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:1.2.1.13 (glyceraldehyde-3-phosphate dehydrogenase)
6,511 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A substantial portion of the primary structure of pig liver glyceraldehyde-3-phosphate dehydrogenase has been investigated and the results compared with those previously reported for the pig muscle enzyme. Liver and muscle glyceraldehyde-3-phosphate dehydrogenases show the same amino acid content, and the first N-terminal residues occur in the same sequence. No differences in N-terminal residues and amino acid composition have been evidenced by analysis of several tryptic peptides, which account for about 50% of the total amino acid sequence. From the electrophoretic mobilities of peptides T8 T9 and T25 it is concluded that residues Asp 60, Asp 67 and Glu 220 in the reported sequence of the pig muscle enzyme must be present as amides in the liver enzyme. The NAD+ content was found to be 2 mol per tetramer, while higher values have been reported for the muscle enzyme from various mammalian sources. The reactivity of lysyl side chains towards pyridoxal 5'-phosphate has been examined: the results indicate that Lys 212 is the main site reacted in fully inactivated pig liver holoenzyme. A similar result has been found for rabbit muscle apoenzyme, whereas rabbit muscle holoenzyme reacts at Lys 212 and 191.
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PMID:A structural study of pig liver glyceraldehyde-3-phosphate dehydrogenase. 18 38

Amino acid sequences have been compared for thermophilic and mesophilic molecules of ferredoxin, glyceraldehyde-3-phosphate dehydrogenase, and lactate dehydrogenase. It is shown that Gly, Ser, Ser, Lys, and Asp in mesophiles are generally substituted by Ala, Ala, Thr, Arg, and Glu, respectively, in thermophiles. These exchanges suggest that thermal stability can be achieved by the addition of many small changes throughout the molecule without significant change in the backbone conformation. Their overall effect is primarily to increase internal and decrease external hydrophobicity as well as to favor helix stabilizing residues in helices. These substitutions minimize interruption of function or internal residue packing arrangements. Although the analysis has been confined to the above-mentioned molecules, the observed stabilizing principles may be more generally applicable.
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PMID:Thermal stability and protein structure. 51 63

The NH2-terminal amino acid sequence of rat skeletal muscle glyceraldehydephosphate dehydrogenase (D-glyceraldehyde-3-phosphate : NAD+ oxidoreductase(physphorylating), EC 1.2.1.12) was determined to be Val-Lys-Val-Gly-Val-Asn-Gly-Phe-Gly-Arg-Ile-Gly-Arg-Leu-Val-Thr-Arg-Ala-Ala-Phe-Ser-Ser-(-)-(-)--Val-Asx-Ile-Val-Ala-Ile. The presence of Asn instead of Asp in position 6 differentiates this enzyme from other glyceraldehyde-3-phosphate dehydrogenases so far sequenced with the exception of the enzymes isolated from liver. The location of Asn in position 6 has been considered as a specific property of liver glyceraldehyde-3-phosphate dehydrogenase (Kulbe, K.D., Jackson, K.W. and Tang, J. (1975) Biochem. Biophys. Res. Commun. 67, 35--42); this suggestion is not sustained by the results of the present investigation. The amino acid composition of the rat skeletal muscle dehydrogenase demonstrates the unusually low histidine content of this enzyme as compared to other mammalian muscle glyceraldehyde-phosphate dehydrogenases.
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PMID:Structural studies on glyceraldehyde-phosphate dehydrogenase from rat skeletal muscle. 62 46

