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Query: UNIPROT:P06889 (Mol)
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In this chapter, we have focused on the biochemistry of IRP-1 and the features which distinguish it from the related RNA-binding protein, IRP-2. IRP-1 is the cytoplasmic isoform of the enzyme aconitase, and, depending on iron status, may switch between enzymatic and RNA-binding activities. IRP-1 and IRP-2 are trans-acting regulators of mRNAs involved in iron uptake, storage and utilisation. The finding of an IRE in the citric acid cycle enzymes, mitochondrial aconitase and succinate dehydrogenase, suggests that the IRPs may also influence cellular energy production. These two proteins appear to bind RNAs with different but overlapping specificity, suggesting that they may regulate the stability or translation of as yet undefined mRNA targets, possibly extending their regulatory function beyond that of iron homeostasis. The interaction between the IRPs and the IRE represents one of the best characterised model systems for posttranscriptional gene control, and given that each IRP can also recognise its own unique set of RNAs, the search for new in vivo mRNA targets is expected to provide yet more surprises and insights into the fate of cytoplasmic mRNAs.
Prog Mol Subcell Biol 1997
PMID:Interaction between iron-regulatory proteins and their RNA target sequences, iron-responsive elements. 899 63

Inactivation of aconitase by oxidative stress was analyzed under the in vivo and in situ conditions of yeast cells. Treatment of yeast cells with paraquat caused a specific inactivation of aconitase without affecting the activity of other citric acid cycle enzymes. Addition of copper plus ascorbic acid to permeabilized yeast cells also inactivated aconitase, but did not affect other TCA cycle-related enzymes. Inactivation of aconitase was suggested to be due to the superoxide and hydroxyl radicals produced from the reaction of O2 with paraquat and by Fenton reaction with copper and ascorbic acid under the in vivo and in situ conditions of yeast, respectively. Citrate the substrate of aconitase effectively protected aconitase from the oxidative inactivation. Toxicity of oxygen to yeast cells can be explained by the specific inactivation of aconitase by oxygen radicals. Increased concentrations of citrate can act as a defense mechanism against oxidative inactivation of aconitase under the exposure of aerobically grown yeast to oxidative stress.
Biochem Mol Biol Int 1997 Mar
PMID:Inactivation of aconitase in yeast exposed to oxidative stress. 909 Apr 55

Culture of neuroblastoma cells in the presence of low thiamine concentration (16 nM) and of the transport inhibitor amprolium leads to the appearance of signs of necrosis: the chromatin condenses, the oxygen consumption decreases and is uncoupled, the mitochondrial cristae are disorganized, the thiamine diphosphate-dependent dehydrogenase activities are impaired. When 10 microM thiamine are added to these cells, the basal respiration increases, the coupled respiration is restored and mitochondrial morphology is recovered within 1 h. Addition of succinate, which is oxidized via a thiamine diphosphate-independent dehydrogenase, to digitonin-permeabilized cells immediately restores a coupled respiration. Our results suggest that the slowing of the citric acid cycle is the cause of the biochemical lesion induced by severe thiamine deficiency and that part of the mitochondria remain functional.
Mol Cell Biochem 1997 Sep
PMID:Reversibility of thiamine deficiency-induced partial necrosis and mitochondrial uncoupling by addition of thiamine to neuroblastoma cell suspensions. 930 75

Fumarase deficiency is a rare autosomal recessive disorder of the citric acid cycle causing severe neurological impairment. The cDNA for both the rat and human enzymes has been cloned previously and shown to encode a coding region of 1.46 kb. To scan for mutations in fumarase-deficient patients we amplified the coding region of fumarase from fibroblast/lymphoblast cDNA employing the oligonucleotide primers designed from the published human and rat cDNA sequence. We then directly sequenced the polymerase chain reaction product. In seven unrelated patients, we detected four missense mutations (A265T, D383V, F269C, K187R), a nonsense mutation (W458X), a 3-bp AAA insertion that introduces an additional lysine residue at codon 435, and a spontaneous new mutation resulting in a 74-bp deletion (66del74). Seven at-risk pregnancies were monitored with one prenatal diagnosis of fumarase deficiency by molecular analysis and favorable outcome of the other pregnancies as predicted by enzyme assay of cultured fetal cells or molecular analysis.
Mol Genet Metab 1998 Apr
PMID:Molecular analysis and prenatal diagnosis of human fumarase deficiency. 963 93

