Metabolites of procainamide and practolol inhibit complement components C3 and C4.
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ABSTRACT:
SUBMITTER: Sim E
PROVIDER: S-EPMC1149005 | biostudies-other | 1988 Apr
REPOSITORIES: biostudies-other
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Project description:The thioester bond in complement components C3 and C4 and the protease inhibitor alpha2-macroglobulin have traditionally been thought of as fulfilling the dual roles of mediating covalent attachment and maintaining the native conformational states of these molecules. We previously reported that several human C3 thioester-region mutants, including variants E1012Q and C1010A, in the latter of which thioester-bond formation is precluded, display an unexpected phenotype. Despite the lack of a thioester bond in these mutants, they appear to adopt a native-like conformation as suggested by the finding that they are cleavable by the classical pathway C3 convertase, C4b2a, whereas the C3b-like C3(H2O) species is not. Subsequently, a species referred to as C3(NH3)* was described which potentially could account for the observations with the above mutants. C3(NH3)* is a transient species formed on aminolysis of native C3 that can spontaneously re-form the thioester bond. Importantly, it has a mobility on cation-exchange HPLC that is distinct from both native C3 and C3(H2O), but like the native molecule, it is cleavable by an alternative-pathway C3 convertase. In this study we showed by using cation-exchange HPLC as an additional conformational probe that C3 C1010A and E1012Q mutant proteins did not resemble C3(NH3)*. Instead they displayed a chromatographic behaviour that was indistinguishable from that of native C3. To assess the general applicability of these observations, we engineered the equivalent mutations into human C4, specifically C4 C1010A and C4 E1012Q. As expected, thioester-bond formation did not occur in either of these C4 mutants, but in contrast with the results with C3 we found no evidence for the formation of a stable native-like conformation in either C4 mutant, as assessed using cleavability by C1s as the conformational probe. A possible interpretation of our data is that the adoption of the native conformational state during biosynthesis of C3 and C4 is an energetically permissible process, even if it is not locked in via thioester-bond formation. Whereas this conformational state is stable in mature C3, it is unstable in mature C4, perhaps reflecting the additional post-translational cleavage of C4 before its secretion.
| S-EPMC1219096 | biostudies-other
Project description:Most physiology comparisons of C3 and C4 plants are made under current or elevated concentrations of atmospheric CO2 which do not reflect the low CO2 environment under which C4 photosynthesis has evolved. Accordingly, photosynthetic nitrogen (PNUE) and water (PWUE) use efficiency, and the activity of the photosynthetic carboxylases [Rubisco and phosphoenolpyruvate carboxylase (PEPC)] and decarboxylases [NADP-malic enzyme (NADP-ME) and phosphoenolpyruvate carboxykinase (PEP-CK)] were compared in eight C4 grasses with NAD-ME, PCK, and NADP-ME subtypes, one C3 grass, and one C3-C4 grass grown under ambient (400 μl l(-1)) and glacial (180 μl l(-1)) CO2. Glacial CO2 caused a smaller reduction of photosynthesis and a greater increase of stomatal conductance in C4 relative to C3 and C3-C4 species. Panicum bisulcatum (C3) acclimated to glacial [CO2] by doubling Rubisco activity, while Rubisco was unchanged in Panicum milioides (C3-C4), possibly due to its high leaf N and Rubisco contents. Glacial CO2 up-regulated Rubisco and PEPC activities in concert for several C4 grasses, while NADP-ME and PEP-CK activities were unchanged, reflecting the high control exerted by the carboxylases relative to the decarboxylases on the efficiency of C4 metabolism. Despite having larger stomatal conductance at glacial CO2, C4 species maintained greater PWUE and PNUE relative to C3-C4 and C3 species due to higher photosynthetic rates. Relative to other C4 subtypes, NAD-ME and PEP-CK grasses had the highest PWUE and PNUE, respectively; relative to C3, the C3-C4 grass had higher PWUE and similar PNUE at glacial CO2. Biomass accumulation was reduced by glacial CO2 in the C3 grass relative to the C3-C4 grass, while biomass was less reduced in NAD-ME grasses compared with NADP-ME and PCK grasses. Under glacial CO2, high resource use efficiency offers a key evolutionary advantage for the transition from C3 to C4 photosynthesis in water- and nutrient-limited environments.
