Lysine binding site

The plasminogen molecule contains several sites that specifically bind a number of antifibrinolytic amino acids, such as lysine [56-87-1] and S-aminocaproic acid [60-32-2] (EACA). These sites are known as lysine binding sites (LBS), and are localized mainly to the A or heavy chain of the molecule. One is located in K4 and at least one more is in K1 through K3. One LBS, which is beheved to reside in Kl, has a stronger affinity for EACA, whereas the others have a weaker affinity. The LBS are important for the interaction of plasminogen with several components of the endogenous fibrinolytic system. 

The lysine binding sites on free Lys-plasminogen or free Lys-plasmin are susceptible to inhibition by a2 plasmin, the primary inhibitor of plasmin, because these sites are not protected by interaction with fibrin. However, when Lys-plasminogen is tightly bound to the fragment E domain, it is rapidly activated by the... 

Since apo(a) contains kringles that are almost identical to the kringles in plasminogen, with a moderate affinity to fibrin through their lysine-binding sites, the possible role of Lp(a) in fibrinolysis could be at that level (R17, R18). 

Tranexamic acid (Cyklokapron, Transamin) is a synthetic derivative of the amino acid lysine. It exerts its antifibrinolytic effect through the reversible blockade of lysine binding sites on plasminogen molecules. 

Tranexamic acid produces an antifibrinolytic effect by blocking the lysine binding site on plasminogen which is essential for binding to fibrin and thereby prevents the activation of plasminogen on the surface of fibrin. 

Figure 17.4 Antifibrinolytic action of the lysine analogues. Normally, plasminogen binds to fibrin at a lysine-binding site and is converted in the presence of tissue plasminogen activator (tPA) to piasmin. The lysine analogues block the lysine-bIndIng site and prevent access of plasminogen to tfie fibrin molecule. Reproduced from Dunn O, Goa KL. Drugs 1999 57 1005-32, with permission.)...

Lijnen HR, Hoylaerts M, Collen D. Isolation and characterization of human plasma protein with high affinity for lysine binding sites in plasminogen. J Biol Chem 1980 225 10,214-10,222. 

Cockell, C.S., et ah. Evidence that the conformation of unliganded human plasminogen is maintained via an intramolecular interaction between the lysine-binding site of kringle 5 and the N-terminal peptide. Biochem J 1998, 333, 99-105. 

Fig. 6. A model of lipoprotein(a) assembly. Lipoprotein(a) assembly proceeds through a two-step model in which an initial non-covalent interaction between apo(a) and apo B precedes specific disulfide bond formation. The initial non-covalent interaction is mediated by interaction between two lysine residues (K and K ) within the N-terminal 18% of apo BlOO and the weak lysine-binding sites (LBS) in apo(a) kringle IV types 7 and 8. A disulfide bond is subsequently formed between a cysteine in the C-terminal region of apo BlOO and apo(a). The types of kringle IV are indicated by boxed numbers. From Dr. J.P. Segrest, University of Alabama at Birmingham Medical Center, with premission.

LDLs and apo(a) have been secreted. Initially, two lysine residues (Lys-680 and Lys-690) in the N-terminal 18% of apo BlOO interact non-covalently with a lysine-binding site in apo(a) (Fig. 6) (M.L. Koschinsky, 2001). Next, the C-terminal region of apo BlOO interacts non-covalently with amino acids 4330-4397 of apo(a), and a disulfide bond is subsequently formed between apo BlOO and apo(a). The kringle-4 domain of apo(a) can be present in a variable number of copies (3 to >40), resulting in size heterogeneity of lipoprotein(a). Generally, the plasma level of lipoprotein(a) is inversely correlated with apo(a) isoform size (i.e., the number of kringles). An inverse relationship has also been observed between apo(a) isoform size and the efficiency of covalent association of apo(a) with apo B. Consequently, it has been proposed that this relationship contributes to the inverse correlation between apo(a) isoform size and plasma lipoprotein(a) levels [22]. 

Vidler, L.R., Brown, N, Knapp, S, and Hoelder, S. (2012) Druggability analysis and structural classification of bromod-omain acetyl-lysine binding sites. /. Med. Chem., 55 (17), 7346-7359. 

Various other compounds are used clinically as antifibrinolytics. As mentioned above, aprotinin, a small polypeptide that inhibits plasmin, trypsin and kallikrein, is often used in coagulation tlierapy and in fibrin sealant formulations (Trautschold et al, 1967). In the latter applications, the aprotinin serves to delay the fibrinolytic action of plasmin until the fibrin has fiilfilled its function. A monoamino carboxylic acid, e-amino caproic acid, is similar in structure to lysine and interacts with the active kringles or lysine-binding sites of plasminogen and plasminogen activators to inhibit their binding to fibrin and thus their fibrinolytic actions (Thorsen, 1992). This compound is also used in some clinical applications. 

Once the generation of plasmin is completed, fibrin is cleaved into small soluble monomers, introducing carboxy-terminal lysine residues. Both tPA and uPA contain lysine binding sites that permit further binding to fibrin and thus regeneration of plasmin and more fibrin removal. 

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