Official Project Description
These simulations are exploring the landscape of the dimer pantothenate kinase 2 and 3 from humans.
This enzyme is the rate-limiting step in the synthesis of Acetyl-CoA, and is widely expressed across many tissues.
The enzyme processes vitamin B5 (pantothenate) yielding phosphopantothenate, which is then worked up by other enzymes into Acetyl-CoA.
Acetyl-CoA binds to the same site as pantothenate, and thus prevents the enzyme from overproducing pantothenate through product inhibition.
These simulations are part of an effort to identify conformations that are important for other inhibitors of that site.
Being able to control when the enzyme is productive regardless of whether AcCoA is abundant gives a framework for manipulating cellular metabolism and signalling in many diseases.
These projects are related to 12266, and will allow us to compare the properties of the three enzymatically active pantothenate kinases.
This becomes interesting because these enzymes are expressed quite differentially, with Pank1 ('66) more present in the heart than the other two. These simulations will advance the state of research on this important protein, so that subsequent studies can better understand modulating compounds relevant to protecting damage to heart tissues during a heart attack by gliflozin molecules (such as Empagliflozin).
These two projects will help us understand what other effects such medication may have in other parts of the body beyond the heart.