The unusual thermolability of glyceraldehyde-3-phosphate dehydrogenase from the facultative thermophile Bacillus coagulans KU (Crabb et al., Biochemistry 16:4840-4847, 1977) has provided the first opportunity to study a homologous enzyme from the same genus that exhibits a marked difference in thermostability. In pursuit of the structural bases for the thermostability of proteins, the sequences of the amino terminus (residues 1 through 27) and the active-site cysteine cyanogen bromide peptide (residues 130 through 167) of this enzyme have been determined and compared with sequences of the enzyme from other sources. The importance of comparing phylogenetically related proteins is evident from the 87% identity found between these sequences in the enzyme from B. coagulans and Bacillus stearothermophilus, versus only 45% identity for all other known sequences. The marked sequence identity of the enzyme from the two Bacillus species drew attention to the variable region (residues 138 through 140a) which is exposed to the exterior of the quaternary structure of this enzyme. Based on the reported crystallographic structures of the enzyme from lobster muscle and B. stearothermophilus and space-filling models of the variable region, the segment Asp-Pro-Lys-Ala in B. stearothermophilus should be more thermostable than the analogous sequence, Asp-Ala-Ala-Asn, from B. coagulans. In addition, the space-filling models suggested that the spatial relationship of an amino acid side chain and its potential for close packing and interactions with neighboring side chains may be more important than the type of amino acid substituted.
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PMID:Sequence homology in the amino-terminal and active-site regions of thermolabile glyceraldehyde-3-phosphate dehydrogenase from a thermophile. 746 49

Polyglutamine-containing proteins expressed in the CAG repeat diseases Huntington's disease and dentatorubralpallidoluyisian atrophy have recently been suggested to inhibit the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). To examine the consequences of GAPDH inhibition upon neuronal survival, we exposed murine neocortical cell cultures to the inhibitor of GAPDH and triosephosphate isomerase, alpha-monochlorohydrin. Cultures exposed to 6-15 mM alpha-monochlorohydrin for 48 h exhibited an increase in dihydroxyacetone phosphate and a decrease in neuronal ATP that was followed by progressive neuronal death; some glial death occurred at high drug concentrations. The neuronal death was characterized by cell body shrinkage and chromatin condensation and was sensitive to cycloheximide and to the caspase inhibitors Z-Val-Ala-Asp fluoromethylketone and tert-butoxycarbonyl-Asp fluoromethylketone. Neurons in striatal cell cultures were more vulnerable to death induced by exposure to alpha-monochlorohydrin, except that NADPH-diaphorase(+) neurons were selectively spared. Repeated addition of the glycolytic endpoint metabolite pyruvate to the bathing medium attenuated both the drop in neuronal ATP and the neuronal cell death.
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PMID:Neuronal death in cultured murine cortical cells is induced by inhibition of GAPDH and triosephosphate isomerase. 970 87

Treatment with cytosine beta-D-arabinoside (AraC; 300 microM) induced a time-dependent accumulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) protein in nuclei purified from cultured cerebellar granule cells, with a concomitant degradation of lamin B1, a nuclear membrane protein and a substrate of CPP32/caspase-3. Moreover, Asp-Glu-Val-Asp-fluoromethyl ketone (DEVD-fmk), a CPP32-selective antagonist, dose-dependently suppressed AraC-induced apoptosis of these neurons. Nuclear accumulation of GAPDH protein was associated with a progressive decrease in the activity of uracil-DNA glycosylase (UDG), one of the nuclear functions of GAPDH. The nuclear dehydrogenase activity of GAPDH was initially increased after treatment and then decreased parallel to UDG activity. Six GAPDH isoforms were detected in the nuclei of AraC-treated cells. The more alkaline isoforms, 1-3, constituted the bulk of the nuclear GAPDH, and the remaining isoforms, 4-6, were the minor species. Levels of all six isoforms were increased after treatment with AraC for 16 h; a 4-h treatment increased levels of only isoforms 4 and 5. Thus, it appears that various GAPDH isoforms are differentially regulated and may have distinct apoptotic roles. Pretreatment with GAPDH antisense oligonucleotide blocked the nuclear translocation of GAPDH isoforms, and the latter process occurred concurrently with a decrease in cytosolic GAPDH isoforms. Sodium nitroprusside-induced NAD labeling of nuclear GAPDH showed a 60% loss of GAPDH labeling after AraC treatment, suggesting that the active site of GAPDH may be covalently modified, denatured, or improperly folded. The unfolded protein response elicited by denatured GAPDH may contribute to AraC-induced neuronal death.
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PMID:Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase isoforms during neuronal apoptosis. 1003 63

