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PubMed2004

Human aldolase A natural mutants: relationship between flexibility of the C-terminal region and enzyme function.

We have identified a new mutation in the FBP (fructose 1,6-bisphosphate) aldolase A gene in a child with suspected haemolytic anaemia associated with myopathic symptoms at birth and with a subsequent diagnosis of arthrogryposis multiplex congenita and pituitary ectopia. Sequence analysis of the whole gene, also performed on the patient's full-length cDNA, revealed only a Gly346-->Ser substitution in the heterozygous state. We expressed in a bacterial system the new aldolase A Gly346-->Ser mutant, and the Glu206-->Lys mutant identified by others, in a patient with an aldolase A deficit. Analysis of their functional profiles showed that the Gly346Ser mutant had the same Km as the wild-type enzyme, but a 4-fold lower kcat. The Glu206-->Lys mutant had a Km approx. 2-fold higher than that of both the Gly346-->Ser mutant and the wild-type enzyme, and a kcat value 40% less than the wild-type. The Gly346-->Ser and wild-type enzymes had the same Tm (melting temperature), which was approx. 6-7 degrees C higher than that of the Glu206-->Lys enzyme. An extensive molecular graphic analysis of the mutated enzymes, using human and rabbit aldolase A crystallographic structures, suggests that the Glu206-->Lys mutation destabilizes the aldolase A tetramer at the subunit interface, and highlights the fact that the glycine-to-serine substitution at position 346 limits the flexibility of the C-terminal region. These results also provide the first evidence that Gly346 is crucial for the correct conformation and function of aldolase A, because it governs the entry/release of the substrates into/from the enzyme cleft, and/or allows important C-terminal residues to approach the active site.

Amino Acid Substitution↗

PubMed1986

Human monoclonal antibody recognizing liver-type aldolase B.

A human hybridoma clone (4E3) has been established by fusing lymphocytes from a lymph node taken from a breast cancer patient and human lymphoblastoid cells, LICR-LON-HMy2, by the poly(ethylene glycol) method. 4E3 has been stabilized and continued to secrete IgMk antibody into culture medium (greater than 10 micrograms/ml) for over 1 year. The following characteristics of the antigen strongly suggested that 4E3 recognizes liver-type aldolase B (EC 4.1.2.13): the Mr of the native molecule is 160,000 and that of the subunit is 40,000, and thus it has a tetrameric structure of identical subunits; the antigen is abundant in the liver and kidney of human, mouse and rabbit, and is localized by immunohistochemical methods in the cytoplasm of hepatocytes and in the proximal tubules of the kidney; the antigen is precipitable by 50-80% saturation with (NH4)2SO4; the antigen shows charge-dependent heterogeneity on DEAE-cellulose chromatography. To confirm this notion, aldolase B was purified to homogeneity from the liver of human, mouse and rabbit by phosphocellulose chromatography. During the chromatographic purification, the antigen activity as assayed by enzyme-linked immunosorbent assay (e.l.i.s.a.) was superimposed on the enzymic activity of aldolase. Furthermore, monoclonal antibody 4E3 strongly reacted with purified aldolase B in SDS/polyacrylamide-gel electrophoresis followed by Western blotting and also in e.l.i.s.a. using microplates coated with purified enzyme. The reaction between aldolase B and 4E3 activated the human complement system as assessed by the attachment of C3 to the immune complex of aldolase B and 4E3.

Animals↗

PubMed1989

Cloning, sequence analysis and over-expression of the gene for the class II fructose 1,6-bisphosphate aldolase of Escherichia coli.

