Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P36980 (CFHR2)
 30 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the major forms of cytochrome P-450, named P-450 HFLa, of human fetal livers was purified and characterized. The cytochrome P-450 preparation had an apparent molecular weight of 51,500 as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. N-Terminal amino acid sequence of P-450 HFLa was similar but not identical to that of P-450NF involved in nifedipine oxidation in adult human livers. P-450 HFLa catalyzed 16 alpha-hydroxylation of dehydroepiandrosterone 3-sulfate (DHEA-sulfate) in a reconstituted system. The concentration of P-450 HFLa in liver homogenates from human fetuses highly correlated with the activity of DHEA-sulfate 16 alpha-hydroxylase. Furthermore, anti-P-450 HFLa antibodies inhibited the 16 alpha-hydroxylation. P-450 HFLa was also found to catalyze the mutagenic activation of aflatoxin B1 (AFB1) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). The antibodies to P-450 HFLa inhibited efficiently the mutagen-producing activities from AFB1 and IQ in human fetal livers. The nucleotide and the deduced amino acid sequences of lambda HFL33 containing the entire coding region for a form of cytochrome P-450 related to P-450 HFLa, were highly similar to but clearly distinct from those of NF25 and HLp complementary deoxyribonucleic acids. The oligonucleotide probes specific to the coding and 3'-noncoding region of lambda HFL 33 (oli-HFL and oli-HFL3', respectively) gave hybridizable bands with ribonucleic acid (RNA) from fetal but not adult livers. In contrast, an oligonucleotide probe specific to the coding region of NF 25 and HLp (oli-NF) gave hybridizable bands with RNA from only adult but not fetal livers.
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PMID:[Cytochrome P-450 in human fetal liver. Properties of P-450 HFLa,a form of cytochrome P-450 in human fetal livers]. 206 64

The developmentally regulated expression of forms of cytochrome P-450, namely, those encoded by lambda HFL33 and NF25 or HLp cDNAs, which were isolated from respective fetal and adult human liver cDNA libraries, was investigated. When EcoRI fragments of cDNA clones of lambda HFL33 and NF25 were used as probes, these probes hybridized with RNA from both fetal and adult human livers. However, when oligonucleotides specific to the coding and 3'-noncoding region of lambda HFL33 (oli-HFL and oli-HFL3', respectively) were used as probes, these probes gave hybridizable bands with RNA from fetal but not adult livers. On the other hand, an oligonucleotide probe specific to the coding region of NF25 and HLp (oli-NF) gave positive bands with RNA only from adult livers. These results indicate that P-450(HFL33) is expressed specifically in fetal livers and that neither P-450NF nor HLp is expressed in fetal livers, but one or both are expressed in adult livers.
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PMID:Fetus-specific expression of a form of cytochrome P-450 in human livers. 235 May 47

The human factor H-related gene 2 (FHR2) encodes a serum protein structurally and immunologically related to complement factor H. We describe the isolation and genomic organization of the human FHR2 gene from a yeast artificial chromosome library. The FHR2 gene is organized in five exons and spans about 7 kilobases (kb) of human genomic DNA. A comparison with the corresponding cDNA sequence (clone DDESK59) shows that the analyzed FHR2 gene has a deleted region within exon 4. A new splice acceptor site created in the truncated exon indicates that the analyzed gene could be translated to a truncated protein. Further, we demonstrate that the genes for FHR2 and beta subunit of coagulation factor XIII are located in the same 165 kb YAC DNA. Thus, the three structurally related genes FXIIIb, FHR2, and factor H are linked on human chromosome 1 in the regulators of complement activation (RCA) gene cluster. The physical linkage of the FHR2 and the factor H genes provides additional evidence for a close relatedness of complement factor H and the factor H-related proteins. The linkage and the almost exclusive organization in short consensus repeat-containing domains indicates a close evolutionary relationship of the FXIIIb, FHR2, and factor H genes.
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PMID:The human factor H-related gene 2 (FHR2): structure and linkage to the coagulation factor XIIIb gene. 767 21

