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:4.1.2.13 (aldolase)
3,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alkyl glycolamido phosphoric esters (P-O-CH2-CO-NH-(CH2)n-CH3) and alkyl monoglycolate phosphoric esters (P-O-CH2-CO-O-(CH2)n-CH3), which are analogs of the aldolase substrate fructose-1-phosphate, were synthesized and use for probing the active site of rabbit muscle aldolase. The inhibition constants (Ki) were affected by the length of the alkyl groups of these compounds and a maximum value of Ki was observed between the number of methylene groups 2 and 4, depending on the type of compound. In the previous investigation, N-(omega-hydroxyalkyl)-glycolamido bisphosphoric esters (P-O-CH2-CO-NH-(CH2)n-O-P) and alkanediol monoglyclolate bisphosphoric esters (P-O-CH2-CO-O-(CH2)n-O-P) have a minimum Ki value between the number of methylene groups 1 and 4. The difference spectra of aldolase caused by binding of alkyl glycoamido phosphoric esters or alkyl monophosphates resembled that of their analogous bisphosphoric esters, but the intensity of absorbance was smaller than that of the bisphosphoric ester analogs. These results suggest that rabbit muscle aldolase has two binding sites for the phosphate groups on the entrance end of the active site cavity, the singly wound beta-barrel of the parallel alpha/beta class structure. The distance between the phosphate binding site Lys-107 in the beta-sheet structure (c) and Arg-148 in the beta-sheet structure (d) may possibly be expanded or contracted by the forms of the bending structure of the biphosphate compounds. Also, the change of distance between the beta-sheet structure (c) and (d) containing Trp-147, may have an effect on the environment of the tryptophan and cause a change of the absorbance of aldolase especially at 295-299 nm. On the other hand, the synthetic monophosphate compounds bind at only one of the two phosphate binding sites and have very little effect on the absorbance of Trp-147, in a similar manner as orthophosphate. The alkyl groups of monophosphate may be repelled by the ionic amino acid side chains, Asp-33, Lys-146, Glu-187 and/or Lys-229 in the middle of the active site cavity. However, the end of the long alkyl group of some monophosphates may possibly contact the hydrophobic bottom of the active site cavity without effect on the environment of Trp-147.
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PMID:An exploration of the binding site of aldolase using alkyl glycolamido phosphoric esters and alkyl monoglycolate phosphoric esters. 154 Jun 43

P. falciparum lacks a functional citric acid cycle. Unlike most tissues of the mammalian host, it is totally dependent on glycolysis for energy generation. A compound which selectively inhibits the parasite's ATP-generating machinery is therefore a potential antimalarial agent. Such a drug may interact in two ways: a) by inhibiting the activity of an enzyme or b) by disturbing the micro-organization of consecutive enzymes in a metabolic pathway. In mammalian tissues the glycolytic pathway involves the cytoskeleton as a matrix to keep phosphofructokinase, aldolase and glyceraldehyde-3-phosphate dehydrogenase in an optimal sterical position for rapid substrate conversion. For instance, these three enzymes bind to the band 3 protein in erythrocytes or to actin in muscle cells. P. falciparum aldolase binds with very high affinity to the band 3 protein of human erythrocyte ghosts. However, the true in vivo site of association is believed to be actin II of P. falciparum. This actin has a sequence element which is almost identical to that of the band 3 aldolase binding site. We therefore suppose that plasmodia exploit a similar matrix organization. If true, the association of these enzymes with the cytoskeleton is a target for novel antimalarials. In contrast to all vertebrate aldolases, P. falciparum and P. berghei aldolases have two neighbouring lysine residues near the carboxy-terminus. We show here that mutagenesis of these basic residues has an effect on the catalytic constants Vmax and KM and moreover, the ability to bind to band 3 is reduced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Is Plasmodium falciparum aldolase useful for rational drug design? 182 Jul 2

When assayed in vitro, the activity of the photosynthetic enzyme ribulose 1,5 bisphosphate carboxylase oxygenase is both enhanced and protected from spontaneous decay by exogenous proteins such as hemoglobin, serum albumin, and aldolase. Other proteins and amino acids tested are either ineffective (lysozyme, ferritin, lysine, and cysteine) or afford only partial protection (catalase, glycine, and phenylalanine). Protective proteins do not bind to, or exchange disulfides with, ribulose 1.5 bisphosphate carboxylase/oxygenase. Since their effect can be mimicked by reductively treated detergents such as Triton X-100, it appears that proteins protect from decay by quenching the spontaneous oxidative degradation and inhibiting surface adsorption which could lead to enzyme unfolding. Release of adsorbed molecules from the container surface is likely to be the cause of carboxylase activity enhancement.
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PMID:Protection and enhancement of ribulose 1,5 bisphosphate carboxylase activity by exogenous proteins. 191 Apr 60

