded all the compounds that did not bind TH enzyme or did not increase its thermal stability, thus only 123 elements remained in the race. Then, they determined which compounds were able to protect TH from time dependent loss of activity, and they found that only twelve of them could do it. Interestingly, most of these molecules were also able to preserve the activity of hTH1-p.R202H, the mutant form of TH carrying the most recurrent human mutation associated with type B THD. Based on the results obtained in the previous experiments, the researchers then selected the five best candidates, which shared also a highly similar structure, to confirm their capacity to act as chaperons, namely to bind and stabilize TH enzyme, and preserve its functionality. The most interesting observation was that the compounds did not behave the same way because some had higher capacity to stabilize the enzyme, whereas other were more effective in protecting enzyme activity. Thus, the authors concluded that not always conformational stabilization means TH activity protection and vice versa, and they suggested that different chaperons might be eventually used together to reach better results.

The employment of pharmacological chaperones could be useful for the management of diseases for which a cure does not yet exist, or for which expensive, invasive and  life-long approaches have been adopted. Indeed, since chaperones are small molecules, they are supposed to easily reach all the cells and  the tissues. Moreover, they can be ingested, hence rendering the living conditions of patients more tolerable. Finally, they should be relatively inexpensive. So far, the use of chaperones for clinical practice is not common, although phase I and II clinical trials are being conducted for Fabry, Gaucher and Pompe diseases, with encouraging results. Without doubt, hundreds of diseases caused by misfolded proteins, could have similar therapeutic benefits. However, more studies are needed to determine the efficacy, safety and long-tem effects of these protocols.



Six possible candidates with TH activating function have been determined. They could be used as pharmacological chaperones in the treatment of  THD, an inborn error of metabolism, as well as in more common neurological disorders like  Parkinson’s disease and Alzheimer’s disease.

Pharmacological chaperones might provide new and potent therapies for inherited neurometabolic disorders.


Reference: Hole M. et al.Discovery of compounds that protect tyrosine hydroxylase activity through
different mechanisms. Biochim Biophys Acta. 2015 Sep;1854(9):1078-89.