PPM1K

PPM1K, or protein phosphatase Mg2+/Mn2+-dependent 1K, is a serine/threonine phosphatase belonging to the Mg2+/Mn2+-dependent protein phosphatase (PPM) family. It is localized to mitochondria and is found in various tissues, with notable expression in liver and skeletal muscle. As a catalytic enzyme, PPM1K participates in the regulation of mitochondrial metabolism through dephosphorylation of specific target proteins.

The primary well-characterized function of PPM1K is the dephosphorylation and activation of the branched-chain α-ketoacid dehydrogenase complex (BCKDH). BCKDH activity is controlled by phosphorylation: BCKDK kinase adds phosphate groups to the E1α subunit, inhibiting the complex, while PPM1K removes those phosphates, restoring BCKDH activity. Active BCKDH promotes the catabolism of branched-chain amino acids (valine, leucine, and isoleucine), linking PPM1K activity to the regulation of cellular energy production and amino acid homeostasis.

Structurally, PPM1K contains the characteristic catalytic motifs of the PPM family and possesses a mitochondrial targeting sequence that directs it to the mitochondrial matrix, where it encounters its substrates. Regulation of PPM1K activity can be influenced by cellular energy status and mitochondrial conditions, and it functions in concert with BCKDK, the kinase that phosphorylates and inhibits BCKDH.

Clinical and research interest in PPM1K centers on its role in branched-chain amino acid metabolism and its potential contribution to metabolic disorders where BCAA metabolism is disrupted. Dysregulation of BCAA catabolism is linked to metabolic diseases, and PPM1K is a key component in the mitochondrial control of this pathway.