The structure of the type I fructose 1,6-bisphosphate aldolase from human muscle has been extended from 3 A to 2 A resolution. The improvement in the resulting electron density map is such that the 20 or so C-terminal residues, known to be associated with activity and isozyme specificity, have been located. The side-chain of the Schiff's base-forming lysine 229 is located towards the centre of an eight-stranded beta-barrel type structure. The C-terminal "tail" extends from the rim of the beta-barrel towards lysine 229, thus forming part of the active site of the enzyme. This structural arrangement appears to explain the difference in activity and specificity of the three tissue-specific human aldolases and helps with our understanding of the type I aldolase reaction mechanism.
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PMID:Activity and specificity of human aldolases. 205 25

Enzymatic studies on aldolase isozymes have been carried out by techniques of protein engineering. Site-directed mutagenesis helps us to verify the roles of amino acid residues in catalytic reactions. Chimeric fusion proteins give us information about the regions which specify the characteristics of the isozymes. The results are: (1) In aldolase A, COOH terminal Tyr and Lys-107 residues play important roles in catalysis, especially in binding of FDP. (2) Aspartic acid at the 128th residue in aldolase A is essential to thermostability; no other residue such as glutamic acid can substitute for it. (3) Studies on chimeric fusion proteins indicate that the C-terminal region (including C-terminus Tyr) or aldolase A is responsible for its substrate specificity, which is not seen in aldolase B. (4) A region near NH2 terminus in aldolase B determines its specific structure. (5) The region including His-107, Asp-128, and Tyr-137 (B-A junction of BA137) is located in a turn which is exposed outward (a model architecture by Sygusch et al [1987]). In BA137, this region would be constrained, and play a significant role in catalysis, thermostability, etc. (6) Tertiary structure of aldolase B seems to be dissimilar to that of aldolase A.
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PMID:Structural studies on aldolase isozymes through protein engineering. 220 67

To study the structure/function relationships of human aldolase isozymes, particularly isozyme-specific functions, we constructed Escherichia coli expression plasmids for six BA chimeric enzymes (BA34, BA108, BA137, BA212, BA306, and BA306*), each composed of the N-terminal side of isozyme B and the C-terminal side of isozyme A, and one BAB chimeric enzyme which contains a fragment of isozyme A (residues 213-306) inserted in between the N-terminal and the C-terminal fragments of isozyme B. They were transfected into E. coli, and the generated enzymes were characterized. This study reveals the following. (i) For isozyme A, the C-terminal Tyr-363 and the N-terminal region bearing isozyme group-specific sequences 1-3 and Lys-107 (the C-6 phosphate-binding site) are responsible for the higher catalytic activity toward fructose 1,6-bisphosphate, which is 7 times higher than that of aldolase B. Conversely, an internal region spanning positions 108-212 is required for the lower activity toward fructose 1-phosphate. (ii) For isozyme B, an internal sequence spanning positions 108-212 which includes some isozyme B-specific residues and a postulated C-1 phosphate-binding site (Lys-146 or Arg-148) is responsible for a higher catalytic activity toward fructose 1-phosphate, which is 8-10 times that of isozyme A. The more upstream sequence containing positions 1-107 is responsible for the lower catalytic activity toward fructose 1,6-bisphosphate. (iii) At least residues 212-306, composing a long stretch near the active-site Lys-229 and highly conserved among isozymes A, B, and C, may be required for the basal framework of the aldolase molecule to exhibit the activity common to the three isozymic forms.
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PMID:Construction and properties of active chimeric enzymes between human aldolases A and B. Analysis of molecular regions which determine isozyme-specific functions. 221 42

