Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Role of haem in the synthesis and assembly of cytochrome P-450.

ABSTRACT: By using 3-amino-1,2,4-triazole, an inhibitor of haem synthesis, and 2-allyl-2-isopropylacetamide, a drug that degrades the haem moiety of cytochrome P-450, the involvement of haem in cytochrome P-450 synthesis and assembly was investigated. Phenobarbital was used to stimulate apo-(cytochrome P-450) synthesis. Degradation of preformed cytochrome P-450 haem does not result in a concomitant release of the apoprotein from the endoplasmic reticulum. The availability of haem for cytochrome P-450 synthesis in the normal animal is not rate-limiting. Prolonged inhibition of haem synthesis in vivo decreases the rate of apo-(cytochrome P-450) synthesis, although this effect is not discernible under conditions of short-term inhibition of haem synthesis. Under the former conditions exogenous haemin is able to counteract the decrease in the rate of apoprotein synthesis. In animals receiving successive injections of phenobarbital plus 3-amino-1,2,4-triazole, compared with those receiving phenobarbital only, the holo-(cytochrome P-450) content measured spectrally shows a greater decrease than could be accounted for by the decrease in the content of the total apoprotein. In addition to less haem being available under these conditions, the free apoprotein appears to have undergone some modification, such that its haem-binding capacity is considerably decreased. This particular effect could be due to a direct interaction of 3-amino-1,2,4-triazole or its metabolites with cytochrome P-450 rather than a consequence of haem deficiency. Apo-(cytochrome P-450) is capable of binding to the endoplasmic reticulum in a form and at a site, which can be reconstituted with haemin to yield the functional protein.

SUBMITTER: Bhat KS

PROVIDER: S-EPMC1164794 | biostudies-other | 1977 May

REPOSITORIES: biostudies-other

ACCESS DATA

Json Xml

Similar Datasets

Essential histidine pairs indicate conserved haem binding in epsilonproteobacterial cytochrome c haem lyases.

Project description:Bacterial cytochrome c maturation occurs at the outside of the cytoplasmic membrane, requires transport of haem b across the membrane, and depends on membrane-bound cytochrome c haem lyase (CCHL), an enzyme that catalyses covalent attachment of haem b to apocytochrome c. Epsilonproteobacteria such as Wolinella succinogenes use the cytochrome c biogenesis system II and contain unusually large CCHL proteins of about 900 amino acid residues that appear to be fusions of the CcsB and CcsA proteins found in other bacteria. CcsBA-type CCHLs have been proposed to act as haem transporters that contain two haem b coordination sites located at different sides of the membrane and formed by histidine pairs. W. succinogenes cells contain three CcsBA-type CCHL isoenzymes (NrfI, CcsA1 and CcsA2) that are known to differ in their specificity for apocytochromes and apparently recognize different haem c binding motifs such as CX(2)CH (by CcsA2), CX(2)CK (by NrfI) and CX(15)CH (by CcsA1). In this study, conserved histidine residues were individually replaced by alanine in each of the W. succinogenes CCHLs. Characterization of NrfI and CcsA1 variants in W. succinogenes demonstrated that a set of four histidines is essential for maturing the dedicated multihaem cytochromes c NrfA and MccA, respectively. The function of W. succinogenes CcsA2 variants produced in Escherichia coli was also found to depend on each of these four conserved histidine residues. The presence of imidazole in the growth medium of both W. succinogenes and E. coli rescued the cytochrome c biogenesis activity of most histidine variants, albeit to different extents, thereby implying the presence of two functionally distinct histidine pairs in each CCHL. The data support a model in which two conserved haem b binding sites are involved in haem transport catalysed by CcsBA-type CCHLs.

| S-EPMC3068706 | biostudies-literature

Analysis of polymorphisms of canine Cytochrome P 450-CYP2D15.

Project description:Cytochrome P450 (CYP) proteins constitute a large ancient family of oxidative enzymes essential for the efficient elimination of a wide variety of clinically used drugs. Polymorphic variants of human CYP2D6 are associated with the conversion rate and efficacy of several drugs such as antidepressants. Polymorphisms of the canine orthologue CYP2D15 are of interest because these antidepressants are also used in dogs with behavioral problems and the outcome of the treatment is variable. However, the annotated CYP2D15 gene is incomplete and inaccurately assembled in CanFam3.1, hampering DNA sequence analysis of the gene in individual dogs. We elucidated the complete exon-intron structure of CYP2D15 to enable comprehensive genotyping of the gene using genomic DNA. We surveyed variations of the gene in four diverse dog breeds and identified novel polymorphisms in exon 2 in border collies. Further investigation to establish the impact of these canine CYP2D15 polymorphisms on interindividual variability in expression and function of this metabolizing enzyme is now feasible. Further knowledge of CYP pharmacogenetics will help individualize therapy and thereby increase therapeutic efficacy, especially in the use of antidepressants in veterinary behavioral medicine.

| S-EPMC7689907 | biostudies-literature

Understanding Role of DNA Repair and Cytochrome p-450 Gene Polymorphisms in Cervical Cancer Patient Treated With Concomitant Chemoradiation.

