Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.2.13 (aldolase)
 3,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Membrane-mediated excessive intracellular calcium accumulation (EICA) is a fundamental pathogenetic event associated with chronic muscle degeneration in patients with Duchenne muscular dystrophy (DMD), and in animals with hereditary muscular dystrophy (HMD). Because of potential Ca(2+)-channel blocking properties, we investigated the relative efficacies of chronic diltiazem (DTZM) (50 mg/kg/d), nifedipine (NFDN) (6 mg/kg/d), and verapamil (VPML) (25 mg/kg/d) therapies in reducing EICA and improving dystrophic pathobiology beginning in 30-day-old male BIO-14.6 strain dystrophic hamsters (DH). Each agent, and sterile distilled water as vehicle control, was given in a single daily oral dose for 180 days to four groups each of DH and BIO-F1B strain normal hamsters (NH). Plasma [Ca] and [Mg]; plasma aldolase (ALD), creatine kinase (CK), and lactate dehydrogenase (LDH) activities; relative cardiac hypertrophy and relative soleus hypertrophy; tissue [Ca] and [Mg] of the heart and rectus femoris muscle, histology of rectus femoris, and overall mortality rate were quantitated. Muscle Mg was not modified in DH, or by any of these agents. NFDN produced significant edema in the soleus and myocardium. During the 6-month therapeutic trial, 45% DH and 18% NH died on VPML, 27% DH and 9% NH on NFDN, and 20% DH controls on distilled water, but none on DTZM; suggesting that DTZM treated DH lived longer than DH controls. Relative efficacy in regulating EICA in both the cardiac and skeletal muscles; plasma ALD, CK, and LDH; and improving associated dystrophic pathobiology was found to be DTZM >>> NFDN > VPML. DTZM appears to be the most effective and safest agent in mitigating EICA in cardiac and skeletal muscles, efflux of intracellular enzymes, histopathology of dystrophic muscle with sporadic necrosis, and chronic muscle degeneration in DH with HMD. DTZM therapy also halted the high morbidity and mortality associated with the dystrophic pathobiology inherent in DH.
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PMID:Regulation of membrane-mediated chronic muscle degeneration in dystrophic hamsters by calcium-channel blockers: diltiazem, nifedipine and verapamil. 846 95

We show here that in rat diaphragm muscle, a short time of incubation with the Ca(2+)-ionophore A23187 induced an increase in cytoskeleton-bound phosphofructokinase (EC 2.7.1.11) and aldolase (EC 4.1.2.13), whereas a longer period of incubation, which causes a pathological rise in intracellular Ca2+, induced a decrease in bound enzymes. Lactate concentration correlated with both phases of Ca2+ action on the binding of the enzymes. The increase in cytoskeleton-bound enzymes could be prevented by treatment with the calmodulin antagonists trifluoperazine or CGS 9343B (a novel, potent, and selective inhibitor of calmodulin activity). These results suggest that calmodulin is involved in the Ca(2+)-induced binding of the enzymes to muscle cytoskeleton.
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PMID:The dual effects of Ca2+ on binding of the glycolytic enzymes, phosphofructokinase and aldolase, to muscle cytoskeleton. 848 59

Complementary and genomic DNA clones coding for aldolase C-1, the fourth-type isozyme of aldolase in rice Oryza sativa L., have been characterized. The organization of the gene is quite similar to those encoding rice aldolase C-a and a maize cytoplasmic-type aldolase, in that introns are located in the same position. Amino acid sequences are highly conserved among cytoplasmic aldolases in plants. Expression of the gene in rice callus is activated by a protein phosphatase inhibitor okadaic acid, and is inhibited in the presence of thapsigargin, a reagent which increases calcium influx into the cytoplasm. The inhibition is rescued by the simultaneous addition of protein kinase inhibitor H-7. Thus, it is suggested that expression of the aldolase C-1 gene is regulated through a signal transduction pathway involving a Ca 2+ -mediated protein kinase-protein phosphatase system.
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PMID:Genomic structure of the rice aldolase isozyme C-1 gene and its regulation through a Ca 2+ -mediated protein kinase-phosphatase pathway. 861 63

Statistically significant charge clusters (basic, acidic, or of mixed charge) in tertiary protein structures are identified by new methods from a large representative collection of protein structures. About 10% of protein structures show at least one charge cluster, mostly of mixed type involving about equally anionic and cationic residues. Positive charge clusters are very rare. Negative (or histidine-acidic) charge clusters often coordinate calcium, or magnesium or zinc ions [e.g., thermolysin (PDB code: 3tln), mannose-binding protein (2msb), aminopeptidase (1amp)]. Mixed-charge clusters are prominent at interchain contacts where they stabilize quaternary protein formation [e.g., glutathione S-transferase (2gst), catalase (8act), and fructose-1,6-bisphosphate aldolase (1fba)]. They are also involved in protein-protein interaction and in substrate binding. For example, the mixed-charge cluster of aspartate carbamoyl-transferase (8atc) envelops the aspartate carbonyl substrate in a flexible manner (alternating tense and relaxed states) where charge associations can vary from weak to strong. Other proteins with charge clusters include the P450 cytochrome family (BM-3, Terp, Cam), several flavocytochromes, neuraminidase, hemagglutinin, the photosynthetic reaction center, and annexin. In each case in Table 2 we discuss the possible role of the charge clusters with respect to protein structure and function.
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PMID:Clusters of charged residues in protein three-dimensional structures. 871 Aug 74

