Enzyme study may bring insights into AADC deficiency’s causes
AADC enzyme can undergo phosphorylation to regulate its activity
The AADC enzyme can undergo a process called phosphorylation at a specific molecular site to increase its activity, a study shows.
These findings provide deeper insight into the functionality of this enzyme, and may help scientists to better understand the effects of certain specific mutations that cause AADC deficiency.
Trying to more fully understand what causes AADC enzyme to go awry
AADC deficiency is caused by mutations that interfere with the function of the AADC (aromatic L-amino acid decarboxylase) enzyme. This enzyme, or protein, is required to make certain neurotransmitters — chemicals that nerve cells use to communicate with each other and the rest of the body. In AADC deficiency, the lack of the functional enzyme impairs production of these signaling molecules, which ultimately gives rise to disease symptoms.
Although it’s well established that problems with AADC can give rise to disease, exactly how this protein normally works is not fully understood. A better understanding can help experts gain insight into what causes the enzyme’s function to go awry in diseases like AADC deficiency.
Previous research has shown that AADC can undergo a type of molecular modification called phosphorylation, where a small chemical group — one atom of the element phosphorous and three atoms of oxygen — is attached to the protein.
Scientists in Italy and the U.S. determined that AADC can specifically undergo phosphorylation at a particular location: the serine located at the 193rd spot in the AADC protein chain. (Serine is an amino acid, one of the building blocks used to make AADC and other proteins.)
Notably, this location is right by AADC’s active site, which is the part of the enzyme that directly interacts with other molecules to make neurotransmitters. Mutations affecting the active site of the enzyme have been reported to cause AADC deficiency.
The researchers determined that, when AADC is phosphorylated at this site, the enzyme’s neurotransmitter-making abilities get boosted.
They further showed that when the enzyme is modified so that it can no longer be phosphorylated at this site, its activity is reduced but not completely eliminated. This suggests that this modification may help to regulate AADC activity, but it isn’t absolutely required for the protein to function.
Based on the totality of the data, the researchers speculated that phosphorylation of AADC at the serine-193 location might help to stabilize the enzyme, allowing it to be more efficient when making neurotransmitters.
Further research is needed to confirm this idea, they stressed, and they noted that since these experiments all were done using molecules in dishes, additional work is needed to confirm whether these processes also occur in living cells. Regardless, the team said this work highlights a need to consider how mutations that affect AADC phosphorylation may contribute to the disease.
“The value here is to point out that in the context of pathological defects found for AADC, until now overlooked, the possibility for a regulation of AADC by phosphorylation should be reconsidered,” they wrote.