Protein phosphatase Mn(2+)-dependent 1K

PPM1K (protein phosphatase Mn(2+)-dependent 1K) is a serine/threonine phosphatase that functions as a metabolic regulatory hub coordinating branched-chain amino acid (BCAA) catabolism with glucose and lipid metabolism. It forms a functional kinase-phosphatase pair with BCKDK and regulates two key substrates: the mitochondrial BCKDHA subunit of the branched-chain alpha-ketoacid dehydrogenase complex and the cytosolic lipogenic enzyme ACLY. The protein also influences mitochondrial calcium-induced apoptotic pathways (UniProt: Q8N3J5).

PPM1K activity is tightly linked to nutrient sensing and metabolic transitions. Its substrate specificity for phosphosites with SxS or RxxS motifs and strict dependence on Mn(2+) ions enable its regulatory function across fasting-feeding states. Mutations in PPM1K are associated with mild variant maple syrup urine disease (MSUDMV, MIM 615135), reflecting the protein's essential role in BCAA catabolic homeostasis (UniProt: Q8N3J5).

PPM1K is elevated in Alzheimer's disease brain tissue relative to age-matched controls, with a mean log2 fold-change of 0.547 measured in post-mortem AD samples across subcellular fractions (Chaparral AD proteomics). This upregulation may reflect altered metabolic substrate utilization or mitochondrial dysregulation characteristic of AD pathology, though the mechanistic relationship remains to be clarified.