We have generated monoclonal antibodies (mAbs) specific for the C-terminus of factor H that can be used as inhibitory antibodies for heparin binding and for the specific detection of factor H and factor H-related proteins (FHRs) in plasma and triacylglycerol-rich lipoproteins. Four distinct mAbs were established: IXF9 (IgG1), VD3 (IgG2a), VIG8 (IgG1) and IIC5 (IgG1). Each reacts specifically with FHR-1 and factor H (and also with FHR-2 in the case of VIG8), but none binds to the related FHR-3 and FHR-4 proteins nor to factor H-like protein 1. By the use of deletion mutants of factor H and by comparing the reactivity with FHR-1 and FHR-2, the binding epitopes of the mAbs were identified and localized to different short consensus repeats (SCRs): mAbs IXF9 and VD3 bind to related or even identical sites within SCR18 (factor H) and SCR3 (FHR-1) respectively. mAbs VIG8 and IIC5 bind to different epitopes located within SCRs 19 to 20 of factor H and SCRs 4 to 5 of FHR-1 respectively. Only mAb VIG8 reacts with the corresponding SCRs 3 to 4 of FHR-2. These antibodies are useful for the detection of the corresponding proteins in biological specimens such as fractions of lipoproteins. In addition, mAb VIG8 has the unique feature of inhibiting binding of factor H to heparin. Given the recent identification of a heparin- and a C3b-binding domain within the C-terminus of factor H, these mAbs should provide useful tools for functional analysis and for the precise localization of the domain(s) required for this interaction.
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PMID:The C-terminus of factor H: monoclonal antibodies inhibit heparin binding and identify epitopes common to factor H and factor H-related proteins. 951 60

The factor H gene family provides a prime example of a multidomain multifunctional protein family whose individual members are defined by conserved common structural elements and display diverse but often overlapping functions. The six identified members of this protein family represent secreted plasma proteins that are primarily synthesized in the liver. Here, we summarize the current understanding of the function of these proteins and suggest a common role in complement control. Factor H is the best characterized member and acts as a complement regulator. The protein displays cofactor activity for factor I in the degradation of the central complement component C3b, acts as a decay accelerating factor for the C3 convertase, C3bBb and is a competitor for factor B binding to C3b. Factor H is a multifunctional protein and displays functions outside the complement system: it binds to the cellular integrin receptor (CD11b/CD18), interacts with cell surface glycosaminoglycans and also binds to the surface of certain pathogenic microorganisms. In addition, factor H has several binding sites for the C3 protein. The factor H-like protein 1 (FHL-1) or reconectin shares the complement regulatory functions with factor H and interacts with heparin. The protein displays cell spreading activity and binds to the N-terminus of the streptococcal M protein. The function of the factor H-related proteins (FHR-1 to FHR-4) is currently under investigation. These proteins are differently distributed. Three proteins (FHR-1, FHR-2 and FHR-4) are constituents of lipoproteins, while FHR-3 interacts with heparin. Binding to C3b and C3d has been demonstrated for FHR-3 and FHR-4 and the two proteins display a cofactor related activity.
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PMID:The factor H protein family. 1040 66

The factor H family of genes has been localised to human chromosome 1q32. This region encodes various proteins involved in complement regulation and is known as the regulators of complement activation (RCA) gene cluster. The factor H genes encode seven known plasma proteins. Using fluorescence in situ hybridisation (FISH), radiation hybrid (RH) mapping and BLAST alignment analysis, we have established that the factor H-related 5 (FHR-5) gene is closely linked to the other factor H gene family members. Analysis of the genomic sequence indicates that the FHR-5 gene is situated between FHR-2 and the non-complement protein factor XIIIb (Fl3B). Like all members of the factor H family. transcription of FHR-5 is in the telomeric direction. Furthermore, the short consensus repeats (SCRs) of FHR-5 are encoded by individual exons and splicing is of type 1. These data allow the generation of a more complete map of the factor H gene family.
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PMID:Location and structure of the human FHR-5 gene. 1204 28

Many of the complement regulatory genes within the RCA cluster (1q32) have arisen through genomic duplication and the resulting high degree of sequence identity is likely to predispose to gene conversion events. The highest degree of identity is between the genes for factor H (CFH) and five factor H-related proteins--CFHL1, CFHL2, CFHL3, CFHL4, and CFHL5. CFH mutations are associated with atypical hemolytic uremic syndrome (aHUS). In the Newcastle cohort of 157 aHUS patients we have identified CFH mutations in 25 families or individuals. Eleven of these 25 independent mutations are either c.3226C>G,Q1076E; c.3572C>T,S1191L; c.3590T>C,V1197A or combined c.3572C>T,S1191L/c.3590T>C,V1197A. Sequence analysis shows that all four of these changes could have arisen as a result of gene conversion between CFH and CFHL1. Analysis of parental samples in two patients with S1191L/V1197A has shown that the changes are de novo thus providing conclusive evidence that gene conversion is the mutational mechanism in these two cases. To confirm that S1191L and V1197A are disease predisposing we examined their functional significance in three ways - analysis of the C3b/C3d binding characteristics of recombinant mutant S1191L/V1197A protein, heparin affinity chromatography and haemolytic assays of serum samples from aHUS patients carrying these changes. The results showed that these changes resulted in impaired C3b binding and a defective capacity to control complement activation on cellular surfaces. We, therefore, provide conclusive evidence that gene conversion is responsible for functionally significant CFH mutations in aHUS.
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PMID:De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome. 1647 May 55