The binding of 2-[(2-bis-[carboxymethyl]amino-5-methylphenoxy)-methyl] 6-methoxy-8-bis[carboxymethyl] aminoquinoline, the fluorescent calcium probe Quin2, to serum albumin and several other proteins has been investigated. Changes in fluorescence emission spectra and fluorescence anisotropy revealed interactions between Quin2 and several proteins including human serum albumin, bovine serum albumin, aldolase, phosphoglucose isomerase, glyceraldehyde-3-phosphate dehydrogenase, and alkaline phosphatase. Protein-probe interactions were inhibited by the presence of calcium. Binding was also measured by resonance energy transfer and gel permeation chromatography. Equilibrium binding constants for Quin2 were quantitated by the application of the recently-developed "SPECTRABIND' program to spectroscopic data (D. Toptygin and L. Brand, Anal. Biochem., 224 (1995) 330-338). Binding of Quin2 to human serum albumin is discussed in terms of the published X-ray crystal structure of human serum albumin (X.M. He and D.C. Carter, Nature, 358 (1992) 209-215).
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PMID:Steady-state and time-resolved fluorescence measurements for studying molecular interactions: interaction of a calcium-binding probe with proteins. 896 69

Three isoforms of fructose-1,6-bisphosphate aldolase were found to bind specifically to the actin-containing filament of the cytoskeleton and to show tissue-specific binding patterns. Aldolase A (muscle type) bound more tightly to the skeletal muscle cytoskeleton among the three isozymes, while aldolase B (liver type) preferred the liver cytoskeleton to those of other tissues. The specific binding of aldolase A to the skeletal muscle cytoskeleton was inhibited strongly by the substrates fructose 1,6-bisphosphate and fructose 1-phosphate. Several mutant aldolases A were examined to identify the amino acid residues or regions that play a role in specific binding. Among the mutant aldolases tested, A-E34D, A-K41N, and A-Y363S exhibited remarkably reduced binding activities. Experiments using FITC-labeled enzymes and Rh-labeled phalloidin disclosed that aldolase A associated with the cytoskeleton. Specifically, when aldolase A was incubated with human fibroblast MRC-5 permeabilized with Triton X-100, aldolase A bound to the actin filaments in the stress fibers within the cell. Aldolase A reversibly inhibited the contraction of MRC-5 cells which usually occurred in the presence of Mg2(+)-ATP and Ca2+. These results provide direct evidence that aldolase binds specifically to the actin-containing stress fibers and suggest that aldolase may regulate cell contraction through its reversible binding to the filaments in the permeabilized MRC-5 fibroblast.
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PMID:Mode of interactions of human aldolase isozymes with cytoskeletons. 924 96

Previous studies have demonstrated that the two cysteine residues in the calcium-binding protein S100B are required for its extracellular functions. In the present study, a recombinant S100B protein and mutant S100Bs containing one or no cysteine residue(s) have been used to determine the contribution of cysteine residues to S100B dimerization and interaction with the intracellular target proteins aldolase, phosphoglucomutase, and the microtubule associated tau protein. Mutation of C68 to a valine or C84 to a serine, C68 to valine and C84 to serine, or C68 to valine and C84 to alanine did not significantly alter S100B activation of aldolase. However, mutation of C84 to serine resulted in calcium-independent S100B activation of phosphoglucomutase and a loss of S100B inhibition of tau phosphorylation by Ca2+/calmodulin-dependent protein kinase II. The altered functionality of the C84S mutant with phosphoglucomutase and tau was not due to altered physical properties or dimerization state. All of the mutants exhibited heat stability and calcium dependent conformational changes which were identical to recombinant S100B. In addition, S100B proteins containing two, one or no cysteine residues behaved as dimers in size exclusion chromatography experiments in the presence or absence of calcium as well as in the presence or absence of reducing agent. Dynamic light scattering and analytical ultracentrifugation experiments confirmed that dimerization was not affected by calcium or reducing agent. Altogether these results demonstrate that S100B dimerization is not calcium- or sulfhydryl-dependent. In summary, cysteine residues are not necessary for the noncovalent dimerization of S100B, but are important in certain S100B target protein-interactions.
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PMID:The role of cysteine residues in S100B dimerization and regulation of target protein activity. 942 66