Project description:Background: Evidences suggest that single nucleotide polymorphisms (SNPs) can be considered as potential biomarkers for disease progression and therapeutic response in cervical cancer. The present study investigated the association of CYP1A1 T>C (rs4646903), CYP1A1 A>G (rs1048943), CYP2E1 T>A (rs6413432), RAD51 G>C (rs1801320), XRCC1 G>A (rs25487), XRCC2 G>A (rs3218536) and XRCC3 C>T (rs861539) polymorphisms with treatment outcome of cisplatin based chemoradiation (CRT). Methods: Total 227 cervical cancer cases, treated with the same chemoradiotherapy regimen were selected for the study. Genotyping analysis was performed by PCR-restriction fragment length polymorphisms (PCR-RFLP). Treatment response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST). Association of all clinical data (responses, recurrence and survival of patients) and single nucleotide polymorphisms (SNPs) was analysed by using SPSS (version 21.0). Results: Patients with TA/AA genotype of CYP2E1 T>A polymorphism showed significantly poor response while those with GC/CC genotype of RAD51 G>C showed better response (p = 0.008, p = 0.014 respectively). Death was significantly higher in patients with GG genotypes of RAD51 G>C and XRCC1 G>A (p = 0.006, p = 0.002 respectively). Women with GC+CC genotype of RAD51 G>C and AG+GG of XRCC1 showed better survival and also reduced risk of death (HR = 0.489, p = 0.008; HR = 0.484, p = 0.003 respectively). Conclusion: Results suggested that CYP2E1 T>A (rs6413432), RAD51 G>C (rs1801320), and XRCC1 G>A (rs25487) polymorphisms may be used as predictive markers for clinical outcomes in cervical cancer patients undergoing cisplatin based concomitant chemoradiotherapy.

| S-EPMC8915685 | biostudies-literature

Incorporation of haemoglobin haem into the rat hepatic haemoproteins tryptophan pyrrolase and cytochrome P-450.

Project description:After its administration to intact rats, haemoglobin haem was incorporated into hepatic tryptophan pyrrolase as shown by the marked increase in functional constitution of this enzyme. Incorporation of haemoglobin haem into cytochrome P-450 was demonstrated in intact rats and in the isolated rat liver perfused with haemoglobin-free medium. In both systems, haemoglobin haem restored cytochrome P-450 content and its dependent mixed-function-oxidase activity after substrate-induced destruction of the cytochrome P-450 haem moiety. Further confirmation that haemoglobin haem could be incorporated prosthetically into cytochrome P-450 was achieved by administration of [3H]haemoglobin to rats and subsequent isolation and characterization of radiolabelled substrate-alkylated products of cytochrome P-450 haem. Our findings indicate that, although hepatic uptake of parenteral haemoglobin is slower than that of haem, it appears to serve as an effective haem donor to the intrahepatic 'free' haem pool. Thus parenteral haemoglobin may warrant consideration as a therapeutic alternative to haem in the acute hepatic porphyrias.

| S-EPMC1147212 | biostudies-other

Meta-analysis of cytochrome P-450 2C9 polymorphism and colorectal cancer risk.

Project description:BackgroundCYP2C9 encodes a member of the cytochrome P450 superfamily of enzymes which play a central role in activating and detoxifying many carcinogens and endogenous compounds thought to be involved in the development of colorectal cancer (CRC). In the past decade, the relationship between CYP2C9 common polymorphisms (R144C and I359L) and CRC has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed this meta-analysis.MethodsDatabases including Pubmed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association.ResultsA total of 13 articles involving 9,463 cases and 11,416 controls were included. Overall, the summary odds ratio of CRC was 0.98 (95% CI: 0.89-1.06) and 0.99 (95% CI: 0.87-1.14) for CYP2C9 144C and 359L alleles, respectively. No significant results were observed using dominant or recessive genetic model for these polymorphisms. In the stratified analyses according to ethnicity and sex, no evidence of any gene-disease association was obtained.ConclusionsThis meta-analysis suggests that the CYP2C9 may not be associated with colorectal cancer development.

| S-EPMC3492323 | biostudies-literature

Selective steroidogenic cytochrome P450 haem iron ligation by steroid-derived isonitriles.

