Many biosynthetic reactions are coupled to the cleavage of ATP to yield AMP and pyrophosphate. These reactions are typically freely reversible when carried out with purified substrates and enzymes in vitro. In vivo, however, the pyrophosphate is rapdily and essentially irreversibly hydrolyzed by a ubiquitous inorganic pyrophosphatase. This hydrolysis has the effect of pulling the first reaction strongly in the direction of biosynthesis, at the expense of two high-energy phosphate bonds. Studies of human cells have identified two forms of the enzyme, one localized to the cytosol and the other to the mitochondrial matrix (Raja et al. 1981).Pyrophosphatase activity has likewise been shown for LHPP (Phospholysine phosphohistidine inorganic pyrophosphate phosphatase). Recent work indicates that LHPP acts as well to dephosphorylate phosphohistidine residues, that variants of it may be associated with suceptibilty to depression, and that it may be a tumor suppressor (reviewed in Gohla 2019), although without the molecular detail needed for a Reactome annotation.