Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteins of the plasma kinin-forming cascade bind to endothelial cells and activation of the cascade can be initiated along the surface. The light chain of high molecular weight kininogen (HK) (domain 5) and factor XII bind to gC1qR, the heavy chain of HK (domain 3) binds to cytokeratin 1 and the interactions are zinc dependent. Prekallikrein binds to domain 6 of HK. Antisera to gC1qR and cytokeratin 1 inhibit binding and activation. Incubation of normal plasma with endothelial cells leads to gradual conversion of prekallikrein to kallikrein, while plasma deficient in factor XII or HK are inactive within a 2-hour time frame. Thus factor XII is critical for activation to proceed. Augmentation of these reactions may occur when C1 inhibitor is functionally deficient or with ACE inhibitors which also inhibit kininases.
 ...
PMID:Activation of the plasma kinin forming cascade along cell surfaces. 1130 9

The plasma kinin-forming cascade can be activated by contact with negatively charged macromolecules leading to binding and autoactivation of factor XII, activation of prekallikrein to kallikrein by factor XIIa, and cleavage of high molecular weight kininogen (HK) by kallikrein to release the vasoactive peptide bradykinin. Once kallikrein formation begins, there is rapid cleavage of unactivated factor XII to factor XIIa, and this positive feedback is favored kinetically over factor XII autoactivation. Examples of surface initiators that can function in this fashion are endotoxin, sulfated mucopolysaccharides, and aggregated Abeta protein. Physiological activation appears to occur along the surface of endothelial cells both by the aforementioned contact-initiated reactions as well as bypass pathways that are independent of factor XII. Factor XII binds primarily to cell surface u-PAR (urokinase plasminogen activator receptor); HK binds to gC1qR via its light chain (domain 5) and to cytokeratin 1 by its heavy chain (domain 3) and, to a lesser degree, by its light chain. Prekallikrein circulates bound to HK (as does coagulation factor XI), and prekallikrein is thereby brought to the surface as HK binds. All cell-binding reactions are dependent on zinc ion. Endothelial cells (HUVECs) have bimolecular complexes of u-PAR-cytokeratin 1 and gC1qR-cytokeratin 1 at the cell surface plus free gC1qR, which is present in substantial molar excess. Factor XII appears to interact primarily with the u-PAR-cytokeratin 1 complex, whereas HK binds primarily to the gC1qR-cytokeratin 1 complex and to free gC1qR. Release of endothelial cell heat shock protein 90 (Hsp90) or the enzyme prolylcarboxypeptidase leads to activation of the bradykinin-forming cascade by activating the prekallikrein-HK complex. In contrast to factor XIIa, neither will activate prekallikrein in the absence of HK, both reactions require zinc ion, and the stoichiometry suggests interaction of one molecule of Hsp90 (for example) with one molecule of prekallikrein-HK complex. The presence of factor XII, however, leads to a marked augmentation in reaction rate via the kallikrein feedback as well as to a change to classic enzyme-substrate kinetics. The circumstances in which activation is initiated by factor XII autoactivation or by these factor XII bypasses are yet to be defined. The pathologic conditions in which bradykinin generation appears important include hereditary and acquired C1 inhibitor deficiency, cough and angioedema due to ACE inhibitors, endotoxin shock, with contributions to conditions as diverse as Alzheimer's disease, stroke, control of blood pressure, and allergic diseases.
 ...
PMID:Formation of bradykinin: a major contributor to the innate inflammatory response. 1570 22

Anaphylaxis is a term that implies symptoms that are present in many organs, some of which are potentially fatal. The pathogenic process can either be IgE-dependent or non-IgE-dependent; the latter circumstance may be referred to as anaphylactoid. Bradykinin is frequently responsible for the manifestations of IgE-independent reactions. Blood levels may increase because of overproduction; diseases such as the various forms of C1 inhibitor deficiency (hereditary or acquired) or hereditary angioedema with normal C1 inhibitor are examples in this category. Blood levels may also increase because of an abnormality in bradykinin metabolism; the angioedema due to ACE inhibitors is a commonly encountered example. Angioedema due to bradykinin has the potential to cause airway obstruction and asphyxia as well as severe gastrointestinal symptoms simulating an acute abdomen. Formation of bradykinin in plasma is a result of a complex interaction among proteins such as factor XII, prekallikrein, and high molecular weight kininogen (HK) resulting in HK cleavage and liberation of bradykinin. These proteins also assemble along the surface of endothelial cells via zinc-dependent interactions with gC1qR, cytokeratin 1, and u-PAR. Endothelial cell expression (or secretion) of heat-shock protein 90 or prolylcarboxypeptidase can activate the prekallikrein-HK complex to generate bradykinin in the absence of factor XII, however factor XII is then secondarily activated by the kallikrein that results. Bradykinin is destroyed by carboxypeptidase N and angiotensin-converting enzyme. The hypotension associated with IgE-dependent anaphylaxis maybe mediated, in part, by massive proteolytic digestion of HK by kallikreins (tissue or plasma-derived) or other cell-derived kininogenases.
 ...
PMID:Kinins, airway obstruction, and anaphylaxis. 2051 82

