Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1389183 (autodigestion)
 317 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using components purified from human plasma, we have examined the effects of C1 inhibitor (C1 INH), the primary inhibitor of activated Hageman Factor (HFa) and Hageman factor fragment (HFf), on Hageman Factor (HF) autoactivation. When Hageman factor was exposed to a negatively charged surface, provided by either a glass cuvette or dextran sulfate, the addition of C1 INH gave a dose-dependent inhibition of the activity observed. The ability of C1 INH to decrease the maximal enzymatic activity generated was markedly temperature dependent with inhibition increasing as the temperature was raised from 4 degrees C to 37 degrees C. Although the rates of both autoactivation and inhibition were decreased at lower temperatures (4 degrees C), the latter rate was more sensitive to temperature modulation. When HF (final concentration 1 mumol/L) was incubated with C1 INH (0.54, 1.07, and 2.14 mumol/L) in the absence of an initiating surface, no increases in enzymatic activity were observed for up to 48 hours regardless of the C1 INH concentration. However, SDS polyacrylamide gel electrophoresis of the incubation mixture revealed that HF autodigestion had occurred by 48 hours despite the presence of C1 INH. In addition, the appearance of a new band suggested that a complex had been formed between the inhibitor and activated HF. Our findings indicate that C1 INH does not prevent HF autoactivation but rather inactivates the products of HF autodigestion.
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PMID:The effect of C1 inhibitor upon Hageman factor autoactivation. 348 56

The concentration of bradykinin in human plasma depends on its relative rates of formation and destruction. Bradykinin is destroyed by two enzymes: a plasma carboxypeptidase (anaphylatoxin inactivator) removes the COOH-terminal arginine to yield an inactive octapeptide, and a dipeptidase (identical to the angiotensin-converting enzyme) removes the COOH-terminal Phe-Arg to yield a fragment of seven amino acids that is further fragmented to an end product of five amino acids. Formation of bradykinin is initiated on binding of Hageman factor (HF) to certain negatively charged surfaces on which it autoactivates by an autodigestion mechanism. Initiation appears to depend on a trace of intrinsic activity present in HF that is at most 1/4000 that of activated HF (HFa); alternatively traces of circulating HFa could subserve the same function. HFa then converts coagulation factor XI to activated factor XI (XIa) and prekallikrein to kallikrein. Kallikrein then digests high-molecular-weight kininogen (HMW-kininogen) to form bradykinin. Prekallikrein and factor XI circulate bound to HMW-kininogen and surface binding of these complexes is mediated via this kininogen. In the absence of HMW-kininogen, activation of prekallikrein and factor XI is much diminished; thus HMW-kininogen has a cofactor function in kinin formation and coagulation. Once a trace of kallikrein is generated, a positive feedback reaction occurs in which kallikrein rapidly activates HF. This is much faster than the HF autoactivation rate; thus most HFa is formed by a kallikrein-dependent mechanism. HMW-kininogen is also therefore a cofactor for HF activation, but its effect on HF activation is indirect because it occurs via kallikrein formation. HFa can be further digested by kallikrein to form an active fragment (HFf), which is not surface bound and acts in the fluid phase. The activity of HFf on factor XI is minimal, but it is a potent prekallikrein activator and can therefore perpetuate fluid phase bradykinin formation until it is inactivated by the C1 inhibitor. In the absence of C1 inhibitor (hereditary angioedema) HFf may also interact with C1 and activate it enzymatically. The resultant augmented bradykinin formation and complement activation may account for the pathogenesis of the swelling characteristic of hereditary angioedema and the serologic changes observed during acute attacks.
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PMID:Hageman factor-dependent pathways: mechanism of initiation and bradykinin formation. 655 44

We have compared the cleavage of purified human Hageman factor (HF) by an activated form of human Hageman factor (HFa) (autodigestion) and by kallikrein. In each case, an initial cleavage is seen which produces HFa with Mr = 80,000 consisting of a heavy chain of Mr = 52,000 disulfide-linked to a light chain of Mr = 28,000. As autodigestion proceeds, HFa is shown to be further digested to yield a major active product at a molecular weight of 40,000 as well as Hageman factor fragment (HFf), which appear as two closely related molecular species of Mr = 28,000 and 30,000. A minor active product of Mr = 70,000 is also seen. Upon reduction of each of the active forms, a chain with Mr = 28,000 is released which contains the active site. HF digestion by kallikrein results in rapid formation of HFa, followed by HFa digestion to HFf and degradation of the heavy chain region to an inactive fragment at 40,000 daltons, which is then degraded to an end product of Mr = 36,000. Production of the active species with Mr = 40,000 and 70,000 is greatly diminished when kallikrein is the HF activator, and these active forms are shown to be formed primarily by autodigestion. The time course of HFa and HFf formation indicates that the rate of activation of Hageman factor by kallikrein is much faster than the rate of autoactivation; the addition of high molecular weight kininogen increases the rate of HFa and HFf formation as well as the extent of HG digestion. These data indicate that HFa is the active intermediate from which other active species are derived. The patterns of HF and HFa digestion by HFa and kallikrein are distinct; a model for HF digestion is presented.
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PMID:The cleavage and formation of activated human Hageman factor by autodigestion and by kallikrein. 691 37