Nucleotide sequence analysis of the Escherichia coli chromosomal DNA inserted in the plasmid pLC33-5 of the Clarke and Carbon library [Clarke & Carbon (1976) Cell 9, 91-99] revealed the existence of the gene, fda, encoding the Class II (metal-dependent) fructose 1,6-bisphosphate aldolase of E. coli. The primary structure of the polypeptide chain inferred from the DNA sequence of the fda gene comprises 359 amino acids, including the initiating methionine residue, from which an Mr of 39,146 could be calculated. This value is in good agreement with that of 40,000 estimated from sodium dodecyl sulphate-polyacrylamide gel electrophoresis of the purified dimeric enzyme. The amino acid sequence of the Class II aldolase from E. coli showed no homology with the known amino acid sequences of Class I (imine-forming) fructose 1,6-bisphosphate aldolases from a wide variety of sources. On the other hand, there was obvious homology with the N-terminal sequence of 40 residues already established for the Class II fructose 1,6-bisphosphate aldolase of Saccharomyces cerevisiae. These Class II aldolases, one from a prokaryote and one from a eukaryote, evidently are structurally and evolutionarily related. A 1029 bp-fragment of DNA incorporating the fda gene was excised from plasmid pLC33-5 by digestion with restriction endonuclease HaeIII and subcloned into the expression plasmid pKK223-3, where the gene came under the control of the tac promoter. When grown in the presence of the inducer isopropyl-beta-D-thiogalactopyranoside, E. coli JM101 cells transformed with this recombinant expression plasmid generated the Class II fructose 1,6-bisphosphate aldolase as approx. 70% of their soluble protein. This unusually high expression of an E. coli gene should greatly facilitate purification of the enzyme for any future structural or mechanistic studies.

Amino Acid Sequence↗

PubMed1997

Subunit interaction in mammalian aldolases.

Enzyme inactivation was utilized to study subunit interaction in the homotetrameric glycolytic enzyme, aldolase. Isoenzymes from rabbit liver and skeletal muscle were inactivated in the presence of Pi and d-glyceraldehyde-P to a maximum stoichiometry of one modification per aldolase subunit. Subunit modification increased net negative charge on each subunit surface and was used to resolve modified aldolase isoenzymes into various chromatographic species. A combination of anion-(Mono Q) and cation- (Mono S) exchange chromatography separated the modified aldolase homotetramers into three distinct enzyme populations: unchanged enzyme, fully modified enzyme corresponding to one ligand molecule incorporated per subunit and partially modified enzyme in which only one subunit out of four is modified. Both fully and partially modified species were devoid of catalytic activity. Activity loss through modification of a single subunit in both aldolase isoenzymes indicates tightly coupled communication between subunit active sites and suggests simple functional regulation of aldolases.

Animals↗

PubMed1998

A moderate decrease of plastid aldolase activity inhibits photosynthesis, alters the levels of sugars and starch, and inhibits growth of potato plants.

Antisense expression of a full length cDNA encoding plastid aldolase led to decreased expression of aldolase at the transcript and protein level in several 'antisense' potato transformants. To quantify the inhibition, activity was compared in corresponding leaves down a plant and in plants of different ages. Aldolase activity was decreased by 32-43%, 56-71%, 79-83% and 91-97% in A-70, A-3, A-51 and A-2. Separation on a Q-Sepharose-FF column showed the decrease was due to inhibition of plastid aldolase. The transformants showed a small increase of Rubisco activity, a small decrease of phosphoribulokinase activity, and larger but subproportional decreases of sedoheptulose-1,7-biphosphatase and plastid fructose-1,6-bisphosphatase activity. Ambient photosynthesis was inhibited by 10%, 40%, 66% and 85% in A-70, A-3, A-51 and A-2. The transformants contained increased triose phosphates, and very low ribulose-1,5-bisphosphate and glycerate-3-phosphate. Chlorophyll fluorescence indicated that photosystem II was more reduced and thylakoid energization was increased. Starch synthesis was decreased by 16% and 36% in A-70 and A-3, whereas sucrose synthesis was less strongly inhibited. Plant growth was not significantly altered in A-70, was decreased by 41% in A-3, and was severely inhibited in plants with under 20% of wild-type aldolase activity. Although plastid aldolase catalyses a readily reversible reaction, possesses no known regulatory properties, and would appear irrelevant for the control of metabolism and growth, small changes in its activity have marked consequences for photosynthesis, carbon partitioning and growth.

Carbohydrate Metabolism↗

PubMed1984

Complete amino acid sequence for human aldolase B derived from cDNA and genomic clones.