Tetrameric phosphorylating glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from Bacillus stearothermophilus has been described as a "dimer of dimers" with three nonequivalent interfaces, P-axis (between subunits O and P and between subunits Q and R), Q-axis (between subunits O and Q and between subunits P and R), and R-axis interface (between subunits O and R and between subunits P and Q). O-P dimers, the most stable and the easiest to generate, have been created by selective disruption of hydrogen bonds across the R- and Q-axis interfaces by site-directed mutagenesis. Asp-186 and Ser-48, and Glu-276 and Tyr-46, which are hydrogen bond partners across the R- and Q-axis interfaces, respectively, have been replaced with glycine residues. All mutated residues are highly conserved among GAPDHs from different species and are located in loops. Both double mutants D186G/E276G and Y46G/S48G were dimeric, while all single mutants remained tetrameric. As previously described [Clermont, S., Corbier, C., Mely, Y., Gerard, D., Wonacott, A., and Branlant, G. (1993) Biochemistry 32, 10178-10184], NAD binding to wild type GAPDH (wtGAPDH) was interpreted according to the induced-fit model and exhibited negative cooperativity. However, NAD binding to wtGAPDH can be adequately described in terms of two independent dimers with two interacting binding sites in each dimer. Single mutants D186G, E276G, and Y46G exhibited behavior in NAD binding similar to that of the wild type, while both dimeric mutants D186G/E276G and Y46G/S48G exhibited positive cooperativity in binding the coenzyme NAD. The fact that O-P dimer mutants retained cooperative behavior shows that (1) the P-axis interface is important in transmitting the information induced upon NAD binding inside the O-P dimer from one subunit to the other and (2) the S-loop of the R-axis-related subunit is not directly involved in cooperative binding of NAD in the O-P dimer. In both O-P dimer mutants, the absorption band of the binary enzyme-NAD complex had a highly decreased intensity compared to that of the wild type and, in addition, totally disappeared in the presence of G3P or 1,3-dPG. However, no enzymatic activity was detected, indicating that the formed ternary enzyme-NAD-G3P or -1, 3-dPG complex was not catalytically efficient. In the O-P dimers, the interaction with the S-loop of the R-axis-related subunit is disrupted, and therefore, the S-loop should be less structured. This resulted in increased accessibility of the active site to the solvent, particularly for the adenosine-binding site of NAD. Thus, together, this is likely to explain both the lowered affinity of the dimeric enzyme for NAD and the absence of activity.
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PMID:Dimers generated from tetrameric phosphorylating glyceraldehyde-3-phosphate dehydrogenase from Bacillus stearothermophilus are inactive but exhibit cooperativity in NAD binding. 1058 31

The rat luminal endoplasmic-recticulum calcium-binding proteins 1 and 2 (CaBP1 and CaBP2 respectively) are members of the protein disulphide-isomerase (PDI) family. They contain two and three thioredoxin boxes (Cys-Gly-His-Cys) respectively and, like PDI, may be involved in the folding of nascent proteins. We demonstrate here that CaBP1, similar to PDI and CaBP2, can complement the lethal phenotype of the disrupted Saccharomyces cerevisiae PDI gene, provided that the natural C-terminal Lys-Asp-Glu-Leu sequence is replaced by His-Asp-Glu-Leu. Both the in vitro RNase AIII-re-activation assays and in vivo pro-(carboxypeptidase Y) processing assays using CaBP1 and CaBP2 thioredoxin (trx)-box mutants revealed that, whereas the three trx boxes in CaBP2 seem to be functionally equivalent, the first trx box of CaBP1 is significantly more active than the second trx box. Furthermore, only about 65% re-activation of denatured reduced RNase AIII could be obtained with CaBP1 or CaBP2 compared with PDI, and the yield of PDI-catalysed reactions was significantly reduced in the presence of either CaBP1 or CaBP2. In contrast with PDI, neither CaBP1 nor CaBP2 could catalyse the renaturation of denatured glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which is a redox-independent process, and neither protein had any effect on the PDI-catalysed refolding of GAPDH. Furthermore, although PDI can bind peptides via its b' domain, a property it shares with PDIp, the pancreas-specific PDI homologue, and although PDI can bind malfolded proteins such as 'scrambled' ribonuclease, no such interactions could be detected for CaBP2. We conclude that: (1) both CaBP2 and CaBP1 lack peptide-binding activity for GAPDH attributed to the C-terminal region of the a' domain of PDI; (2) CaBP2 lacks the general peptide-binding activity attributed to the b' domain of PDI; (3) interaction of CaBP2 with substrate (RNase AIII) is different from that of PDI and substrate; and (4) both CaBP2 and CaBP1 may promote oxidative folding by different kinetic pathways.
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PMID:Functional roles and efficiencies of the thioredoxin boxes of calcium-binding proteins 1 and 2 in protein folding. 1141 39