Effect of oral administration of aluminum sulphate (200 and 400 mg/kg body wt/day) without or with citric acid (62 mg/kg body wt/day) to day-old White Leghorn male chicks (n = 5 per group) for 30 days was studied on the activities of superoxide dismutase (SOD) and catalase, and level of lipid peroxidation in cerebral hemisphere and liver. A 400 mg dose of Al in the presence of citric acid inhibited cytosolic total and CN -sensitive superoxide dismutase activities of the cerebral hemisphere in 7- and 30-day treated chicks, whereas in 15-day treated chicks the enzyme activities were decreased in response to both doses in the presence of citric acid. In case of liver, activities of these enzymes significantly decreased after 7, 15 and 30 days of treatment with 200 and 400 mg Al together with citric acid, whereas 400 mg Al alone inhibited the enzyme activities after 15 and 30 days of treatment. Cerebral catalase activity decreased in response to 400 mg Al when the chicks were also fed with citric acid for 7 and 30 days, but in 15-day treated chicks the enzyme activity was depleted following treatment with 200 and 400 mg Al combined with citric acid. 400 mg Al treatment for 7 days in combination with citric acid inhibited hepatic catalase activity and extension of the treatment period to 15 and 30 days also produced reduction in its activity even in response to the lower Al dose mixed with citric acid. CN -insensitive SOD activity of cerebral hemisphere and liver was unaffected by Al. Al also failed to induce lipid peroxidation in both the tissues throughout the course of exposure. Activities of SOD and catalase of cerebral hemisphere and liver of 30-day old chicks were observed to be inhibited by in vitro incubation with different concentrations of Al. Our in vivo study demonstrates that only CN -sensitive SOD is susceptible to Al. Further, responses of SOD and catalase to Al is tissue specific. The observed inhibition of antioxidant enzyme activities by Al is suggestive of a prooxidant state. Induction of such an oxidative condition of the tissues may be attributed to a direct effect of the metal on enzyme molecules or in their synthesis.
Mol Cell Biochem 1998 Oct
PMID:Effects of aluminum sulphate and citric acid ingestion on lipid peroxidation and on activities of superoxide dismutase and catalase in cerebral hemisphere and liver of developing young chicks. 978 54

Succinyl-CoA synthetase (SCS) carries out the substrate-level phosphorylation of GDP or ADP in the citric acid cycle. A molecular model of the enzyme from Escherichia coli, crystallized in the presence of CoA, has been refined against data collected to 2.3 A resolution. The crystals are of space group P4322, having unit cell dimensions a=b=98.68 A, c=403.76 A and the data set includes the data measured from 23 crystals. E. coli SCS is an (alphabeta)2-tetramer; there are two copies of each subunit in the asymmetric unit of the crystals. The crystal packing leaves two choices for which pair of alphabeta-dimers form the physiologically relevant tetramer. The copies of the alphabeta-dimer are similar, each having one active site where the phosphorylated histidine residue and the thiol group of CoA are found. CoA is bound in an extended conformation to the nucleotide-binding motif in the N-terminal domain of the alpha-subunit. The phosphoryl group of the phosphorylated histidine residue is positioned at the amino termini of two alpha-helices, one from the C-terminal domain of the alpha-subunit and the other from the C-terminal domain of the beta-subunit. These two domains have similar topologies, despite only 14 % sequence identity. By analogy to other nucleotide-binding proteins, the binding site for the nucleotide may reside in the N-terminal domain of the beta-subunit. If this is so, the catalytic histidine residue would have to move about 35 A to react with the nucleotide.
J Mol Biol 1999 Jan 29
PMID:A detailed structural description of Escherichia coli succinyl-CoA synthetase. 991 2

