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Function
Lactate Dehydrogenase is a large, two domain- protein which catalyzes the conversion of pyruvate to lactate under anaerobic conditions. This conversion is coupled with the reduction of NAD+ to form the electron carrying NADH. Muscular lactate dehydrogenase is involved in the Cori Cycle where it transports newly synthesized lactate to the liver. Liver lactate dehydrogenase converts the lactate back to pyruvate in order to provide the precursor for gluconeogenesis.
Disease
Relevance
Structural highlights
Lactate dehydrogenase is a tetramer protein which can form five different isoenzymes. Lactate dehydrogenase subunits exist primarily in two isoforms: M and H, which differ in a single residue. The M subunit contains an alanine while the H subunit contains a glutamine. The combination of subunits defines which isoenzyme is formed and indicates where the enzyme will be present in the body. Lactate dehydrogenase A is composed of four M subunits. The subunits can adopt two conformations, open and closed, which determine the subunits activity.
The active site contains three different binding pockets to accommodate the substrate, Nicotinamide, and adenine.
The substrate binding pocket relies on heavily on hydrogen binding and ionic interactions in order to effectively bind the substrate. Upon substrate binding, the substrate binding pocket undergoes a conformation change where interactions between the substrate or inhibitor and a glutamine residue (Q99) essentially pull the active loop closed.
The nicotinamide and adenine binding pockets work together to sufficiently bind NADH. Both binding pockets implement hydrogen bonding and hydrophobic interactions with their ligand fragment. In addition to the interactions within the binding pockets, NADH is also supported by ionic forces between arginine (R99) and the pyrophosphate groups.
The hydroxyl groups of NADH's ribose fragments interacts with the H-bond network created by the substrate and asparagine (N137).