| S-EPMC4085965 | biostudies-literature
Project description:IgA Nephropathy (IgAN) is the most prevalent glomerular disease worldwide. Complement system activation is crucial in its pathogenesis. Few studies correlated serum C3 and C4 with disease activity and prognosis. This retrospective study investigated the prognostic value of serum complement at the time of diagnosis in patients with IgAN. Specifically we evaluated whether adding serum C3 and C4 levels to established predictive models-one based on variables related to chronic kidney disease (CKD) progression and another incorporating variables from the International IgA Prediction Tool (IntIgAPT)-enhances the accuracy of outcome prediction. A composite renal outcome was defined as 50% decline in eGFR or onset of kidney failure. 101 patients were stratified according to baseline C3 levels in three groups (Low, Medium and High). During a median follow-up of 54 months, the Low group exhibited higher incidence of primary outcome (16.3 events vs 2.9 and 1.7 events × 100 pts/year, p = 0.0026). Model-1 (M1), consisting of CKD progression variables, and Model-3 (M3), comprising IntIgANPT variables, were implemented with baseline C3 and C4 to create Model-2 (M2) and Model-4 (M4), respectively. M2 demonstrated better predictive performance over M1, showing higher discrimination (lower AIC and BIC, higher C-index and NR2). Similarly, M4 outperformed M3, showing enhanced outcome prediction when C3 and C4 levels were added. Implementation of serum C3 and C4 can enhance prediction accuracy of already-validated prognostic models in IgAN. Lower C3 and higher C4 levels were associated with poorer prognosis, highlighting a more 'Complement-Pathic' subset of patients.
| S-EPMC11246413 | biostudies-literature
Project description:The alpha polypeptide chain of the complement protein C3 splits into two fragments of 74 000 and 46 000 apparent mol.wt. under certain conditions used to prepare the protein for SDS (sodium dodecyl sulphate)/polyacrylamide-gel electrophoresis. The cleavage reaction occurs over a wide range of temperatures and from pH 4.6 to 10.6 in the presence of denaturants such as urea, SDS and guanidine hydrochloride. It is also induced by heat-denaturation of C3 in the absence of chemical denaturants. The reaction occurs only with haemolytically active C3, and is not observed with hydroxylamine-inactivated C3 or with C3b. A similar cleavage of the alpha-chain of complement component C4 occurs under the same conditions, forming fragments of 53 000 and 41 000 apparent mol.wt. This reaction is again specific for haemolytically active C4, and does not occur with C4b or hydroxylamine-inactivated C4. The complement component C5, although structurally similar to C3 and C4, does not undergo a reaction of this type. The characteristics of the denaturation-induced cleavage of C3 and C4 match those described for the 'heat-induced' cleavage of alpha 2-macroglobulin [Harpel, Hayes & Hugli (1979) J. Biol. Chem. 254, 8669-8678]. Cleavage of alpha 2-macroglobulin is also specific for the active form of the protein, and does not occur with chemically inactivated or proteinase-cleaved forms. The unusual conditions and specificity of the peptide-bond cleavage in all three proteins suggest that it is an autolytic process rather than being the result of trace proteinase contamination. The active forms of C3, C4 and alpha 2-macroglobulin have the transient ability to form covalent bonds after activation. The autolytic cleavage reaction is likely to be related to the covalent-bond-forming reactions of these proteins.
