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PubMed1987

Redistribution of plasma zinc between albumin and alpha 2-macroglobulin in pregnancy.

A cross sectional study involving 12 non-pregnant and 71 pregnant women was undertaken to determine the effect of pregnancy on the concentration in the plasma of zinc and copper and the binding of zinc to plasma proteins. The results confirmed the relationship observed by others between reduced zinc and increased copper concentrations in the plasma of pregnant women. These changes occurred during the first and second trimesters of pregnancy. The concentrations of plasma albumin-bound zinc and alpha 2-macroglobulin-bound zinc were observed to decrease 27.5% and 52.1%, respectively, during the second and third trimesters of pregnancy. During the second and third trimesters of pregnancy a redistribution of zinc occurred within the total plasma zinc pool between albumin and alpha 2-macroglobulin. In the process, the contribution of albumin-bound plasma zinc pool was increased 16.2%, whereas the contribution of alpha 2-macroglobulin-bound plasma zinc was decreased 31.6%. The former is considered more "dynamic" than the latter and the observed shift of zinc within the plasma pool to the albumin-bound state, during pregnancy, may represent an adaptive response designed to offset any adverse effects of reduced maternal plasma zinc concentrations on the developing fetus.

Copper↗

PubMed1976

Action of fibrin-stabilizing factor on cold-insoluble globulin and alpha2-macroglobulin in clotting plasma.

Experiments were performed to investigate whether proteins other than fibrin are substrates for activated fibrin-stabilizing factor (FSF, blood coagulation Factor XIII, plasma transglutaminase) in clotting whole plasma. Three fluorescently labeled polypeptides were identified in serum prepared by clotting normal, but not FSF-deficient, plasma in the presence of the fluorescent amine, N-(5-aminopentyl)-5-dimethyl-aminonaphthalene-1-sulfonamide (dansylcadaverine). The major labeled polypeptide had a Mr (estimated by polyacrylamide gel electrophoresis in sodium dodecyl sulfate) of 1.6 times 10(5) and was found in the protein fraction precipitated by 33 to 50% saturated ammonium sulfate. The second had a Mr of 2.0 times 10(5), was found in the protein fraction insoluble in 33% saturated ammonium sulfate, and was precipitated by gamma-globulin directed against cold-insoluble globulin. The third had a Mr of 1.1 times 10(5) and was precipitated by 33 to 50% saturated ammonium sulfate. All three polypeptides were found in the first protein peak when labeled serum was chromatographed on Sephadex G-200. The immunoprecipitin arc containing alpha2-macroglobulin was fluorescent when labeled serum was analyzed by immunoelectrophoresis. These results indicate that alpha2-macroglubulin, cold-insoluble globulin, and an unidentified third protein with a subunit of Mr = 1.1 times 10(5) are transamidated by FSF in clotting plasma. The concentration of cold-insoluble globulin was decreased in serum formed at 37 degrees from normal, but not from FSF-deficient, plasma. The depletion of cold-insoluble globulin in normal serum was partially blocked by clotting in the presence of dansylcadaverine and completely blocked by clotting in the absence of calcium ions. Sera formed at 2 degrees from both normal and FSF-deficient plasma contained less cold-insoluble globulin than plasma. Polyacrylamide gel electrophoresis in sodium dodecyl sulfate of clots formed at 2 degrees demonstrated cross-linking of cold-insoluble globulin to fibrin in the normal, but not the FSF-deficient, sample. The serum concentration of alpha2-macroglobulin was the same as the plasma concentration irrespective of the conditions of clotting. Thus, the experiments suggest that FSF catalyzes the cross-linking of cold-insoluble globulin (but not alpha2-macroglobulin) to fibrin in clotting plasma.

Binding Sites↗

PubMed1975

A proposed role for alpha1 macroglobulin in the promotion of alpha1 acute-phase globulin synthesis by the perfused rat liver.

