A Fundamental Modulator of Vascular Function

Enzymes are critical components of every cell, and their activity is tightly regulated by substrate availability, competitive or allosteric inhibitors, and the presence of cofactors. Enzymatic activity may also be modulated by posttranslational modifications, such as cleavage of the polypeptide chain or phosphorylation/dephosphorylation of amino acid residues. Under pathological conditions, other modifications, such as oxidation or nitration, may occur, thereby disturbing enzyme activity. Beside these well-known principles of enzyme biology, temperature and pH are crucial determinants of enzyme activity, but corresponding changes in the cellular environment have attracted surprisingly little attention as putative disease mechanisms. Changes in intracellular pH can affect the ionization state of acidic or basic amino acid residues, which may disrupt ionic bonds that help to determine the 3-dimensional shape of the enzyme. These conformational alterations can lead to inactivity of the enzyme, because they may prevent binding of the substrate or cofactors. In addition, the modification of intracellular pH may change the charge properties of the substrate, so that either the substrate cannot bind to the active site or it cannot undergo catalysis.