We have previously obtained indirect evidence that sarcoplasmic reticulum (SR) vesicles from cardiac and skeletal muscle contain the complete chain of glycolytic enzymes from aldolase to pyruvate kinase. To investigate directly whether pyruvate kinase and other glycolytic enzymes are anatomically associated with the SR, electron microscopic immunogold++ labeling studies were carried out in isolated SR vesicles using specific primary antibodies against selected glycolytic enzymes and Ca2+-ATPase, and appropriate secondary antibodies labeled with 6-nm or 12-nm gold particles. Pyruvate kinase was broadly dispersed on the cytoplasmic side of the SR membrane of both cardiac and skeletal muscle vesicles. With 6-nm gold particles, density of binding to pyruvate kinase was 2522 +/- 445 and 4171 +/- 1379 particles/microm2 for cardiac and skeletal muscle SR, respectively. Binding densities to Ca2 +/- ATPase were similar (2550 +/- 639 particles/ microm2 for cardiac SR, 3877 +/- 408 particles/microm2 for skeletal muscle SR). Immunogold labeling of ultrathin sections indicated that pyruvate kinase was attached to the SR membrane and located immediately adjacent to the Ca2+-ATPase. Aldolase and glyceraldehyde phosphate dehydrogenase were also found to be attached to the cytoplasmic side of SR vesicles and located in close proximity to Ca2+-ATPase. These results provide the first ultrastructural evidence that glycolytic enzymes are anatomically associated with SR membranes and located near the SR C2+-ATPase. The results further support the hypothesis that ATP generated by SR-associated glycolytic enzymes is coupled to SR Ca2+ active transport.
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PMID:Ultrastructural localization of glycolytic enzymes on sarcoplasmic reticulum vesticles. 957 39

A low-affinity fluorescent Ca2+ indicator Indo-1FF was used to measure cytoplasmic Ca2+ increments in single smooth muscle cells isolated from the urinary bladder of the guinea-pig. The in vitro Kd of Indo-1FF for Ca2+ measured at the microscope stage was 21 microM. Calibration parameters measured in the cell differed substantially from respective in vitro values suggesting that the properties of the cytoplasmic dye had been altered. Addition of proteins (aldolase or albumin) increased the in vitro F405/F495 ratio close to the range observed intracellularly. Emission spectra of Ca(2+)-free Indo-1FF demonstrated a blue-shift of 29 nm with 10 mg/ml aldolase and 60 nm with 10 mg/ml albumin. The Kd value of Indo-1FF for Ca2+ in vitro was not changed by addition of aldolase (up to 20 mg/ml) and was approximately doubled in the presence of 20 mg/ml albumin. Intracellular calibration either by skinning the cells with beta-escine, 'opening' the cell or by intracellular perfusion of 100 microM free Ca2+ (40 mM DPTA-Ca2+ buffer) suggest that the affinity of intracellular Indo-1FF for Ca2+ is not markedly changed. The Indo-1FF concentration of 20 microM in the patch-pipette was found to be a reasonable compromise between acceptable signal-to-noise ratio and increased cytoplasmic Ca2+ buffering. This is because neither the amplitude nor the time-course of depolarization-induced micromolar Ca2+ increments were significantly changed during cell loading with this concentration of the dye. In contrast to Indo-1 loaded cells where rapid changes of [Ca2+]i were buffered, in Indo-1FF loaded cells ICa evoked rapid (rate of rise 150 microM/s) and large (4-6 microM in 35-60 ms) increments of free Ca2+. This results suggest that [Ca2+]i increments in smooth muscle cells are fast and large.
Cell Calcium 1998 May
PMID:Use of Indo-1FF for measurements of rapid micromolar cytoplasmic free Ca2+ increments in a single smooth muscle cell. 968 Nov 94

Rhabdomyolysis is a condition affecting body homeostasis that results from impaired supply of muscles with energy, nutritional factors and blood. Complex pathophysiological mechanism causes that extended myolysis may complicate different clinical conditions, such as: crush syndrome, excessive physical effort (work, seizures), toxic effect of drugs and toxins, water-electrolyte disturbances, congenital enzymatic deficiencies etc. It seems that on the cellular level, essential role is played by excessively high intracytoplasmatic calcium level, which affects metabolic processes. So high calcium level is a consequence of muscular cell injury irrespective to its reason. It manifests clinically as muscular weakness, pal and oedema and laboratory tests reveal elevated CK, GOT, GPT, aldolase and LDH levels as well as dark brown urine colour. Demonstration of elevated serum myoglobin level or its presence in urine directly confirms development of rhabdomyolysis. In unfavorable conditions, rhabdomyolysis may result in acute renal failure. Appropriately early and adequate water supply and alkalization plays an essential role in prevention of impairment in renal function. In advanced phase of renal failure, hemodialysis is a standard treatment.
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PMID:[Rhabdomyolysis: clinical features, causes, complications and treatment]. 974 Nov 96


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