Several aldolase B clones from a human liver cDNA library have been identified by using a rabbit aldolase A cDNA as a hybridization probe. The most complete of these, pHL413, is 1389 base pairs long and covers approximately equal to 80% of the length of the mRNA, including 90% of the translated region. The cDNA, pHL413, was used to identify a genomic clone, lambda HG313, which encoded the remaining amino acids of human aldolase B. We demonstrate that the amino acid and nucleotide sequences of aldolase are strongly conserved even between different isozymes. Furthermore, in the 3'-untranslated regions of the mRNAs for the B isozyme of human and rat there is an extensive stretch of homology. Aldolase B lacks a cysteine at positions 72 and 338 and lacks a histidine at position 361. These residues, which are present in rabbit aldolase A, have previously been proposed to take part in catalysis. Our findings suggest that this may not be the case.

Amino Acid Sequence↗

PubMed1987

Molecular architecture of rabbit skeletal muscle aldolase at 2.7-A resolution.

The molecular architecture of the rabbit skeletal muscle aldolase (D-fructose-1,6-bisphosphate D-glyceraldehyde-3-phosphate-lyase, EC 4.1.2.13) tetramer has been determined to 2.7-A resolution. Solution of the three-dimensional structure of rabbit muscle aldolase utilized phase information from a single isomorphous Pt(CN)4(2-) derivative, which was combined with iterative-phase refinement based upon the noncrystallographic 222-fold symmetry exhibited by the tetramer subunits. The electron-density map calculated from the refined phases (mf = 0.72) was interpreted on the basis of the known amino acid sequence (363 amino acids per subunit). The molecular architecture of the aldolase subunit corresponds to a singly wound beta-barrel of the parallel alpha/beta class structures as has been observed in triose phosphate isomerase, pyruvate kinase, phosphogluconate aldolase, as well as others. Close contacts between tetramer subunits are virtually all between regions of hydrophobic residues. Contrary to other beta-barrel structures, the known active-site residues are located in the center of the beta-barrel and are accessible to substrate from the COOH side of the beta-barrel. Biochemical and crystallographic data suggest that the COOH-terminal region of aldolase covers the active-site pocket from the COOH side of the beta-barrel and mediates access to the active site. On the basis of sequence studies, active-site residues as well as residues lining the active-site pocket have been totally conserved throughout evolution. By comparison, homology in the COOH-terminal region is minimal. It is suggested that the amino acid sequence of the COOH-terminal region may be, in part, the basis for the variable specific activities aldolases exhibit toward their substrates.

Animals↗

PubMed2003

Sites of interaction between aldolase and thrombospondin-related anonymous protein in plasmodium.

Gliding motility and host cell invasion by apicomplexan parasites are empowered by an acto-myosin motor located underneath the parasite plasma membrane. The motor is connected to host cell receptors through trans-membrane invasins belonging to the thrombospondin-related anonymous protein (TRAP) family. A recent study indicates that aldolase bridges the cytoplasmic tail of MIC2, the homologous TRAP protein in Toxoplasma, and actin. Here, we confirm these unexpected findings in Plasmodium sporozoites and identify conserved features of the TRAP family cytoplasmic tail required to bind aldolase: a subterminal tryptophan residue and two noncontiguous stretches of negatively charged amino acids. The aldolase substrate and other compounds that bind to the active site inhibit its interaction with TRAP and with F-actin, suggesting that the function of the motor is metabolically regulated. Ultrastructural studies in salivary gland sporozoites localize aldolase to the periphery of the secretory micronemes containing TRAP. Thus, the interaction between aldolase and the TRAP tail takes place during or preceding the biogenesis of the micronemes. The release of their contents in the anterior pole of the parasite upon contact with the target cells should bring simultaneously aldolase, TRAP and perhaps F-actin to the proper subcellular location where the motor is engaged.

Actins↗

PubMed1984

Isolation and nucleotide sequence of a full-length cDNA coding for aldolase B from human liver.

Two recombinant clones, pA2 and pA3, containing cDNA sequences for human aldolase B have been isolated from a full length human liver cDNA library. The larger one, pA3, has been subcloned in M13 phage and completely sequenced with the chain terminator method. The sequence covers 1,600 nucleotides including the whole coding region (1,050 nucleotides), 67 nucleotides from the 5' non-coding region and the whole 3' non-coding region, 440 nucleotides long, down to the poly-A tail. Comparison with rabbit aldolase A and with a partial sequence of rat aldolase B, shows a homology of about 76% for aldolase A and of about 94% for aldolase B, which indicates that the sequenced cDNA codes for the liver isoenzyme. This is the first complete sequence reported for human aldolase B. The pA3 clone strongly hybridizes to 18S mRNA from human adult liver as expected from the size of the isolated cDNA.