Project description:Alkyl isonitriles, R-NC, have previously been shown to ligate the heme (haem) iron of cytochromes P450 in both accessible oxidation states (ferrous, Fe2+, and ferric, Fe3+). Herein, the preparation of four steroid-derived isonitriles and their interactions with several P450s, including the steroidogenic CYP17A1 and CYP106A2, as well as the more promiscuous drug metabolizers CYP3A4 and CYP2D6, is described. It was found that successful ligation of the heme iron by the isonitrile functionality for a given P450 depends on both the position and stereochemistry of the isonitrile on the steroid skeleton. Spectral studies indicate that isonitrile ligation of the ferric heme is stable upon reduction to the ferrous form, with reoxidation resulting in the original complex. A crystallographic structure of CYP17A1 with an isonitrile derived from pregnanalone further confirmed the interaction and identified the absolute stereochemistry of the bound species.

| S-EPMC10475101 | biostudies-literature

Haem synthesis during cytochrome P-450 induction in higher plants. 5-Aminolaevulinic acid synthesis through a five-carbon pathway in Helianthus tuberosus tuber tissues aged in the dark.

Project description:Chlorophyll and haem synthesis in illuminated Jerusalem artichoke tuber tissues were very efficiently inhibited by gabaculine (3-amino-2,3-dihydrobenzoic acid). This inhibition seems to be due specifically to a blockade of the pathway for 5-aminolaevulinate biosynthesis which used glutamate as a substrate (the so-called C5 pathway) since we could not detect any inhibition of protein synthesis in the treated tissues and there was no effect of gabaculine on the glycine-dependent yeast 5-aminolaevulinate synthase used as a model. In dark-aged artichoke tissues, gabaculine also effectively blocked cytochrome P-450 induction, peroxidase activity and 5-aminolaevulinic acid synthesis, thus suggesting the involvement of a C5 pathway in cytoplasmic and microsomal haemoprotein synthesis in this higher plant. Allylglycine and (2-amino-ethyloxyvinyl)glycine, two olefinic glycine analogues which are potential suicide inhibitors of pyridoxal phosphate enzymes, were also demonstrated to be effective blockers of chlorophyll synthesis in artichoke tuber and Euglena cells exposed to light.

| S-EPMC1148727 | biostudies-other

Prolonged induction of hepatic haem oxygenase and decreases in cytochrome P-450 content by organotin compounds.

Project description:The administration of organotin compounds to rats in single doses causes a significant and prolonged induction of haem oxygenase and a sustained decrease in haemoprotein content in the liver. The extent of induction of hepatic haem oxygenase varied between 3 and 5-fold at 72h after a single injection of water-insoluble organotins of differing structure. The alterations in haem metabolism produced by tricyclohexyltin hydroxide were studied in detail. The effects were dose-dependent, with doses as low as 3.75 mg/kg body wt. resulting in significant induction of haem oxygenase and a decrease in cytochrome P-450 and cytochrome b5 contents at 72h in the liver. The effects with time of a single dose of tricyclohexyltin on various parameters of liver haem metabolism were also examined. The organotin produced a substantial and very prolonged induction of haem oxygenase accompanied by a steady decline in cytochrome P-450 content for periods up to 8 days. The long duration of action of these organotins with respect to induction of haem oxygenase and depletion of cellular haemoprotein content provides a highly sensitive metabolic system with which to define further the toxic potential of organometals as well as to study the adaptive responses in liver to long-term perturbations of haem metabolism by foreign chemicals.

| S-EPMC1162114 | biostudies-other

Metal induction of haem oxygenase without concurrent degradation of cytochrome P-450. Protective effects of compound SKF 525A on the haem protein.

Project description:The induction of hepatic haem oxygenase (EC 1.14.99.3) by a series of metals, organometals and metalloporphyrins was examined in vivo in the presence of compound SKF 525A, which is known to complex with the prosthetic group of cytochrome P-450. Concurrent administration of SKF 525A and an inducing metal did not affect the extent and time course of haem oxygenase induction. The decrease in cytochrome P-450 content normally associated with metal administration was, however, prevented, indicating that haem oxygenase induction by metals can proceed without the significant labilization of the haem moiety of cytochrome P-450. In addition, the integrity of this haem protein can be maintained by chemical means in the presence of sustained high activities of haem oxygenase.

| S-EPMC1158074 | biostudies-other

Effect of thioacetamide on cytochrome P-450 synthesis in rat liver.

Project description:A single injection of thioacetamide to rats results in a striking decrease in liver cytochrome P-450. The drug blocks the phenobarbitone-mediated induction of cytochrome P-450b. Under these conditions, there is a decrease in the synthesis of cytochrome P-450b, which is essentially due to a decrease in the amount of translatable mRNA for cytochrome P-450b. This effect of thioacetamide is not due to a general effect on protein synthesis or polyribosome stability. Multiple injections of thioacetamide also decrease the synthesis of cytochrome P-450b and the amounts of its translatable mRNA.

| S-EPMC1153350 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data