The secreted production of heterologous proteins in Kluyveromyces lactis was studied. A glucoamylase (GAA) from the yeast Arxula adeninivorans was used as a reporter protein for the study of the secretion efficiencies of several wild-type and mutant strains of K. lactis. The expression of the reporter protein was placed under the control of the strong promoter of the glyceraldehyde-3-phosphate dehydrogenase of Saccharomyces cerevisiae. Among the laboratory strains tested, strain JA6 was the best producer of GAA. Since this strain is known to be highly sensitive to glucose repression and since this is an undesired trait for biomass-oriented applications, we examined heterologous protein production by using glucose repression-defective mutants isolated from this strain. One of them, a mutant carrying a dgr151-1 mutation, showed a significantly improved capability of producing heterologous proteins such as GAA, human serum albumin, and human interleukin-1beta compared to the parent strain. dgr151-1 is an allele of RAG5, the gene encoding the only hexokinase present in K. lactis (a homologue of S. cerevisiae HXK2). The mutation in this strain was mapped to nucleotide position +527, resulting in a change from glycine to aspartic acid within the highly conserved kinase domain. Cells carrying the dgr151-1 allele also showed a reduction in N- and O-glycosylation. Therefore, the dgr151 strain may be a promising host for the production of heterologous proteins, especially when the hyperglycosylation of recombinant proteins must be avoided.
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PMID:Improved production of heterologous proteins by a glucose repression-defective mutant of Kluyveromyces lactis. 1512 12

Protein l-isoaspartyl methyltransferase (PIMT) repairs the isoaspartyl residues (isoAsp) that originate from asparagine deamidation and aspartic acid (Asp) isomerization to Asp residues. Deletion of the gene encoding PIMT in mice (Pcmt1) leads to isoAsp accumulation in all tissues measured, especially in the brain. These PIMT-knockout (PIMT-KO) mice have perturbed glutamate metabolism and die prematurely of epileptic seizures. To elucidate the role of PIMT further, brain proteomes of PIMT-KO mice and controls were analyzed. The isoAsp levels from two of the detected 67 isoAsp sites (residue 98 from calmodulin and 68 from glyceraldehyde-3-phosphate dehydrogenase) were quantified and found to be significantly increased in PIMT-KO mice (p < 0.01). Additionally, the abundance of at least 151 out of the 1017 quantified proteins was found to be altered in PIMT-KO mouse brains. Gene ontology analysis revealed that many down-regulated proteins are involved in cellular amino acid biosynthesis. For example, the serine synthesis pathway was suppressed, possibly leading to reduced serine production in PIMT-KO mice. Additionally, the abundances of enzymes in the glutamate-glutamine cycle were altered toward the accumulation of glutamate. These findings support the involvement of PIMT in glutamate metabolism and suggest that the absence of PIMT also affects other processes involving amino acid synthesis and metabolism.
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PMID:Brain proteomics supports the role of glutamate metabolism and suggests other metabolic alterations in protein l-isoaspartyl methyltransferase (PIMT)-knockout mice. 2394 66


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