Amino Acid Sequence↗

PubMed1990

Human aldolase A of a hemolytic anemia patient with Asp-128----Gly substitution: characteristics of an enzyme generated in E. coli transfected with the expression plasmid pHAAD128G.

Aldolase A derived from a hemolytic anemia patient with aldolase A deficiency was shown to have an amino acid substitution of glycine for aspartic acid at the 128th position (Asp-128) in the enzyme [Kishi et al. (1987) Proc. Natl. Acad. Sci. U.S.A. 84, 8623-8627]. We constructed an Escherichia coli expression plasmid, pHAAD128G, which carries the mutant aldolase A [aldolase A(D-G)] cDNA, and the enzyme generated in E. coli transfected with the expression plasmid was purified and characterized. Conversion of Asp to Gly at the 128th position in the enzyme rendered the enzyme thermolabile and susceptible to tryptic digestion. CD spectra analysis also revealed that the mutant enzyme had a remarkable conformation change with a decrease of regular form in the molecule. Addition of glycerol or some other polyalcohols during thermal treatment protected this altered enzyme (but not the normal enzyme) against denaturation and activity decrease. In order to determine the function of the amino acid residue at the 128th position, two artificial mutant enzymes with the substitutions of Glu for Asp [aldolase A(D-E)] and Ser for Asp [aldolase A(D-S)], respectively, at the position were constructed by site-directed mutagenesis and characterized. These analyses demonstrated the necessity for Asp to be present at the 128th residue in order for this enzyme to be thermally stable.

Amino Acid Sequence↗

PubMed1991

Monoclonal antibodies recognizing amino-terminal and carboxy-terminal regions of human aldolase A: probes to detect conformational changes of the enzyme.

Three monoclonal antibodies (MAbs1A2, 3C5, and 4C2) for human aldolase A [EC 4.1.2.13] were established. MAbs1A2, 3C5, and 4C2 were shown to belong to subclasses IgM, IgG1, and IgG2a, respectively. None of the MAbs inhibits aldolase A activity. Their epitopes were mapped in detail on the molecule by examining the reactivities of the MAbs to chimeric proteins between aldolases A and B [Kitajima et al. (1990) J. Biol. Chem. 265, 17493-17498] in ELISA and to the CNBr-cleaved fragments of aldolase A in immuno-blotting. MAbs1A2 and 3C5 reacted with sites located within amino acid residues 306-363 at the C-terminal region of the enzyme. MAb4C2 recognized an epitope of the enzyme present within amino acid residues 34-108 at the N-terminal region. In a competitive binding assay, MAbs1A2 and 3C5 competed with each other for binding to the antigen and also interfered with the binding of MAb4C2, whereas MAb4C2 failed to inhibit the binding of MAbs1A2 and 3C5 to the antigen. MAb3C5 showed a species-specificity in the reaction with the antigen; it reacted with human and rabbit aldolase A with similar reactivity but not at all with the rat and mouse enzymes, which differ from the human and rabbit enzymes in two amino acid residues at positions 328 and 348. Reactivities of MAbs to aldolase A were further examined with engineered enzymes containing an amino acid substitution.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed1980

Biosynthesis of aldolase B by free ribosomes in rat liver.

Free ribosomes and membrane-bound ribosomes were prepared from rat livers, and the contributions of these two types of ribosomes to the synthesis of aldolase B were studied by the immunoprecipitation of [3H]puromycin-labeled nascent peptides with a rabbit antibody to this enzyme. Although rat liver aldolase was recovered in both cytosolic and microsomal fractions by the fractionation of liver homogenate, the microsomal aldolase was immunologically identical with its cytosolic counterpart as confirmed by Ouchterlony immunodiffusion test. We examined the nascent peptide fractions prepared from free and bound ribosomes, and found that the nascent peptides of aldolase were mainly localized in free ribosomes. About 0.5% of the total nascent peptides of free ribosomes and 0.08% of those of bound ribosomes was aldolase. The site of synthesis of serum albumin was also examined as a reference standard by the immunoprecipitation of labeled nascent peptides, and the nascent peptides of this secretory protein were mainly associated with bound ribosomes, as reported by other workers. These observations confirm that aldolase B is mainly synthesized by free ribosomes in rat liver cells.