In a continuing structure-activity relationship study of potent anti-HIV agents, seven new triterpene derivatives were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, moronic acid derivatives 19, 20, and 21 showed significant activity in HIV-1 infected H9 lymphocytes. Compounds 19 and 20 were also evaluated against HIV-1 NL4-3 and drug resistant strains in the MT-4 cell line. Compounds 19 and 20 showed better antiviral profiles than the betulinic acid analogue 8 (PA-457), which has successfully completed a Phase IIa clinical trial. Compound 20 showed potent anti-HIV activity with EC50 values of 0.0085 microM against NL4-3, 0.021 microM against PI-R (a multiple protease inhibitor resistant strain), and 0.13 microM against FHR-2 (an HIV strain resistant to 8). Promising compound 20 has become a new lead for modification, and further development of 20-related compounds as clinical trial candidates is warranted.
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PMID:Anti-AIDS agents 69. Moronic acid and other triterpene derivatives as novel potent anti-HIV agents. 1694 19

Spirochetes belonging to the Borrelia burgdorferi sensu lato complex differ in resistance to complement-mediated killing by human serum. Here, we characterize complement sensitivity of a panel of B. lusitaniae isolates derived from ticks collected in Germany and Portugal as well as one patient-derived isolate, PoHL. All isolates are highly susceptible to complement-mediated lysis in human serum and activate complement predominantly by the alternative pathway, leading to an increased deposition of complement components C3, C6, and the terminal complement complex. Interestingly, serum-sensitive B. lusitaniae isolates were able to bind immune regulator factor H (CFH), and some strains also bound CFH-related protein 1 (CFHR1) and CFHR2. Moreover, CFH bound to the surface of B. lusitaniae was inefficient in mediating C3b conversion. Furthermore, the identification and characterization of a potential CFH-binding protein, OspE, revealed that this molecule possesses a significantly reduced binding capacity for CFH compared to that of CFH-binding OspE paralogs expressed by various serum-resistant Borrelia species. This finding suggests that a reduced binding capability of CFH is associated with an increased serum sensitivity of B. lusitaniae to human complement.
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PMID:Inadequate binding of immune regulator factor H is associated with sensitivity of Borrelia lusitaniae to human complement. 2082 2

Group A streptococci (GAS) utilize soluble human complement regulators to evade host complement attack. Here, we characterized the binding of the terminal complement complex inhibitor complement Factor H-related protein 1 (CFHR1) and of the C3 convertase regulator Factor H to the streptococcal collagen-like proteins (Scl). CFHR1 and Factor H, but no other member of the Factor H protein family (CFHR2, CFHR3, or CFHR4A), bound to the two streptococcal proteins Scl1.6 and Scl1.55, which are expressed by GAS serotypes M6 and M55. The two human regulators bound to the Scl1 proteins via their conserved C-terminal attachment region, i.e. CFHR1 short consensus repeats 3-5 (SCR3-5) and Factor H SCR18-20. Binding was affected by ionic strength and by heparin. CFHR1 and the C-terminal attachment region of Factor H did not bind to Scl1.1 and Scl2.28 proteins but did bind to intact M1-type and M28-type GAS, which express Scl1.1 and Scl2.28, respectively, thus arguing for the presence of an additional binding mechanism to CFHR1 and Factor H. Furthermore mutations within the C-terminal heparin-binding region and Factor H mutations that are associated with the acute renal disease atypical hemolytic uremic syndrome blocked the interaction with the two streptococcal proteins. Binding of CFHR1 affected the complement regulatory functions of Factor H on the level of the C3 convertase. Apparently, streptococci utilize two types of complement regulator-acquiring surface proteins; type A proteins, as represented by Scl1.6 and Scl1.55, bind to CFHR1 and Factor H via their conserved C-terminal region and do not bind the Factor H-like protein 1 (FHL-1). On the contrary, type B proteins, represented by M-, M-like, and the fibronectin-binding protein Fba proteins, bind Factor H and FHL-1 via domain SCR7 and do not bind CFHR1. In conclusion, binding of CFHR1 is at the expense of Factor H-mediated regulatory function at the level of C3 convertase and at the gain of a regulator that controls complement at the level of the C5 convertase and formation of the terminal complement complex.
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PMID:Binding of the human complement regulators CFHR1 and factor H by streptococcal collagen-like protein 1 (Scl1) via their conserved C termini allows control of the complement cascade at multiple levels. 2085 86


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