The effects of intravenously administered rat alpha1 macroglobulin (alpha1M), alone and in combination with pancreatic trypsin, on the synthesis of alpha1 acute-phase globulin (alpha1AP globulin) have been measured in the isolated perfused rat liver 24 h after injection. Maximum promotion (approximately five-fold) of alph1AP globulin synthesis was observed after administration of alpha1M complexed with trypsin or alpha1M alone, which after purification had lost most of its trypsin-protein-esterase (T.P.E.) activity. Slightly lesser but still significant degrees of enhancement (approximately four-fold) of alpha1AP globulin synthesis resulted from the injection of alpha1M alone or complexed with trypsin, which after purification had retained sitnificant T.P.E. activity. All these responses were greater than those generated by injection of trypsin or plasma alone, or rabbit plasma complexed with trypsin. However, the synthetic response did not reach the maximum rate observed 24 h after an intramuscular injection or sterile turpentine. An hypothesis is proposed for the role of alpha1 macroglobulin (and its homologue in man, alpha2 macroglobulin) in the mediation of the acute-phase synthetic response by the liver. This predominantly intravascular glycoprotein serves as the principal circulatory porteinase binder. Proteinases released in response to tissue injury, necrosis or inflammation would be bound and inactivated by alpha1M, and in turn the alpha1M-proteinase complex would stimulate the liver to synthesize a number of acute-phase proteins. Certain of these, e.g. alpha2 acute-phase globulin also possess proteinase binding activity and, being of low molecular weight, would be more effective than alpha1M in the inactivation of released tissue enzymes at extravascualr sites. The data presented in this paper are compatible with this biphasic role for plasma proteinase inhibitors in the biological response to injury.

Albumins↗

PubMed1980

[Measurement of alpha 2-macroglobulin in human sera by quantitative inhibition of an acid staphylococcal protease (author's transl)].

Concentrations of alpha 2-macroglobulin could be determined in the sera of 215 blood donors and 94 patients with various internal diseases by quantitative inhibition of an acid protease from Staphylococcus aureus, M 135 (fig. 1, 2). The determinations agreed closely with those obtained by immunodiffusion (tab. 1, fig. 3). However, the alpha 2-macroglobulin-measurements by the protease method required only 4 h and 40 microliter serum. This procedure would also be suitable for the determination of alpha 2-macroglobulin in sera from experimental and domestic animals.

Humans↗

PubMed1981

Clearance and binding of two electrophoretic "fast" forms of human alpha 2-macroglobulin.

These studies explore the role of conformational change and exposed carbohydrate residues in the clearance of alpha 2-macroglobulin-trypsin (alpha 2M-T) complexes in the mouse. Human alpha 2-macroglobulin (alpha 2M) was purified and demonstrated to be homogeneous in the electrophoretic "slow" form. Two conformationally altered derivatives, alpha 2M-T and alpha 2-macroglobulin-methylamine (alpha 2M-MeNH2), were prepared and demonstrated to exist in the electrophoretic "fast" form. Radiolabeled alpha 2M-T and alpha 2M-MeNH2 were cleared rapidly with a half-life of 2-4 min following injection into mice. Radiolabeled native alpha 2M, however, remained in the circulation with a half-life of several hours. Both alpha 2M-T and alpha 2M-MeNH2 bound specifically to mouse peritoneal macrophages at 4 degrees C and occupancy of receptor sites increased with increasing time and radioligand concentration. Excess amounts of unlabeled alpha 2M-T or alpha 2M-MeNH2 cross-completed with trace amounts of the other in both clearance studies and binding assays, indicating that both derivatives were removed by the same receptor pathway. The clearance and binding of alpha 2M-T and alpha 2M-MeNH2 were not inhibited by excess amounts of unlabeled asialoorosomucoid, fucosyl-bovine serum albumin, mannosyl-BSA, or N-acetylglucosaminyl-BSA. Our results indicate that the clearance pathway removing alpha 2M-T complexes from the circulation recognizes a fundamental conformational change in alpha 2M secondary to protease binding, which can also be induced by exposure to methylamine. Therefore, other chemical or physical alterations that occur in alpha 2M upon binding trypsin, apart from the conformational change also present in alpha 2M-MeNH2, do not seem necessary for the recognition of alpha 2M-T by cells in the clearance pathway. In addition, this pathway appears distinct from several systems already described mediating clearance of glycoproteins through recognition of terminal galactose, fucose, N-acetylglucosamine, or mannose on oligosaccharide side chains.