Animals↗

PubMed1994

Human aldolase B: liver-specific properties of the isozyme depend on type B isozyme group-specific sequences.

A series of chimeric enzymes between two human aldolases A, B or C were constructed to identify the molecular regions responsible for isozyme-specific functions. Chimeras constructed between aldolases A and B were AB34 (an AB chimera connected at position 34), ABA34-306 and ABA212-306 (the ABA chimeras). Those between aldolases B and C are BC243, BC263 and BC306 (the BC chimeras connected at positions as indicated), as well as CB55, CB243, CB263 and CB306 (the CB chimeras connected at positions as indicated), CBC55-263 (a CBC chimera), and BCB55-193, BCB55-306, BCB79-193 and BCB79-306 (the BCB chimeric enzymes). Through the analysis of the properties of these chimeras, it was found that for aldolase B, isozyme B group-specific sequences (IGSs)-1 and -4 were required for exerting type B-specific functions, while the IGSs-2 and -3 enhanced, in collaboration with the IGS-1, the catalytic activity of aldolase B. In addition, the alpha/beta-barrel and the restricted stretches, which were not specified but occupied two distinct regions spanning the amino acid positions 108-137 (designated connector 1) and 243-306 (designated connector 2), were found to be indispensable for showing full catalytic activity of aldolase B.

Amino Acid Sequence↗

PubMed1983

Interaction of the dissociable glycerol-3-phosphate dehydrogenase and fructose-1,6-bisphosphate aldolase. Quantitative analysis by an extrinsic fluorescence probe.

Cytoplasmic sn-glycerol-3-phosphate dehydrogenase, labelled covalently with fluorescein isothiocyanate, shows an enzyme-concentration-dependent fluorescence anisotropy. The anisotropy versus enzyme concentration curve is shifted towards higher concentrations when substrates are present. The comparison of the dissociation constants estimated from anisotropy measurements and derived from kinetic experiments suggests that the substrate-induced dissociation of the dimeric dehydrogenase is slow with respect to the enzymatic reaction catalyzed by either its monomeric or dimeric form. The fluorescence anisotropy of the fluorescent dye-labelled dehydrogenase increase with time upon addition of unlabelled fructose-1,6-bisphosphate aldolase approaching a limiting value. This fact indicates the binding of fructose-1,6-bisphosphate aldolase aldose aldolase to glycerolphosphate dehydrogenase. A model is proposed assuming simultaneous binding of tetrameric fructose-1,6-bisphosphate aldolase to monomeric and dimeric glycerolphosphate dehydrogenase with 1:1 stoichiometry. The dissociation constants, as parameters fitted to the experimental curves, were estimated as 0.2 microM and 1 microM for aldolase-dimeric-glycerolphosphate-dehydrogenase and aldolase-monomeric-glycerolphosphate-dehydrogenase complexes respectively.

Animals↗

PubMed1984

Two different aldolase A mRNA species in rat tissues.

Double-stranded DNA was synthesized with reverse transcriptase from size-fractionated poly(A)-containing RNA from rat ascites hepatoma cells. The cDNA was introduced into Escherichia coli HB101 using pBR322 DNA as a cloning vector. Several plasmids containing aldolase A cDNA were identified by colony hybridization with 32P-labeled cDNA prepared from immunologically purified aldolase A mRNA. The partial amino acid sequence of the cDNA sequence was determined, and found to coincide with that of rabbit aldolase A. Using aldolase A cDNA as a hybridization probe, the aldolase A mRNA concentrations in various rat tissues were analysed, and two aldolase A mRNA species differing in nucleotide length were found; the smaller mRNA (about 1550 nucleotides) in muscle, and the larger one (about 1650 nucleotides) in brain and hepatoma cells.

Animals↗

PubMed1985

Temperature-induced conformational transition in rabbit muscle aldolase studied by temperature dependence of sulfhydryl reactivity.