The plasma bradykinin-forming cascade and the complement pathways share many elements, including cross-activation, common control mechanisms, and shared binding proteins. The C1 inhibitor (C1 INH) is not only the inhibitor of activated C1r and C1s, but it is the key control protein of the plasma bradykinin-forming cascade. It inhibits the autoactivation of Factor XII, the ability of Factor XIIa to activate prekallikrein and Factor XI, the activation of high molecular weight kininogen (HK) by kallikrein, and the feedback activation of Factor XII by kallikrein. Thus in the absence of C1 INH (hereditary angioedema or acquired C1 INH deficiency) there is unimpeded formation of bradykinin leading to angioedema. Activated Factor XII (Factor XIIa, 80,000 kDa) is further cleaved by kallikrein or plasmin to yield Factor XII fragment (Factor XIIf, 30,000 kDa) and Factor XIIf can activate the C1r subcomponent of C1, particularly when C1 INH (which inhibits Factor XIIf) is absent. Once bradykinin is formed, it causes vasodilatation and increased vascular permeability by interaction with constitutively expressed B-2 receptors. However degradation of bradykinin by carboxypeptidase N (in plasma) or carboxypeptidase M (on endothelial cells) yields des-arg-9 (Kerbiriou and Griffin, 1979) bradykinin which interacts with B-1 receptors. B-1 receptors are induced in inflammatory states by cytokines such as Interleukin 1 and its interaction with bradykinin may prolong or perpetuate the vascular response until bradykinin is completely inactivated by angiotensin converting enzyme or aminopeptidase P, or neutral endopeptidase. The entire bradykinin-forming cascade is assembled and can be activated along the surface of endothelial cells in zinc dependent reactions involving gC1qR, cytokeratin 1, and the urokinase plasminogen activated receptor (u-PAR). Although Factors XII and HK can be shown to bind to each one of these proteins, they exist in endothelial cells as two bimolecular complexes; gC1qR-cytokeratin 1, which preferentially binds HK, and cytokeratin 1-u-PAR which preferentially binds Factor XII. The gC1qR, which binds the globular heads of C1q is present in excess and can bind either Factor XII or HK however the binding sites for HK and C1q have been shown to reside at opposite ends of gC1qR. Activation of the bradykinin-forming pathway can be initiated at the cell surface by gC1qR-induced autoactivation of Factor XII or direct activation of the prekallikrein-HK complex by endothelial cell-derived heat-shock protein 90 (HSP 90) or prolylcarboxypeptidase with recruitment or Factor XII by the kallikrein produced.
 ...
PMID:The plasma bradykinin-forming pathways and its interrelationships with complement. 2058 91

In this work, genes encoding gelatinase (gelE) and serine proteinase (sprE), two extracellular proteases produced by Enterococcus faecalis DBH18, were cloned in the protein expression vector pMG36c, containing the constitutive P32 promoter, generating the recombinant plasmids pCG, pCSP, and pCGSP encoding gelE, sprE, and gelE-sprE, respectively. Transformation of noncaseinolytic E. faecalis P36, E. faecalis JH2-2, E. faecium AR24, and E. hirae AR14 strains with these plasmids permitted detection of caseinolytic activity only in the strains transformed with pCG or pCGSP. Complementation of a deletion (knockout) mutant of E. faecalis V583 for production of gelatinase (GelE) with pCG unequivocally supported that gelE is responsible for the caseinolytic activity of the transformed strain grown in bovine skim milk (BSM). RP-HPLC-MS/MS analysis of hydrolysates of transformed Enterococcus spp. strains grown in BSM permitted the identification of 38 major peptide fragments including peptides with previously reported angiotensin converting enzyme-inhibitory activity (ACE-IA), antihypertensive activity, and antioxidant activity.
...
PMID:Genetic and biochemical evidence that recombinant Enterococcus spp. strains expressing gelatinase (GelE) produce bovine milk-derived hydrolysates with high angiotensin converting enzyme-inhibitory activity (ACE-IA). 2487 44