Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.3.3.1 (citrate synthase)
4,488 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 10 month old female infant was evaluated for severe lactic acidosis. Clinically she was well nourished and had a substantial amount of adipose tissue despite recurrent episodes of acidosis. Her psychomotor development was retarded, her movements were dystonic and generalized seizures punctuated her course. Metabolic abnormalities included elevated blood concentrations of lactate, pyruvate, beta-hydroxybutyrate, acetoacetate, alanine, proline and glycine, decreased blood concentrations of glutamine, aspartate, valine and citrate, and intermittent elevations of serum cholesterol. A trial on a high-fat diet worsened the clinical condition and intensified the ketoacidosis and hyperalaninemia. Analysis of hepatic tissue obtained by open biopsy revealed increased concentrations of lactate, alanine, acetyl-CoA and other short-chain acyl-CoA esters, and decreased concentrations of oxaloacetate, citrate, alpha-ketoglutarate, malate and aspartate. The blood and tissue metabolic perturbations reflected a deficiency of hepatic pyruvate carboxylase. The apparent Km of hepatic citrate synthase for oxaloacetate was 4.6 micrometer. Calculated tissue oxaloacetate concentrations were 0.50--0.84 micrometer suggesting that tricarboxylic acid cycle activity was severely limited by the decreased availability of this substrate. An iv glucose tolerance test resulted in the paradoxical synthesis of ketone bodies. This observation, coupled with the intermittent hypercholesterolemia and the increased tissue acetyl-CoA concentrations, suggests that pyruvate carboxylase is important in modulating the fractional distribution of intracellular acetyl-CoA between the tricarboxylic acid cycle, the beta-hydroxy-beta-methyl-glutaryl-CoA cycle (and the synthesis of cholesterol and ketone bodies), and fatty acid synthesis. Treatment in future cases might be directed toward increasing tissue concentrations of oxaloacetate.
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PMID:The clinical and biochemical implications of pyruvate carboxylase deficiency. 41 60

After a prototrophic strain of Staphylococcus aureus had been exposed to diethyl sulfate, 28 isoleucine- and isoleucine-valine-dependent mutants (ilv mutants) were isolated. On the basis of auxanography, their ability to accumulate intermediates of isoleucine and valine biosynthesis, and intergeneric syntrophism with ilv mutants of Salmonella typhimurium, all mutants were placed into four groups, each of which corresponded to a presumed enzymatic deficiency, as follows: group A, deficient in l-threonine deaminase; group B, deficient in the condensing enzyme; group C, deficient in reductoisomerase; group D, deficient in alpha-beta-dihydroxy acid dehydrase. No mutants blocked in the terminal (transaminase) reactions were isolated. Transduction analyses (best-fit, ratio, and complementation tests) with the use of phage 83 established that the linear arrangement of the structural genes is identical with the order of participation of their enzymes in isoleucine and valine biosynthesis, and that these genes comprise a single linkage group which can exist on a single donor fragment during transduction.
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PMID:Biochemical and genetic analysis of isoleucine and valine biosynthesis in Staphylococcus aureus. 602 2

The activities of key enzymes in the valine catabolic pathway--branched-chain aminotransferase, branched-chain alpha-keto acid dehydrogenase complex, methacrylyl (MC)-coenzyme A (CoA) hydratase (crotonase), and 3-hydroxyisobutyryl-CoA (HIB-CoA) hydrolase--were measured in normal and cirrhotic human livers. Unlike rat liver, which does not contain branched-chain aminotransferase, the aminotransferase activity in the normal liver was measurable and is increased somewhat in cirrhosis of the human liver. The total activity of branched-chain alpha-keto acid dehydrogenase complex in the normal human liver was approximately 1% of that in rat liver, and 20% to 30% of the complex was in the active form in both normal and cirrhotic livers. Only the actual activity of the enzyme was significantly decreased by cirrhosis. These results suggest that human liver is less active than rat liver in the catabolism of branched-chain amino and alpha-keto acids. Activities of MC-CoA hydratase and HIB-CoA hydrolase in human liver were very high compared with that of branched-chain alpha-keto acid dehydrogenase complex, suggesting an important role for these enzymes in catabolism of a potentially toxic compound, MC-CoA, formed as an intermediate in the catabolism of valine and isobutyrate. Cirrhosis resulted in a significant decrease in HIB-CoA hydrolase activity but had no effect on the citrate synthase activity, suggesting that the decrease in HIB-CoA hydrolase activity does not reflect a general decrease in mitochondria but that it may contribute to cellular damage that culminates in liver failure.
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PMID:The valine catabolic pathway in human liver: effect of cirrhosis on enzyme activities. 893 68

