Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The gammaA2 globulins have attracted considerable interest because of the absence of the disulfide bonds linking the heavy and light chains characteristic of all other human immune globulins. Recently a genetic marker (Am(2)) has been found which delineates two genetic variants of gammaA2 globulins that are controlled by allelic genes. These differ markedly in incidence in different populations with a marked preponderance in Caucasians of the type possessing the Am(2) marker. A study of 22 gammaA2 myeloma proteins primarily from Caucasians showed that 20 were Am(2)(+), and 2 were Am(2)(-). All of the positive type dissociated in the presence of acid or urea into heavy and light chain dimers without reduction of disulfide bonds, as expected from the earlier studies. However, the two Am(2)(-) proteins failed to dissociate in the presence of acid, urea, guanidine, or detergent. It was only after partial reduction and alkylation that these molecules split into heavy and light chains. Thus the unique absence of disulfide bonds linking the heavy and light chains is a property of only one genetic variant and not of all gammaA2 proteins.
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PMID:Absence of disulfide bonds linking the heavy and light chains: a property of a genetic variant of gamma-A2 globulins. 526 37

The serum of a patient with a clinically and immunologically identified multiple myeloma of the IgE class was found to contain both IgE-albumin and IgG-albumin complexes. These complexes were partially purified and some of their properties studied by biochemical and immunochemical methods. The IgG-albumin interaction was dissociated by 5.0 M guanidine hydrochloride, while the IgE-albumin interaction was dissociated upon reduction by mercaptoethanol, suggesting that the proteins were linked by intermolecular disulfide bonds. Complex formation between pathological or normal immunoglobulins with albumin have been reported for IgG, IgM and IgA but not for IgD or IgE. The present observation seems to be the first in which an IgE myeloma protein was involved.
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PMID:Co-occurrence of albumin complexes with IgE and IgG in the serum of an IgE myeloma patient. 681 72

The denaturation and renaturation by guanidine hydrochloride of Fc(t) fragment whose interchain disulfide bonds are reduced and alkylated (R.A.Fc(t)) and pFc' fragment of a human myeloma protein (IgGl, kappa) were studied using tryptophyl fluorescence. R.A.Fc(t) was found to consist of a slow-unfolding region and a rapid-unfolding region. The denaturation of pFc' was extremely slow. Comparison of the kinetic and equilibrium data of the denaturation of R.A.Fc(t) with those of pFcl indicated that the slow-unfolding region of R.A.Fc(t) corresponds to the CH3 region and the fast-unfolding region the CH2 domain. This was also confirmed by the analysis of the CD and fluorescence spectra for R.A.Fc(t) and pFc' at various concentrations of guanidine hydrochloride. Although the kinetic stability of the CH3 region was much higher than that of the CH2 region, the thermodynamic stabilities of these domains were almost the same; the free energy change of the denaturation in water being about 6 kcal . mol-1. This value is also the same as the value for the CL fragment (Goto, Y. & Hamaguchi, K. (1979) J. Biochem. 86, 1433--1441). It was suggested that the high kinetic stability of the CH3 region in R.A.Fc(t) is due to the strong tendency for the CH3 domains to form a dimer.
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PMID:Denaturation by guanidine hydrochloride of the Fc(t) and pFc' fragments of human immunoglobulin G. 714 21

We have developed a procedure to purify the recombinant fusion toxin IL6-PE4E from Escherichia coli which results in a high yield of fully active monomeric protein of high purity and very low endotoxin content. The chimeric toxin is composed of human interleukin 6 (IL6) fused to a derivative of Pseudomonas exotoxin (PE) containing mutations in the binding domain which prevent binding to the PE receptor. In a typical preparation, 20 g of E. coli cells expressing the plasmid encoding IL6-PE4E were treated with lysozyme and washed repeatedly with detergent (Triton X-100), to obtain 500 mg of inclusion bodies. The recombinant protein was denatured and reduced in guanidine hydrochloride solution containing dithioerythritol and refolded in a redox buffer containing oxidized glutathione and L-arginine. After purification of the dialyzed protein by anion-exchange, polymyxin B, and sizing chromatography, we obtained 100 mg (20% of recombinant protein) of purified monomer with 0.6-2.5 endotoxin units/mg of protein. Amino terminal sequencing confirmed the first 20 amino acids. IL6-PE4E purified in this manner was fully cytotoxic toward human multiple myeloma, hepatoma, epidermoid carcinoma, and prostate carcinoma cell lines. After intravenous injection into mice, we found the dose-limiting toxicity to be to the liver, by measurement of serum transaminases and histologic evaluation of the liver. The LD50 was 450 micrograms/kg. We conclude that IL6-PE4E can be purified efficiently for preclinical testing.
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PMID:Purification and characterization of IL6-PE4E, a recombinant fusion of interleukin 6 with Pseudomonas exotoxin. 830 30

Prothrombin is the precursor of thrombin, a central enzyme in coagulation. Autoantibodies to prothrombin are associated with thromboembolism, but the mechanisms by which the antibodies modulate the coagulation processes are not understood. We screened a panel of 34 monoclonal antibody light chains isolated from patients with multiple myeloma for prothrombinase activity by an electrophoresis method. Two light chains with the activity were identified, and one of the light chains was characterized further. The prothrombinase activity eluted from a gel-filtration column run in denaturing solvent (6 M guanidine hydrochloride) at the characteristic positions of the light chain dimer and monomer. A constant level of catalytic activity was observed across the width of the light chain monomer peak, assessed as the cleavage of IEGR-methylcoumarinamide, a peptide substrate corresponding to residues 268-271 of prothrombin. Hydrolysis of this peptide by the light chain was saturable and consistent with Michaelis-Menten-Henri kinetics (K(m) 103 microM; k(cat) of 2.62 x 10(-)(2)/min). Four cleavage sites in prothrombin were identified by N-terminal sequencing of the fragments: Arg(155)-Ser(156), Arg(271)-Thr(272), Arg(284)-Thr(285), and Arg(393)-Ser(394). The light chain did not cleave radiolabeled albumin, thyroglobulin, and annexin V under conditions that readily permitted detectable prothrombin cleavage. Two prothrombin fragments (M(r) 55 000 and 38 000), were isolated by anion-exchange chromatography and were observed to cleave a thrombin substrate, tosyl-GPR-nitroanilide. Conversion of fibrinogen to fibrin was accelerated by the prothrombin fragments generated by the light chain. These finding suggest a novel mechanism whereby antibodies can induce a procoagulant state, i.e., prothrombin activation via cleavage of the molecule.
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PMID:Monoclonal antibody light chain with prothrombinase activity. 1082 60


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