Protein phosphatase 1K, mitochondrial (PPM1K)

Protein phosphatase 1K, mitochondrial (PPM1K), is a mitochondrial serine/threonine phosphatase that is strictly dependent on Mg2+ or Mn2+ ions for its activity[1][2][3]. It serves a central regulatory role in mitochondrial metabolism by dephosphorylating and activating the branched-chain α-ketoacid dehydrogenase complex (BCKDH), thereby facilitating the catabolism of branched-chain amino acids (leucine, isoleucine, and valine)[1][2][3]. Through modulation of BCKDH activity, PPM1K is essential for the maintenance of metabolic homeostasis related to BCAA, glucose, and lipid metabolism. Dysfunction or genetic variation in PPM1K can lead to disorders such as maple syrup urine disease, insulin resistance, cardiovascular diseases, and neurodegenerative conditions such as Alzheimer’s disease[1][2][3]. PPM1K also regulates mitochondrial permeability transition pore opening, thereby influencing apoptosis and, under certain circumstances, ferroptosis in neuronal cells[2][6]. Emerging research suggests its therapeutic potential in metabolic, cardiovascular, and neurological diseases, with some investigational compounds targeting its pathway in preclinical studies[2][6].

Other names

Protein phosphatase, Mg2+/Mn2+ dependent 1KPP2C-type mitochondrial phosphoprotein phosphataseProtein phosphatase 2C kappaBranched-chain α-ketoacid dehydrogenase phosphatasePP2CmPP2CkappaPP2C-KappaBCKDHBDPPTMPHPTMPDKFZp761G058[3-methyl-2-oxobutanoate dehydrogenase (2-methylpropanoyl-transferring)]-phosphatase, mitochondrialMSUDMVUG0882E07

BT2 acts by inhibiting BCKDK, thereby indirectly enhancing PPM1K-mediated dephosphorylation and activation of the BCKD complex. Reduction of BCAA levels and associated toxic metabolites via enhanced BCAA oxidation.