Plasminogen (Pg) is synthesized in the liver and circulates in plasma at a concentration of ~200 micrograms/milliliters (~2.3 micrometers). Plasminogen is a single-chain glycoprotein of ~88 kDa that consists of a catalytic domain followed by five kringle structures. Within these kringle structures are four low-affinity lysine binding sites and one high-affinity lysine binding site. It is through these lysine binding sites that plasminogen binds to fibrin and to alpha2-antiplasmin. Native plasminogen (glu-plasminogen) exists in two variants that differ in their extent of glycosylation, and each variant has up to six isoelectric forms with respect to sialic acid content, for a total of 12 molecular forms. Activation of glu-plasminogen by the plasminogen activators urokinase (UPA), or tissue plasminogen activator (tPA) occurs by cleavage after residue Arg⁵⁶⁰to produce the two-chain active serine protease plasmin. In a positive feedback reaction, the plasmin generated cleaves an ~8 kDa peptide from glu-plasminogen, producing lys⁷⁷-plasminogen which has a higher affinity for fibrin and when bound is a preferred substrate for plasminogen activators such as urokinase. Additional activators of plasminogen include kallikrein and activated factor XII. The primary inhibitor of plasmin in plasma is alpha2-antiplasmin. Other physiological inhibitors of plasmin include alpha2-macroglobulin and antithrombin.