| S-EPMC1162584 | biostudies-other
Project description:Group B Streptococcus (GBS) colonizes the human lower intestinal and genital tracts and constitutes a major threat to neonates from pregnant carrier mothers and to adults with underlying morbidity. The pathogen expresses cell-surface virulence factors that enable cell adhesion and penetration and that counteract innate and adaptive immune responses. Among these, the complement interfering protein (CIP) was recently described for its capacity to interact with the human C4b ligand and to interfere with the classical- and lectin-complement pathways. In the present study, we provide evidence that CIP can also interact with C3, C3b, and C3d. Immunoassay-based competition experiments showed that binding of CIP to C3d interferes with the interaction between C3d and the complement receptor 2/cluster of differentiation 21 (CR2/CD21) receptor on B cells. By B-cell intracellular signaling assays, CIP was confirmed to down-regulate CR2/CD21-dependent B-cell activation. The CIP domain involved in C3d binding was mapped via hydrogen deuterium exchange-mass spectrometry. The data obtained reveal a new role for this GBS polypeptide at the interface between the innate and adaptive immune responses, adding a new member to the growing list of virulence factors secreted by gram-positive pathogens that incorporate multiple immunomodulatory functions.-Giussani, S., Pietrocola, G., Donnarumma, D., Norais, N., Speziale, P., Fabbrini, M., Margarit, I. The Streptococcus agalactiae complement interfering protein combines multiple complement-inhibitory mechanisms by interacting with both C4 and C3 ligands.
| S-EPMC6404586 | biostudies-literature
Project description:Complement C3 and C4 play key roles in the main physiological activities of complement system, and their deficiencies or over-expression are associated with many clinical infectious or immunity diseases. A two-stage genome-wide association study (GWAS) was performed for serum levels of C3 and C4. The first stage was conducted in 1,999 healthy Chinese men, and the second stage was performed in an additional 1,496 subjects. We identified two SNPs, rs3753394 in CFH gene and rs3745567 in C3 gene, that are significantly associated with serum C3 levels at a genome-wide significance level (P = 7.33 × 10(-11) and P = 1.83 × 10(-9), respectively). For C4, one large genomic region on chromosome 6p21.3 is significantly associated with serum C4 levels. Two SNPs (rs1052693 and rs11575839) were located in the MHC class I area that include HLA-A, HLA-C, and HLA-B genes. Two SNPs (rs2075799 and rs2857009) were located 5' and 3' of C4 gene. The other four SNPs, rs2071278, rs3763317, rs9276606, and rs241428, were located in the MHC class II region that includes HLA-DRA, HLA-DRB, and HLA-DQB genes. The combined P-values for those eight SNPs ranged from 3.19 × 10(-22) to 5.62 × 10(-97). HBsAg-positive subjects have significantly lower C3 and C4 protein concentrations compared with HBsAg-negative subjects (P<0.05). Our study is the first GWAS report which shows genetic components influence the levels of complement C3 and C4. Our significant findings provide novel insights of their related autoimmune, infectious diseases, and molecular mechanisms.
| S-EPMC3441730 | biostudies-literature
Project description:Disulphide bonds contribute significantly to the maintenance of structural/functional integrity of many proteins. Therefore it was of interest to study the distribution and the effect of disulphides on conformation of complement components C3 and C4. These proteins are precursors of several fragments with various binding sites and distinct physiological functions. The constituents of C3c (beta, alpha 27, alpha 43) and those of C4c (beta, alpha 27, alpha 16, gamma) were investigated, since other fragments of C3 or C4 do not participate in interchain linkages. Inter-and intra-chain disulphide bonds in C3c and C4c were localized by using a modification of conventional SDS (sodium dodecyl sulphate)/polyacrylamide-gel electrophoresis such that the change in mobility of disulphide-bond-containing proteins can be detected throughout the transition from a non-reduced to a fully reduced state. Several forms of the alpha 43 fragment from C3, and of the gamma-chain of C4, with different mobilities can exist, depending on the number of intra-chain disulphide bonds reduced. The intermediates (heterodimers) generated by a partial reduction of C3c or C4c were characterized by two-dimensional SDS/polyacrylamide-gel electrophoresis performed in the absence, then in the presence, of beta-mercaptoethanol. The inter-chain linkages in C3c were determined to be beta-alpha 27 and alpha 27- alpha 43, thus indicating the presence of only one interchain bond in C3. The two interchain bonds in C4c are beta-alpha 27 and alpha 16-gamma. The third interchain bond in C4 (alpha 27-gamma, tentative) remains to be determined.
