Pantothenate kinase

Pantothenate kinase (EC 2.7.1.33, PanK; CoaA) is the first enzyme in the Coenzyme A (CoA) biosynthetic pathway.

It phosphorylates pantothenate (vitamin B5) to form 4'-phosphopantothenate at the expense of a molecule of adenosine triphosphate (ATP).

In mouse models, PanK1 is the predominant species in the heart, liver and brown adipose tissue, along with the kidneys.

The C-terminal ends of the helices are held together by van der Waals interactions between valine and methionine residues of each monomer.

This bundle consists of a hydrophobic core formed by non-polar residues that utilize van der Waals forces to further stabilize the dimer.

Human PanK-II isoforms PanK1α, PanK1β, PanK2, and PanK3 have a common, highly homologous catalytic core of approximately 355 residues.

This region allows for feedback inhibition by free CoA and acyl-CoA and regulation by acetyl-CoA and malonyl-CoA.

On the other hand, the PanK1β transcript starts with exon 1β, which produces a 10-residue N-terminus that does not include a feedback regulatory domain.

The monomer units of PanK-II and PanK-III are virtually identical, but they have distinctly different dimer assemblies.

[11] As a result of this difference in dimerization interface between PanK-II and PanK-III, the conformations of the substrate binding sites for ATP and pantothenate are also distinct.

[16] In this concerted mechanism, the planar phosphorane of the γ-phosphate is transferred in-line to the attacking oxygen of pantothenate.

PanK1-/- mouse models in a fasted state show impaired gluconeogenesis, indicating that this pathway is disrupted.

[20] The activation of PanK2 by palmitoyl-carnitine and other long-chain acyl-carnitines sheds light on the regulatory pathways of this enzyme: Under normal conditions, PanK2 is likely inhibited by high levels of acetyl-CoA.

Without CoA production, fatty acid oxidation decreases, leading to an increase in long-chain acyl-carnitines.

[10][12][13] In humans: The PANK2 gene encodes for PanK2, which regulates the formation of CoA in mitochondria, the cell’s energy-producing centers.