Animals↗

PubMed1982

Characterization of growth-inhibitory activities associated with an alpha-macroglobulin of mice.

An alpha-macroglobulin (AMG) of similar size and proteinase-binding activity as those of human, alpha 2-macroglobulin was purified to homogeneity from mouse plasma. Even after additional purification steps, AMG still retains a growth-inhibitory activity and a more complex subunit structure than does human alpha 2-macroglobulin. AMG can inhibit the DNA synthesis of all types of murine tumor cells tested in vitro. This activity is cytostatic, dose dependent, and unaffected by the serum concentration in culture. Because this inhibitory activity is resistant to heat, pH 3, and methylamine, it is apparently unrelated to the proteinase-binding activity which is labile to all these treatments. Furthermore, in contrast to the proteinase-binding activity, the inhibitory activity can be partially removed from AMG by acid dialysis. Gel filtration of the dialysate yields two fractions (Mr 12,000 and 1,000 to 5,000) which potently inhibit murine tumor cells but stimulate both the B- and T-lymphocyte reactivities to mitogens in vitro. The growth-inhibitory activities in these fractions are resistant to digestions by chymotrypsin, RNase, and DNase. We conclude from this study that AMG does not inhibit tumor growth by virtue of its proteinase-binding activity; it may inhibit tumor cells via the small biomediators it carries.

Animals↗

PubMedDate not supplied

[Levels of alpha 1-antitrypsin and alpha 2-macroglobulin in blood serum and its antitryptic capacity].

Immunochemical analysis in combination with gel filtration and isoelectric focusing made it possible to state that in blood serum of healthy people 81.3 +/- 0.5% of administered trypsin is bound with alpha 1-antitrypsin and 18.7 +/- 0.6%--with alpha 2-macroglobulin. The latter is functionally heterogeneous, only 40% of it is bound with trypsin and in the formed complex the antigenic properties of trypsin and alpha 2-macroglobulin are lost. A great number of blood serum alpha 1-antitrypsin cannot fix trypsin. The content of such alpha 1-antitrypsin rises sharply with pathology available. In the immunochemical estimation of the organism inhibitory potential relative to proteolytic enzymes not only the amount of the inhibitor but also its functional activity should be taken into account. The data of immunochemical research of the blood serum isoelectrophoregrams show that the most considerable changes under conditions of pathology occur in alpha 2-macroglobulin.

Humans↗

PubMed1983

Alpha-macroglobulin-induced release of anti-Ig-coated particles from a subpopulation of rabbit B lymphocytes.

Approximately half of the rosettes formed by rabbit Ig+ lymphocytes (B cells) and anti-coated erythrocytes or glutaraldehyde-fixed bacteria are dissociated upon the addition of rabbit serum. Rabbit serum was fractionated and the rosette-dissociating activity was found in purified preparations of rabbit alpha 1- and alpha 2-macroglobulins. Studies designed to elucidate the mechanism of rosette dissociation suggested that the alpha-macroglobulins dissociated rosettes by causing the release or proteolytic cleavage of the membrane proteins complexed with the anti-Ig-coated particles. These data suggest that the alpha-macroglobulins may have a role in the interaction of B lymphocytes with particulate antigens.

Animals↗

PubMed1983

An endopeptidase inhibitor, similar to mammalian alpha 2-macroglobulin, detected in the hemolymph of an invertebrate, Limulus polyphemus.

