Pnkd

Rat Pnkd (paroxysmal nonkinesigenic dyskinesia protein, also called myofibrillogenesis regulator 1) encodes a glyoxalase-II-related metallo-beta-lactamase-fold protein of the PNKD-related subfamily, distinct from the canonical hydroxyacylglutathione hydrolase HAGH. The 369-residue B4F7D2 product is an alternatively spliced Pnkd isoform (identical to the Ensembl model A0A0G2JTS8) that is collinear with the brain-enriched long isoform PNKD-L over residues 1-340, including the N-terminal region that carries the disease-mutated alanines and the hydrophobic segment, and the complete metallo-beta-lactamase domain with all seven zinc ligands; its last 29 residues are a divergent tail that replaces the C-terminal half of the HAGH_C helical domain. PNKD-L proteins are probable zinc-dependent thioesterases: they hydrolyse the glyoxalase-II substrate S-D-lactoylglutathione only at a very low rate and cannot replace HAGH in vivo, so the physiological substrate, probably another alpha-hydroxythioester, is unknown. In neurons PNKD-L is membrane-associated at synapses, binds the active-zone proteins RIM1 and RIM2 and restrains synaptic-vesicle exocytosis; mitochondrial versus plasma-membrane localization of the long isoform is disputed. Whether this particular alternative product is expressed as protein, folds and shares these properties has not been tested.