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PubMed1994

A molecular model of the inducer binding domain of the galactose repressor of Escherichia coli.

The C-terminal inducer binding domain of the Escherichia coli galactose repressor (GalR) is homologous to several periplasmic chemoreceptor proteins whose three-dimensional structures have been determined at high resolution (Vyas, N. K., Vyas, M. N., and Quiocho, F. A. (1991) J. Biol. Chem. 266, 5226-5237; Mowbray, S. L. and Cole, L. B. (1992) J. Mol. Biol. 225, 155-175). The protein backbone was constructed from the coordinates of glucose/galactose-binding protein using the Homology program (Biosym Technologies, San Diego). Loops were built by searching for substructures in the structure data base, and the side chains were built using a rotamer-base program. A small amount of energy minimization relieved steric strain within the model. The GalR model that has been constructed is consistent with the principles of protein structure; values obtained for the compactness and buried surface area of the model compare favorably with those determined for the chemoreceptor protein structures. The model is consistent with, and provides structural interpretations for, experimental results obtained from physical and biochemical studies. Predictions are made concerning the residues conferring the specificity of galactose induction of GalR and for self-association to dimers. The model provides a first step toward correlating the structure and regulation of GalR and in determining the chemistry of its homologous and heterologous interactions that are critical to its role as a regulator of transcription initiation.

Amino Acid Sequence↗
PubMed1993

Basic properties and results of clinical trials of ultrasound contrast agents based on galactose.

The development of reproducible echogenic contrast agents, which contain physiologically degradable acoustic strays in micrometre dimensions, has been under way for several years; all currently known industrial echocontrast agents are based on microbubbles, due to their special acoustic properties. The currently known echogenic contrast agents can be divided into three physically different types: microbubble-containing liquids, gas-filled microspheres and microbubble-containing suspensions (e.g. SH U 454-Echovist and SH U 508 A). The agents SH U 454 and SH U 508 A are based on galactose microparticles, which are suspended shortly before use. After intravenous injection, SH U 454 dissolves after leaving the right heart before the left heart is reached. SH U 508 A displays greater intravascular stability than SH U 454 and leads to an increase of the echogenicity in the blood which, after intravenous injection, survives pulmonary transit and reaches the arterial vascular bed. This indicates that the microbubbles are stable under physiological pressures. After intravascular dissolution of the microstructures, the remaining galactose (a monosaccharide with no known allergenic potential) is degraded physiologically. To date, a total of more than 2,500 patients has been examined in clinical trials with SH U 454 (Echovist). The intravenous administration of this contrast agent was well tolerated; in particular, no substance-induced severe adverse events were observed, and no clinically relevant changes of cardiovascular function or of laboratory parameters occurred. Extensive clinical experience has been gained in the main indications echocardiography (> 1,850 patients), venous vessels (> 200 patients) and hysterosalpingocontrast sonography (> 500 patients).(ABSTRACT TRUNCATED AT 250 WORDS)

Contrast Media↗
PubMed1995

[Prevention of galactose-induced cataractogenesis in rats by salvianolic acid A].

Salvianolic acid A has been demonstrated to have efficient antioxidative and free radical scavenging effects. In the present experiments, the preventive effects of salvianolic acid A on galactose-induced cataract in rats were investigated. Dropping 0.05% salvianolic acid A in the eyes (two times a day) was found to delay the development of cataract. The contents of MDA and H2O2 in the cataract lens were decreased in salvianolic acid A treated rats. The protein and non-protein thiols in the cataract lens of the salvianolic acid A treated rats were higher than those of control rats. In in vitro experiments salvianolic acid A was shown to inhibit aldose reductase activity. These results indicate that salvianolic acid A can prevent galactose-induced cataract by antioxidation and inhibition of aldose reductase.

Aldehyde Reductase↗
PubMed1976

[Rat jejunal xylose and galactose absorption dependent on the intestinal bacterial flora and after cytostatics administration].

The influence of the bacterial flora of the intestine and of cytostatic drugs on the intestinal xylose and glucose absorption in the rat is studied by a perfusion technique in vivo. Conventional, germfree and decontaminated animals show no different xylose absorption rates while the galactose absorption is decreased in germfree and decontaminated animals compared to conventional rats. Three days after a single injection of cytostatic drugs the xylose absorption is diminished in conventional and decontaminated animals compared to untreated rats. In germfree rats no effect of cytostatics on the xylose absorption can be proved. The galactose absorption is unchanged after cytostatics in conventional and decontaminated animals, but increased in germfree rats.

Animals↗
PubMed1999

Antineoplastic efficacy of doxorubicin enzymatically assembled on galactose residues of a monoclonal antibody specific for the carcinoembryonic antigen.