Succinyl-CoA synthetase (SCS) catalyzes the substrate-level phosphorylation step of the citric acid cycle. The enzyme from Escherichia coli is an (alphabeta)2-heterotetramer with two active sites, one in each alphabeta-dimer. To determine whether the two active sites could function independently, mutations were made to split the tetramer into alphabeta-dimers. Because two choices for the tetramer (I and II) were possible from the X-ray crystallographic analyses, mutations were made at two different interfaces. All mutations based on tetramer I resulted in an intact tetramer. Of the two mutants based on tetramer II, one was insoluble and the other, where M156beta, Y158beta, R161beta and E162beta were changed to D, D, E and R, respectively, was a dimer. This quaternary structure was confirmed by fast protein liquid chromatography, blue native PAGE and ultracentrifugation. The DDER mutant has kinetic parameters similar to the tetrameric E. coli enzyme. Like the tetrameric enzyme, it shows ATP-facilitated dethiophosphorylation, proving that this property is a single-site effect. The ATP-facilitated dethiophosphorylation is inhibited by phosphate. It is concluded that dimerization of alphabeta-dimers is not a prerequisite for catalytic competency nor for alternating sites cooperativity in the tetramer. The rationale behind the dimer-of-dimers in E. coli SCS is still not known, but increased solubility, increased stability and in vivo interactions of the tetramer with other proteins are still possibilities.
J Mol Biol 1999 Jan 29
PMID:A dimeric form of Escherichia coli succinyl-CoA synthetase produced by site-directed mutagenesis. 991 3

Formaldehyde is a compound which is believed to have had a role in evolutionary processes. On the other hand, the (methyl)glyoxalase pathway is a route being present in all biological organisms whereas its function has not yet been recognized in the biochemical machinery. In this article it is raised that (methyl)glyoxalase path might have functioned as a bridge between formose and archaic reductive citric acid cycles in surface metabolists at the early stage of evolution. According to the theory, formaldehyde was essential for the mentioned system as a raw molecule. Based on thermodynamic calculations a simple way of regulation is also shown. The simplicity of the theory may be in a good agreement with and an explanation of why the (methyl)glyoxalase system is of ubiquitous nature.
Exp Mol Med 1999 Mar 31
PMID:A possible evolutionary role of formaldehyde. 1023 Oct 16

The insect form of Trypanosoma brucei depends on respiration for its energy requirements. It contains a fully functional mitochondrion with a complete citric acid cycle. Most of its enyzmes have been characterized to date. The current study presents the characterization of the histidine phosphorylation activity of one of the few remaining enzymes, succinyl CoA synthetase. The trypanosomal enyzme was identified by partial purification, followed by direct protein sequencing. It is rapidly phosphorylated, presumably through auto-phosphorylation, using either ATP or GTP as phosphate donors. The phosphorylation occurs exclusively on histidine residues. The histidine-bound phosphate can be donated to suitable phosphate acceptors in a rapid reaction. This phosphotransfer reaction is highly nucleotide selective, as only ADP, but none of the other nucleoside-diphosphates tested, can be used as a phosphate acceptor.
Mol Biochem Parasitol 1999 May 15
PMID:Histidine-phosphorylation of succinyl CoA synthetase from Trypanosoma brucei. 1037 92

To analyse genetic factors that potentially affect sugar quality and yield in Beta vulgaris, we designed primers based on 18 homologous ESTs and conserved regions of 32 heterologous ESTs encoding gene products that act in the Calvin cycle, the oxidative pentose phosphate cycle, photorespiration, synthesis, transport and degradation of sucrose, glycolysis, the citric acid cycle, nitrogen metabolism and osmoprotection. Data on the amplification of 54 gene homologues from B. vulgaris are presented. Among these are 35 homologues for which DNA sequence information from B. vulgaris is now available for the first time. For genetic mapping a PCR-based strategy using CAPS (cleaved amplified polymorphic sequence), DFLP (DNA fragment length polymorphism), SSCP (single-strand conformation polymorphism) and HD (heteroduplex) analysis was adopted. RFLP analysis was also used in some cases. The different techniques used for the detection of polymorphisms are evaluated with respect to their sensitivity and versatility. In all, 42 functional genes have been assigned to the nine linkage groups of sugar beet.
Mol Gen Genet 1999 Oct
PMID:PCR-based cloning and segregation analysis of functional gene homologues in Beta vulgaris. 1058 40


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