We have studied cultured skin fibroblasts from three siblings and one unrelated individual, all of whom had fatal mitochondrial disease manifesting soon after birth. After incubation with 1 mM glucose, these four cell strains exhibited lactate/pyruvate ratios that were six times greater than those of controls. On further analysis, enzymatic activities of the pyruvate dehydrogenase complex, the 2-oxoglutarate dehydrogenase complex, NADH cytochrome c reductase, succinate dehydrogenase, and succinate cytochrome c reductase were severely deficient. In two of the siblings the enzymatic activity of cytochrome oxidase was mildly decreased (by approximately 50%). Metabolite analysis performed on urine samples taken from these patients revealed high levels of glycine, leucine, valine, and isoleucine, indicating abnormalities of both the glycine-cleavage system and branched-chain alpha-ketoacid dehydrogenase. In contrast, the activities of fibroblast pyruvate carboxylase, mitochondrial aconitase, and citrate synthase were normal. Immunoblot analysis of selected complex III subunits (core 1, cyt c(1), and iron-sulfur protein) and of the pyruvate dehydrogenase complex subunits revealed no visible changes in the levels of all examined proteins, decreasing the possibility that an import and/or assembly factor is involved. To elucidate the underlying molecular defect, analysis of microcell-mediated chromosome-fusion was performed between the present study's fibroblasts (recipients) and a panel of A9 mouse:human hybrids (donors) developed by Cuthbert et al. (1995). Complementation was observed between the recipient cells from both families and the mouse:human hybrid clone carrying human chromosome 2. These results indicate that the underlying defect in our patients is under the control of a nuclear gene, the locus of which is on chromosome 2. A 5-cM interval has been identified as potentially containing the critical region for the unknown gene. This interval maps to region 2p14-2p13.
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PMID:A novel syndrome affecting multiple mitochondrial functions, located by microcell-mediated transfer to chromosome 2p14-2p13. 1115 34

Thiolactomycin (TLM) is an antibiotic that inhibits bacterial type II fatty acid synthesis at the condensing enzyme step, and beta-ketoacyl-acyl carrier protein synthase I (FabB) is the relevant target in Escherichia coli. TLM resistance is associated with the upregulation of efflux pumps. Therefore, a tolC knockout mutant (strain ANS1) was constructed to eliminate the contribution of type I secretion systems to TLM resistance. Six independent TLM-resistant clones of strain ANS1 were isolated, and all possessed the same missense mutation in the fabB gene (T1168G) that directed the expression of a mutant protein, FabB(F390V). FabB(F390V) was resistant to TLM in vitro. Leucine is the only other amino acid found at position 390 in nature, and the Staphylococcus aureus FabF protein, which contains this substitution, was sensitive to TLM. Structural modeling predicted that the CG2 methyl group of the valine side chain interfered with the positioning of the C11 methyl on the isoprenoid side chain of TLM in the binary complex, whereas the absence of a bulky methyl group on the leucine side chain permitted TLM binding. These data illustrate that missense mutations that introduce valine at position 390 confer TLM resistance while maintaining the vital catalytic properties of FabB.
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PMID:A missense mutation in the fabB (beta-ketoacyl-acyl carrier protein synthase I) gene confers tiolactomycin resistance to Escherichia coli. 1195 52

Ramakrishnan, T. (Yale University, New Haven, Conn.), and Edward A. Adelberg. Regulatory mechanisms in the biosynthesis of isoleucine and valine. I. Genetic derepression of enzyme formation. J. Bacteriol. 87:566-573. 1964.-A total of 60 mutants of Escherichia coli K-12 resistant to 10(-2)m valine were isolated from the valine-sensitive F' strain AB1206. Conjugation experiments showed that in five of these mutants the valine-resistance locus is closely linked to the structural genes governing isoleucine-valine biosynthesis. In these five valine-resistant mutants, three enzymes of the isoleucine-valine pathway were found to be coordinately derepressed: l-threonine deaminase, dihydroxy acid dehydrase, and transaminase B. Two other enzymes of this pathway, the condensing enzyme and the reductoisomerase, were unaffected. The mutation from valine-sensitivity to valine-resistance appears to have altered an operator locus, because the derepressed state is dominant over the repressed state in diploids heterozygous for the valine-resistance locus. The valine-resistant mutants excrete isoleucine into the medium. The significance of these findings with respect to the valine-sensitivity of E. coli K-12 and the regulation of the biosynthesis of isoleucine and valine by this organism are discussed.
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PMID:REGULATORY MECHANISMS IN THE BIOSYNTHESIS OF ISOLEUCINE AND VALINE. I. GENETIC DEREPRESSION OF ENZYME FORMATION. 1412 71

Ramakrishnan, T. (Yale University, New Haven, Conn.), and Edward A. Adelberg. Regulatory mechanisms in the biosynthesis of isoleucine and valine. II. Identification of two operator genes. J. Bacteriol. 89:654-660. 1965.-A tightly clustered set of five structural genes governs the synthesis of the five enzymes of isoleucine and valine biosynthesis in Escherichia coli. Three of the genes governing transaminase B, dehydrase, and threonine deaminase, are controlled by a single operator locus, designated oprA. The structural gene governing the condensing enzyme is controlled by a second operator locus, designated oprB. Both oprA and oprB have been shown to regulate structural genes which are cis, but not trans, to their own operator. No mutations have yet been found which affect the level of reductoisomerase, but the existence of a third operator controlling the synthesis of this enzyme can be inferred. Enzyme derepression resulting from mutations in oprA confers resistance to high levels of valine. Derepression of the condensing enzyme resulting from mutations in oprB confers resistance to low levels of valine, and to alpha-aminobutyric acid. The significance of these findings with respect to the valine sensitivity of E. coli strain K-12 is discussed.
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PMID:REGULATORY MECHANISMS IN THE BIOSYNTHESIS OF ISOLEUCINE AND VALINE. II. IDENTIFICATION OF TWO OPERATOR GENES. 1427 40