We have developed a novel procedure to couple enzymatically the antineoplastic agent doxorubicin (Dox) on the galactose residues of a monoclonal antibody specific for the tumor-associated carcinoembryonic antigen. The synthesis of the immunoconjugate consists of covalent attachment of the NH2 terminus of Dox to oxidized galactose residues of desialylated monoclonal antibody, followed by concurrent stabilization of Schiff bases by mild reduction with pyridine borane. The immunoconjugate preserved both antibody specificity and drug cytotoxicity. At equimolar concentrations, the immunoconjugate was 8 times more cytotoxic against two carcinoembryonic antigen-expressing carcinoma cell lines, LoVo and SW-480, than Dox alone. The intracellular drug accumulation was 8-8.5 times higher than that obtained with free Dox, and >50% of the drug delivered by the conjugate was retained for 24 h in the tumor cells. Only 4 days after treatment with a single dose of immunoconjugate carrying 2.5 ng of Dox, LoVo and SW-480 tumor transplants on the chorioallantoic membrane of embryonated hen eggs showed reduced tumor-induced angiogenesis and tumor progression by half, with no detectable damage to surrounding tissues. In contrast, the same amount of free drug induced insignificant changes in tumor progression and tumor-induced angiogenesis. Enzymatically mediated, glycosidic coupling of antineoplastic agents to antibodies specific for tumor-associated antigens may represent a novel platform for the development of more efficient anticancer agents with reduced side effects.

Animals↗
PubMed1998

Suppressed UDP-galactose: ceramide galactosyltransferase and myelin protein mRNA in twitcher mouse brain.

The developmental changes in expression of steady-state mRNA that encode proteins that are important for myelination (myelin basic protein, myelin-associated glycoprotein, proteolipid protein, UDP-galactose: ceramide galactosyltransferase) and glial fibrillary acidic protein were investigated in the brain of the twitcher mouse, a model of human globoid cell leukodystrophy. This disease is caused by a mutation in the gene encoding the lysosomal enzyme, galactosylceramidase, which catalyzes the degradation of the myelin lipid galactosylceramide. Before postnatal day (PND) 20, the levels of myelin protein mRNA were similar in twitcher and normal mice. With progression of demyelination after PND 25-30, myelin protein mRNA levels gradually decreased. The period of maximum expression of the myelin protein genes in twitcher mice was, however, similar to that of normal control mice. mRNA levels for the gene that encodes the enzyme UDP-galactose:ceramide galactosyltransferase which is responsible for catalyzing the final step in galactosylceramide synthesis, was exceptionally down-regulated from the early stages of the disease. The increase of glial fibrillary acidic protein (GFAP) mRNA levels preceded morphological evidence of demyelination.

Animals↗
PubMed1998

Duarte allele impairs biostability of galactose-1-phosphate uridyltransferase in human lymphoblasts.

The Duarte allele (D) is a missense mutation (N314D) that produces a characteristic isoform and partial impairment of galactose-1-phosphate uridyltransferase (GALT) in human erythrocytes, fibroblasts, and transformed lymphoblasts. The position of this amino acid is distant, however, from presumptive catalytic site(s) as deduced from a three-dimensional model of crystallized Escherichia coli galT protein. To evaluate the mechanism(s) involved in the partial impairment of enzymatic activity, we compared the activity, abundance, biological stability, and mRNA of GALT in human lymphoblastoid cell lines cultured from individuals homozygous for wild-type (WT/WT) and Duarte alleles (N314D/N314D). No other nucleotide differences were present in their GALT genes. The apparent Vmax was reduced in N314D/N314D cells to 31 +/- 3.6 compared to WT/WT of 54 +/- 6.5 nmole UDP-galactose formed/g cell protein/hour. Both genotypes had similar apparent KMs for UDP-glucose of 0.142 +/- 0.057 mM and 0.133 +/- 0.056 mM. This reduced Vmax was associated with a reduced abundance of the 86kD GALT dimer as determined by Western blots and densitometry. Using RNase protection assays, this reduced GALT protein in the N314D/N314D cell lines was not associated with reduced abundance of GALT mRNA. Using cycloheximide (3-[2-(3,5-Dimethyl-2-oxocyclohexyl)-2-hydroxyethyl]glutarimide) inhibition of de novo protein synthesis, GALT enzyme activity, and its dimeric protein had a biological T1/2 of approximately 24 hours in N314D/N314D cell lines as compared to 50 hours for WT/WT lymphoblasts. Upon exposure to 50 degrees C for 15 minutes, N314D/ N314D lymphoblasts retained 45% of GALT activity, whereas controls retained 77% activity. Reduced activity and thermal sensitivity caused by the N314D mutation reverted to control values when a lysine was substituted for a glutamic acid at amino acid 203 in cis (E203K). In summary, N314D/N314D lymphoblasts have reduced GALT enzyme capacity, dimeric protein abundance, biological, and thermal stability. We conclude that the substitution of aspartate for asparagine at amino acid 314 in the human GALT protein reduces the biostability of the active enzyme in human lymphoblasts.

Alleles↗
PubMed1995

Identification of cells expressing galectin-1, a galactose-binding receptor, in the rat olfactory system.