A protease inhibitory activity has been detected in the hemolymph of the horseshoe crab, Limulus polyphemus. The inhibitor possesses many of the characteristics of vertebrate alpha 2-macroglobulin. The inhibitor, found in the high speed supernatant of Limulus plasma, is sensitive to mild acidification, inhibits a variety of prokaryotic and eukaryotic endopeptidases, and is sensitive to methylamine treatment. Although the inhibitor completely prevents the trypsin-mediated hydrolysis of protein substrates, the hydrolysis of a low molecular substrate by trypsin is unaffected by the inhibitor, a property characteristic of alpha 2-macroglobulin. The striking similarity of the inhibitor to vertebrate alpha 2-macroglobulin, coupled with the fossil record of Limulus, suggests that such protease inhibitors are ancient molecules.

Animals↗

PubMed1984

Primary structure of human alpha 2-macroglobulin. IV. Primary structure of two large CNBr fragments, located in the COOH-terminal part and accounting for 337 residues.

The amino acid sequences have been determined for two CNBr fragments of human alpha 2-macroglobulin which, due to the presence of an uncleaved Hse-Thr bond, form an Mr = 40,000 fragment. These fragments are located in the COOH-terminal part of alpha 2-macroglobulin (CB21, residues 955-1185 and CB22, residues 1186-1291). CB21 contains one glucosamine-based carbohydrate group attached to Asn-14 and one internal disulfide bridge (Cys-102 bound to Cys-150). CB21 and CB22 account for 337 of the 1451 residues of the subunit of alpha 2-macroglobulin.

Amino Acid Sequence↗

PubMed1994

The carboxyl-terminal domain of lipoprotein lipase binds to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and mediates binding of normal very low density lipoproteins to LRP.

Lipoprotein lipase (LPL) binds with high affinity to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and promotes binding, uptake, and degradation of normal triglyceride-rich lipoproteins in a process mediated by LRP (Chappell, D. A., Fry, G. L., Naknitx, M.A., Muhonen, L. E., Pladet, M. W., Iverius, P-H., and Strickland, D. K. (1993) J. Biol. Chem. 268, 14168-14175). To localize the portion of LPL that is responsible for interacting with LRP, fragments of LPL were expressed in bacteria. A fragment of human LPL containing the COOH-terminal domain (residues 313-448, designated LPLC) which lacks the catalytic site was able to bind to LRP. Purified LRP bound specifically to microtiter wells coated with LPL or LPLC with KD values of 2.8 and 5 nM, respectively. The effects of several mutations of LPLC were tested. Mutation of Lys407 to Ala reduced the affinity of LPLC for LRP by approximately 10-fold. Like native LPL, LPLC prevented the binding of activated alpha 2-macroglobulin and the 39-kDa receptor-associated protein to LRP and inhibited the internalization and degradation of activated alpha 2-macroglobulin and receptor-associated protein in cultured fibroblasts. LPLC also bound to 125I-labeled human normal triglyceride-rich lipoproteins and promoted their binding to purified LRP and to cultured cells. Mutation of Trp393 and Trp394 to Ala completely abolished the ability of LPLC to bind to lipoproteins, but had little effect on its interaction with LRP. These data indicate that the COOH-terminal domain of LPL may function both in binding lipoproteins and mediating their interaction with LRP.

Amino Acid Sequence↗

PubMed1993

Isolation and characterization of a novel serine proteinase complexed with alpha 2-macroglobulin from porcine gastric mucosa.