N-(omega-Hydroxyalkyl)glycolamidobisphosphoric esters (P-O-CH2-CO-NH-(CH2)n -O-P), which are analogues of the aldolase (D-fructose-1,6-bisphosphate D-glyceraldehyde-3-phosphate-lyase, EC 4.1.2.13) substrate fructose 1,6-bisphosphate, were synthesized and used for probing its active site. These phosphate compounds competitively inhibited aldolase activity. The Ki value was lowest when the maximum distance between the phosphorus atoms of the bisphosphate was brought close to that of fructose 1,6-bisphosphate. The inhibitor constants, Ki, were compared to those of alkanediol monoglycolate bisphosphoric esters and alkanediol bisphosphate compounds, which were reported previously by Ogata et al. The values of Ki for the bisphosphate compounds containing an amide group, the amide bisphosphate compounds, were smaller than those for the bisphosphate compounds containing an ester group, the ester bisphosphate compounds, and those for alkanediol bisphosphates were the largest for the same distance between phosphorus atoms in these bisphosphates. The difference spectra of aldolase caused by binding of a saturating concentration of N-(omega-hydroxypropyl)glycolamidobisphosphoric ester resembled that of butanediol monoglycolate bisphosphoric ester. However, the effects of the amide bisphosphate compounds on the absorption spectrum of aldolase were smaller than those of the ester bisphosphate compounds for the same distance between phosphorus atoms in these bisphosphate compounds. These results suggest that the synthesized phosphate compounds bind to aldolase at the active site and the -CO-NH- group of the compounds might be held more tightly than the -CO-O- group by hydrogen bonds, presumably with the amino acid residues in the active site, such as Lys-146 or -229 and Asp-33 or Glu-187. On the other hand, the -CO-O- group might be more effective in changing the environment of the Trp-147 residue in the active site of this enzyme.
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PMID:An exploration of the binding site of aldolase using N-(omega-hydroxyalkyl) glycolamidobisphosphoric esters. 226 71

The three-dimensional structure of fructose-1,6-bisphosphate aldolase from human muscle has been determined at 3.0 A resolution by X-ray crystallography. The active protein is a tetramer of 4 identical subunits each of which is composed of an eight-stranded alpha/beta-barrel structure. The lysine residue responsible for Schiff base formation with the substrate is located near the centre of the barrel in the middle of the sixth beta-strand. While the overall topology of the alpha/beta-barrel is very similar to those found in several other enzymes, the distribution of charged residues inside the core of the barrel seems distinct. The quaternary fold of human muscle aldolase uses interfacial regions also involved in the subunit association of other alpha/beta-barrel proteins found in glycolysis, but exploits these regions in a manner not seen previously.
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PMID:The crystal structure of human muscle aldolase at 3.0 A resolution. 233 8

The effect of the number of active groups of new affinity supports--odigose and odifil (ethylsulfo-activated agarose) on the retention of the specific activity of muscle aldolase was investigated. The active center of the enzyme includes lysine able to react with activated supports. The aldolase completely retained the specific activity after immobilization on the abovementioned relatively high-substituted supports, on which other enzymes, e.g. phosphorylase B, NAD-kinase from pigeon heart, were partially or completely inactivated. The aldolase was inactivated when being immobilized on more substituted supports. The enzyme specific activity completely retained if the high substituted supports were preliminary incubated at 37 degrees to destroy some diazo-groups.
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PMID:[Retention of specific activity of muscle aldolase after its immobilization on odigos and odifil (ethylsulfo-activated agarose)]. 274 Mar 1

The effects of recombinant human interleukin-1 beta (rhIL-1 beta) on various serum constituents were studied following subcutaneous injection (12.5 or 125 micrograms/kg) in female Wistar rats. Protein electrophoresis and the determination of the serum concentrations of carboxypeptidase N (CPN), aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, aldolase, total proteins, iron, urea, creatinine, and several amino acids were performed 12, 24, and 72 hr after injection. With both doses of rhIL-1 beta, iron, albumin, CPN, and lysine were significantly decreased whereas alpha 2-globulin, urea, and creatinine were significantly increased 12 hr after administration. Iron and CPN were still low after 24 hr but returned to normal levels after 72 hr. With the higher dose of rhIL-1 beta, only alanine and phenylalanine levels were increased after 12 and 72 hr, taurine after 12 hr, and methionine after 24 hr. There were no biochemical or histological signs of hepatotoxicity. The findings indicate that rhIL-1 beta produces a reversible alteration of various biochemical plasma constituents without any apparent signs of cytotoxicity. Moreover, the decrease in CPN observed may influence the degradation of inflammatory peptides.
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PMID:Recombinant human interleukin-1 beta decreases serum carboxypeptidase N and modifies serum amino acid concentrations in rats. 278 29


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