Ramakrishnan, T. (Yale University, New Haven, Conn.), and Edward A. Adelberg. Regulatory mechanisms in the biosynthesis of isoleucine and valine. III. Map order of the structural genes and operator genes. J. Bacteriol. 89:661-664. 1965.-A new method has been employed to determine the map order of the structural genes and operator genes governing the enzymes of the isoleucine-valine biosynthetic pathway. This method relies on the observation that phage transduction of markers carried on an F-genote leads to the establishment in the recipient of F-genotes of various lengths. Using this method, we have established that the order of loci is the following: F/ilvE ilvD ilvA oprA/ilvC/ilvB oprB. The operator locus, oprA, regulates the activity of structural genes ilvE (transaminase B), ilvD (dehydrase), and ilvA (threonine deaminase). The operator locus, oprB, regulates the activity of ilvB (condensing enzyme). An operator for ilvC (reductoisomerase) can be inferred to exist, but has not yet been detected genetically. The loci ilvB and oprB have been shown to be at the extreme right end of the sequence, but their positions relative to each other remain to be established.
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PMID:REGULATORY MECHANISMS IN THE BIOSYNTHESIS OF ISOLEUCINE AND VALINE. 3. MAP ORDER OF THE STRUCTURAL GENES AND OPERATOR GENES. 1427 41

Since cardiac cachexia could be associated with alterations in muscular mitochondrial metabolism, we hypothesized that the expected alterations in the activities of mitochondrial oxidative enzymes could be associated with changes in mitochondrial protein synthesis in oxidative skeletal muscles. Cardiac cachexia was provoked in male rats by the ligation of the left coronary artery. Six cachectic and 6 control rats were age-paired, and their food intake was observed. The synthesis of mitochondrial proteins was measured by [1-13C]-valine infusion in soleus, tibilais, myocardium, and liver. Muscles (soleus, gastrocnemius, and tibialis anterior), heart, kidneys, liver, and visceral adipose tissue were weighed. Mitochondrial cytochrome c oxydase IV as well as citrate synthase and myosin ATPase activities were measured. As expected, decreased food intake was observed in the cachectic group. Heart, kidney, and liver weights were higher in the cachectic group, while the visceral adipose tissue weight was lower (P < .01). No changes in muscle weights were observed. Soleus mitochondrial proteins fractional synthesis rate was higher in the cachectic group (P = .054). Cytochrome c oxydase IV activity was reduced (P = .009) and increased (P = .038) in the soleus and liver of the cachectic rats, respectively. No change in citrate synthase activity was observed. Myosin ATPase activity was reduced in the gastrocnemius of the cachectic group (P < .01). Mitochondrial protein synthesis is increased in the soleus of rats with cardiac cachexia, suggesting a compensatory mechanism of the impaired oxidative mitochondrial function. Further work should assess whether the mitochondrial protein synthesis is altered in chronic heart failure patients with cardiac cachexia, and whether this is the cause or the consequence of cachexia.
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PMID:Mitochondrial protein synthesis is increased in oxidative skeletal muscles of rats with cardiac cachexia. 2465 92

The mechanisms by which Anopheles gambiae mosquitoes survive the desiccating conditions of the dry season in Africa and are able to readily transmit malaria soon after the rains start remain largely unknown. The desiccation tolerance and resistance of female An. gambiae M and S reared in contrasting environmental conditions reflecting the onset of dry season ("ods") and the rainy season ("rs") was determined by monitoring their survival and body water loss in response to low relative humidity. Furthermore, we investigated the degree to which the physiology of 1-h and 24-h-old females is altered at "ods" by examining and comparing their quantitative metabotypes and proteotypes with conspecifics exposed to "rs" conditions. Results showed that distinct biochemical rearrangements occurred soon after emergence in female mosquitoes that enhance survival and limit water loss under dry conditions. In particular, three amino acids (phenylalanine, tyrosine, and valine) playing a pivotal role in cuticle permeability decreased significantly from the 1-h to 24-h-old females, regardless of the experimental conditions. However, these amino acids were present in higher amounts in 1-h-old female An. gambiae M reared under "ods" whereas no such seasonal difference was reported in S ones. Together with the 1.28- to 2.84-fold increased expression of cuticular proteins 70 and 117, our data suggests that cuticle composition, rigidity and permeability were adjusted at "ods". Increased expression of enzymes involved in glycogenolytic and proteolytic processes were found in both forms at "ods". Moreover, 1-h-old S forms were characterised by elevated amounts of glycogen phosphorylase, isocitrate dehydrogenase, and citrate synthase, suggesting an increase of energetic demand in these females at "ods".
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PMID:Novel insights into the metabolic and biochemical underpinnings assisting dry-season survival in female malaria mosquitoes of the Anopheles gambiae complex. 2508 9


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