Porcine stomach mucosa was found to contain a 740-kDa protein having endopeptidase activity toward peptide 4-methylcoumaryl-7-amide substrates and low molecular mass peptides. This protein was purified to an apparent homogeneity by a series of chromatographic steps on DEAE-cellulose, Sepharose CL-4B, hydroxylapatite, and fast protein liquid chromatography Mono Q columns. The protein was shown to be a complex of the plasma proteinase inhibitor alpha 2-macroglobulin and a 25-kDa endopeptidase. The enzyme activity was completely inhibited by diisopropyl fluorophosphate, p-amidinophenylmethanesulfonyl fluoride, leupeptin, antipain, bovine pancreatic trypsin inhibitor, soybean trypsin inhibitor, and ovomucoid, indicating that the entrapped enzyme is a serine proteinase. The proteinase could be released from alpha 2-macroglobulin by mild acid treatment and the released enzyme showed activity toward protein substrates. Substrate specificity studies using synthetic and peptide substrates indicated that the enzyme preferentially hydrolyzes Arg-X bonds and, to a much lesser extent, Lys-X bonds, and is apparently distinct from thrombin, kallikrein, plasmin, and other trypsin-like proteinases so far reported including tryptase. Thus, the present enzyme is thought to be a novel type of serine proteinase. The proteinase associated with alpha 2-macroglobulin was also found in porcine intestinal mucosa, but not in plasma.

Amino Acid Sequence↗

PubMed1993

Activation of protein C and its distribution between its inhibitors, protein C inhibitor, alpha 1-antitrypsin and alpha 2-macroglobulin, in patients with disseminated intravascular coagulation.

Activation and inactivation of protein C during the clinical course of disseminated intravascular coagulation (DIC) was studied in three patients by qualitative (Western blotting) and quantitative (ELISA) analysis and the intensity of procoagulant activity monitored by the measurement of thrombin and factor Xa antithrombin III complexes. In one patient, inhibitor complexes of APC with protein C inhibitor (PCI) and alpha 1-antitrypsin (alpha 1-AT) were observed and the latter predominated at presentation. Both disappeared during the development of remission but the loss of alpha 1-AT complexes preceded PCI complexes which on Western blotting appeared to increase in intensity prior to disappearance. The two other patients bled to death from uncontrollable haemorrhage. In both cases, APC/inhibitor complexes with alpha 2-macroglobulin (alpha 2-M) in addition to PCI and alpha 1-AT were detected and persisted until death. Although PCI appeared to be the primary inhibitor in all three cases, alpha 1-antitrypsin and particularly alpha 2-macroglobulin appeared to assume greater roles in the two fatal cases. These data are similar to previous findings in an experimental animal model of DIC that suggested that alpha 2-macroglobulin and alpha 1-antitrypsin become more important inhibitors of APC as the primary inhibitor PCI is consumed in the face of a sustained procoagulant challenge.

Adult↗

PubMedDate not supplied

[Study of alpha 1-antitrypsin and alpha 2-macroglobulin in workers exposed to byssinogenic dusts].

The level of IgG, IgA, IgM, alpha1-antitrypsin and alpha2-macroglobulin was determined by radial immunodiffusion in 27 workmen in the flax processing industry, exposed to the risk of byssinosis and 33 retired workmen with a diagnosis of byssinosis. The control lot included 26 blood donors. A significant increase in IgM, alpha1-antitrypsin and alpha2-macroglobulin levels was noted in the active workmen; the increase was not significant in the retired workmen. The high IgM levels was brought about by the immunological processes taking place under the influence of the antigenic components of the dust inhaled; the increase in antitrypsin and alpha2-macroglobulin was considered as an acute protein reaction to the presence of inflammatory proteases.

Byssinosis↗

PubMed1978

Rotational relaxation of free and protease-bound alpha2-macroglobulin.

The recently described triplet probe depolarization technique has been utilized to investigated the rotational relaxation of free and protease-bound alpha2-macroglobulin. The molecular Stokes radius of the free globulin was found to be 88 A, a value which, when compared to the dry radius, indicates a high degree of hydration. The correlation time of alpha2-macroglobulin does not change after its binding with chymotrypsin, but slightly increases in the presence of plasmin. In the presence of 4 M urea, alpha2-macroglobulin dissociates into subunits and this dissociation does not lead to a release of the bound proteases.