| S-EPMC1153103 | biostudies-other
Project description:Schizophrenia is a common neuropsychiatric disorder with complex pathophysiology. Recent reports suggested that complement system alterations contributed to pathological synapse elimination that was associated with psychiatric symptoms in schizophrenia. Complement component 3 (C3) and complement component 4 (C4) play central roles in complement cascades. In this study, we compared peripheral C3 and C4 protein levels between first-episode psychosis (FEP) and healthy control (HC). Then we explored whether single nucleotide polymorphisms (SNPs) at C3 or C4 genes affect peripheral C3 or C4 protein levels. In total, 181 FEPs and 204 HCs were recruited after providing written informed consent. We measured serum C3 and C4 protein levels using turbidimetric inhibition immunoassay and genotyped C3 and C4 polymorphisms using the Sequenom MassArray genotyping. Our results showed that three SNPs were nominally associated with schizophrenia (rs11569562/C3: A > G, p = 0.048; rs2277983/C3: A > G, p = 0.040; rs149898426/C4: G > A, p = 0.012); one haplotype was nominally associated with schizophrenia, constructed by rs11569562-rs2277983-rs1389623 (GGG, p = 0.048); FEP had higher serum C3 and C4 (both p < 0.001) levels than HC; rs1389623 polymorphisms were associated with elevated C3 levels in our meta-analysis (standard mean difference, 0.50; 95% confidence interval, 0.30 to 0.71); the FEP with CG genotype of rs149898426 had higher C4 levels than that with GG genotypes (p = 0.005). Overall, these findings indicated that complement system altered in FEP and rs149898426 of C4 gene represented a genetic risk marker for schizophrenia likely through mediating complement system. Further studies with larger sample sizes needs to be validated.
| S-EPMC8301372 | biostudies-literature
Project description:C4 photosynthesis is a carbon-concentrating mechanism that evolved independently more than 60 times in a wide range of angiosperm lineages. Among other alterations, the evolution of C4 from ancestral C3 photosynthesis requires changes in the expression of a vast number of genes. Differential gene expression analyses between closely related C3 and C4 species have significantly increased our understanding of C4 functioning and evolution. In Chenopodiaceae, a family that is rich in C4 origins and photosynthetic types, the anatomy, physiology and phylogeny of C4, C2, and C3 species of Salsoleae has been studied in great detail, which facilitated the choice of six samples of five representative species with different photosynthetic types for transcriptome comparisons. mRNA from assimilating organs of each species was sequenced in triplicates, and sequence reads were de novo assembled. These novel genetic resources were then analyzed to provide a better understanding of differential gene expression between C3, C2 and C4 species. All three analyzed C4 species belong to the NADP-ME type as most genes encoding core enzymes of this C4 cycle are highly expressed. The abundance of photorespiratory transcripts is decreased compared to the C3 and C2 species. Like in other C4 lineages of Caryophyllales, our results suggest that PEPC1 is the C4-specific isoform in Salsoleae. Two recently identified transporters from the PHT4 protein family may not only be related to the C4 syndrome, but also active in C2 photosynthesis in Salsoleae. In the two populations of the C2 species S. divaricata transcript abundance of several C4 genes are slightly increased, however, a C4 cycle is not detectable in the carbon isotope values. Most of the core enzymes of photorespiration are highly increased in the C2 species compared to both C3 and C4 species, confirming a successful establishment of the C2 photosynthetic pathway. Furthermore, a function of PEP-CK in C2 photosynthesis appears likely, since PEP-CK gene expression is not only increased in S. divaricata but also in C2 species of other groups.
| S-EPMC5694442 | biostudies-literature
Project description:Age-related macular degeneration (AMD) remains a major cause of legal blindness, and treatment for the geographic atrophy form of AMD is a significant unmet need. Dysregulation of the complement cascade is thought to be instrumental for AMD pathophysiology. In particular, C3 and C5 are pivotal components of the complement cascade and have become leading therapeutic targets for AMD. In this article, we discuss C3 and C5 in detail, including their roles in AMD, biochemical and structural aspects, locations of expression, and the functions of C3 and C5 fragments. Further, the article critically reviews developing therapeutics aimed at C3 and C5, underscoring the potential effects of broad inhibition of complement at the level of C3 versus more specific inhibition at C5. The relationships of complement biology to the inflammasome and microglia/macrophage activity are highlighted. Concepts of C3 and C5 biology will be emphasized, while we point out questions that need to be settled and directions for future investigations.
| S-EPMC8197769 | biostudies-literature