A temperature-induced non-denaturing conformational transition in rabbit muscle aldolase has been as subject of discussion and controversy for some period of time. In this study the temperature dependence of the reactivity of aldolase SH groups is investigated in order to detect subtle changes in the enzyme conformation. For model thiol-containing systems such as cysteine, glutathione and bovine serum albumin, linear Arrhenius plots have been obtained for the reaction with 5,5'-dithiobis(2-nitrobenzoic acid). On the other hand, for rabbit muscle pyruvate kinase, a protein which undergoes temperature-induced conformational transition, the plot obtained is nonlinear with a break at the temperature (18 degrees C) close to that reported earlier. In the case of aldolase the Arrhenius plots for three slowly reacting SH groups (Cys-72, 289, 338) and a fast reacting group (Cys-239) are nonlinear with a break at about 26-27 degrees C. The fluorescence measurements show that a plot of the fluorescence intensity of tryptophan residues versus temperature exhibits a break at the same temperature. It is shown that the observed conformational change is fully reversible. In the presence of the competitive inhibitor hexitol 1,6-bisphosphate, which is known to protect Cys-72 and Cys-338 from chemical modification, the Arrhenius plot exhibits a break for the fast reacting Cys-239 residue and is linear for the slowly reacting Cys-289. It is found that 0.6 M urea increases the transition temperature for all exposed SH groups of aldolase. The above results show that at several points in the aldolase molecule, including the active-site region, an abrupt change of microenvironments takes place with temperature. The competitive inhibitor protects a portion of aldolase molecule against the thermal transition.

Animals↗

PubMed1985

Dietary and hormonal regulation of aldolase B gene expression.

Aldolase B is an enzyme of the glycolytic pathway whose activity and mRNA levels in the liver fluctuate according to dietary status. Both the enzyme activity and the mRNA concentration decline during fasting and increase four- to eightfold upon refeeding of a carbohydrate-rich diet. The mechanism, however, of the mRNA induction remains unknown. To elucidate the mechanisms that regulate this induction responsive to dietary stimuli, we have studied the roles of hormones and glycolytic substrates on aldolase B gene expression in three tissues that synthesize the enzyme. Using a cDNA probe complementary to rat aldolase B mRNA, we determined the amount of cytoplasmic RNAs in the liver, kidney, and small intestine of normal, adrenalectomized, thyroidectomized, diabetic, and glucagon- or cAMP-treated animals refed either a fructose-rich or a maltose-rich diet. The in vivo hormonal control of gene expression was found to be very different in the three organs tested. In the liver, cortisone and thyroid hormones were required for the induction of the specific mRNA by carbohydrates, while in the kidney none of the hormonal modifications tested altered the level of mRNA induction. In the liver, but not in the kidney, diabetes and glucagon administration abolished the induction of aldolase B mRNAs in animals refed the maltose-rich diets. In the small intestine, only diabetes and thyroidectomy affected the gene expression. Finally, no induction occurred when normal fasted rats were given any of the hormones. Thus, the in vivo hormonal control of liver aldolase B gene expression differs significantly from that of kidney and small intestine. In the liver, the mRNA induction requires the presence of dietary carbohydrates, of permissive hormones, and the cessation of glucagon release, while in the kidney, the induction of the mRNAs by fructose occurs regardless of the hormonal status of the animals. The hormonal control of aldolase B mRNA levels in the small intestine is intermediate.

Adrenalectomy↗

PubMed1980

Immunoreactive aldolase C in cerebrospinal fluid of patients with neurological disorders.

Nervous-system specific aldolase C has been detected in human cerebrospinal fluid (CSF) by radioimmunoassay. Measurement of 138 samples of CSF showed a mean level of 92 +/- 28 ng/ml. There was no correlation between the level of CSF aldolase C and the CSF total protein, albumin, IgG, or IgA levels. Aldolase C immunoreactivity present in concentrated CSF diluted out in parallel with the standard curve in the assay and showed an elution profile on ion-exchange and gel filtration chromatography similar to that of aldolase present in whole human brain extracts. Addition of known quantities of purified aldolase C4 to CSF gave quantitative recovery on subsequent radioimmunoassay. Measurement of aldolase C in the CSF of 66 patients with neurological disorders showed several patients with levels considerably in excess of 120 ng/ml, but there was no statistically significant difference in the mean levels between groups of patients with different diseases.

Brain↗