Chymotrypsin↗

PubMed1978

[Effects of serums and plasmas of various species on a protease of Staphylococcus aureus. Human alpha2-macroglobulin as an inhibitor (author's transl)].

Serums and plasmas from various animals and man inhibited 85-100% of the activity of a purified protease from Staphylococcus aureus, strain M 135 (table 1). The inhibitory effects of corresponding serums and plasmas were approximately equal. The inhibition in human serum was caused by alpha2-macroglobulin. On the other hand, alpha1-antitrypsin proved to be ineffective (table 2). The complex alpha2-macroglobulin-protease could be separated by vertical polyacrylamide discelectrophoresis. Immunelectrophoretic analysis revealed no changes by the staphylococcal protease neither on alpha2-macroglobulin, nor on other human serum proteins. Only fibrinogen was split into at least 2 components (fig. 1).

Animals↗

PubMed1996

Addition of purified prostate specific antigen to serum from female subjects: studies on the relative inhibition by alpha 2-macroglobulin and alpha 1-antichymotrypsin.

PURPOSE: Two forms of prostate specific antigen (PSA), 1 complexed to alpha 1-antichymotrypsin and the other a free PSA, are recognized by current commercially available immunoassays. A third form of PSA complexed to alpha 2-macroglobulin also is present in the serum. To study these 3 different molecular forms of PSA in vivo, we simulated leakage of PSA from the prostate into the serum in vitro. MATERIALS AND METHODS: Purified seminal fluid PSA was incubated with fresh sera from female subjects at different concentrations. Following gel filtration chromatography, the 3 forms of PSA were studied by immunoassays and Western blot analysis. RESULTS: Using a commercial immunoassay, 60% of immunoreactivity of seminal fluid PSA was lost after incubation with sera from female subjects. Western blot analysis showed that most of this loss in PSA signal was caused by complexation to alpha 2-macroglobulin. Minimal, if any, complexation to alpha 1-antichymotrypsin occurred even when excess alpha 1-antichymotrypsin was added to the serum. CONCLUSIONS: Our studies demonstrated that alpha 2-macroglobulin is a much stronger inhibitor to PSA than alpha 1-antichymotrypsin. Further studies of these complexes may be important. They clearly explain why spiking PSA into sera from female subjects to be used as quality controls for PSA assays leads only to the free form of enzymatically inactive PSA in the serum, and not to the dominant form of complexed PSA and alpha 1-antichymotrypsin present in human serum.

Female↗

PubMed1979

Effects of bacterial endotoxin and corticosteroids on plasma concentrations of alpha 2 macroglobulin, haptoglobin and fibrinogen in rats.

Bacterial endotoxin injected into rats resulted in increased plasma concentration of alpha 2 macroglobulin, haptoglobin and fibrinogen. Cortisone acetate injected i.m. by itself was sufficient to increase the plasma concentration of haptoglobin by 54% and to a lesser extent the concentrations of the other two proteins. When cortisone acetate and/or cortisol succinate were injected simultaneously with varying doses of endotoxin, the effects of the corticosteroid differed for each plasma protein. Doubtless because of the effect of cortisone by itself the slope of the dose-response relationship for haptoglobin was greatly reduced. In contrast to this the slope for alpha 2 macroglobulin was reduced and that for fibrinogen was unaffected. These findings suggest that, if effects due to endogenous corticosteroids are to be avoided, increases in plasma fibrinogen will serve best as indicators of stimulation of the acute-phase response. Since, however, the relative increase of alpha 2 macroglobulin due to the lowest dose of endotoxin was much greater than that of fibrinogen, increases in concentration of the former protein represent the most sensitive indication of the acute-phase response. Consideration of the responses in individual rats has made possible division into those with more or less than average increases for all 3 plasma proteins and those showing irregular responses. Especially in the group which had received the lowest dose of endotoxin, a much larger number than would be expected on a random basis was found to respond regularly with either more or less than average increases for all 3 proteins.

Animals↗