Interactions between carbohydrate ligands and their receptors play an important role in cell adhesion and migration in many tissues. Cell-surface carbohydrates that contain terminal galactose have previously been implicated in primary sensory axon growth in the rodent olfactory system. The aim of the present study was to determine whether galectin-1, a galactose-binding receptor, was expressed within the rat primary olfactory pathway. Immunohistochemical and in situ hybridisation analyses revealed expression of galectin-1 by primary sensory olfactory neurons during the major embryonic period of axonogenesis as well as in maturity. In the adult olfactory bulb, galectin-1 was expressed by both second-order projection neurons and interneurons and was selectively localised to the synaptic neuropil layers. Mitral cells, the principal postsynaptic target of primary olfactory axons, began expressing this lectin soon after genesis and maintained high levels into adulthood. The expression of galectin-1 in the primary olfactory pathway and olfactory bulb neuropil suggests a role for this lectin both in the initial formation and in the subsequent maintenance of neuronal connections between the peripheral and the central olfactory neurons as well as between neurons within the bulb.

Animals↗
PubMed1990

Fucose and galactose receptor and liver recognition by lymphoma cells.

A syngeneic model system for the study of metastases is described. The system consisted of 2 lymphoma clones (A/63-I and A/63-2) derived from a single thymoma (A/63) induced by a wild-type Abelson-Moloney viral complex. Phenotype and genotype analyses revealed that both clones were derived from transformation of early T-cell precursors. An in vivo study of the colonizing potential following intravenous (i.v.) injection of clones showed that only the A/63-I cell clone colonized the liver. This observation was confirmed by quantitative analysis of organ distribution of both cell clones consecutive to i.v. injection of 125IUdR-labelled cells. In the same way, an in vitro study of the invasive potential of both clones was performed on frozen liver sections and showed that only the A/63-I cell clone had the ability to attach to liver. This specific adhesion was inhibited by L-fucose, D-galactose, N-acetyl-D-galactosamine (D-GalNAc) and with D-galactose- and L-fucose-containing neoglycoproteins. Differences in cell surface carbohydrates of the 2 cell clones were detected using various lectins: peanut agglutinin (PNA), Dolichos biflorus (DBA), Aleuria aurantia (AAA) and Galactia tenuiflora agglutinins (GTA). A/63-I was found to react strongly with PNA, DBA and GTA, and the removal of sialic acid by neuraminidase treatment increased DBA and PNA receptor sites of A/63-2 as compared to A/63-I. The present data suggest that cell-surface GalNAc, galactosyl and fucosyl residues are responsible for the ability of the A/63-I cell clone to recognize liver tissue probably through binding to a Kupffer-cell-associated lectin.

Abelson murine leukemia virus↗
PubMed1978

Use of guinea pigs as model to study galactose-induced cataract formation.

Because the dietary requirement for ascorbic acid is similar in humans and guinea pigs, galactose-induced cataract research with the guinea pig as an experimental model instead of the rat might be appropriate and may represent a closer analogy to galactosemic cataract formation in humans. In this study, dietary ascorbic acid was found in all guinea pigs to have a retarding or delaying effect on the development of galactose-induced cataracts.

Animals↗
PubMed1999

Conjugation of plasmid DNAs with lactose via diazocoupling enhances resistance to restriction enzymes and acquires binding affinity to galactose-specific lectin.

Oligosaccharide-plasmid DNA conjugates were synthesized simply and effectively via the diazocoupling method. Plasmids (pUC19, pTRI-beta-actin, and pEGFP-C1) were treated with an N-beta-lactoside-substituted diazonium salt to yield diazocoupling products with degree of substitutions of 2.5-3.1 mol% of overall nucleobases. The lactose-pUC19 conjugate was found to resist restriction enzymes more strongly than the nonconjugated plasmid DNA and to acquire a strong binding affinity to galactose-specific lectin RCA(120). The diazocoupling modification of pTRI-beta-actin plasmid DNA little influenced in vitro transcription with T7 RNA polymerase. When lactose-pEGFP-C1 conjugate was transfected to baby hamster kidney (BHK) cells by means of cationic lipids, transduced gene was expressed in BHK cells similarly with the nonconjugated pEGFP-C1. The modification of plasmid DNA with carbohydrate enhanced the resistance to restriction enzymes and developed a strong binding affinity to galactose-specific lectin.

Actins↗
PubMed1995

Characterization of the N314D allele of human galactose-1-phosphate uridylyltransferase using a yeast expression system.

Transferase-deficiency galactosemia is an inborn error of metabolism resulting from impairment of the enzyme galactose-1-phosphate uridylyltransferase (GALT), which normally catalyzes the second step of the Leloir pathway of galactose metabolism. Several recent studies have linked a previously reported substitution, N314D (asn to asp at position 314), with both the Duarte and Los Angeles (LA) variant alleles of GALT. While both variants demonstrate similar mobility shifts relative to the normal enzyme on isoelectric focusing (IEF) gels, one (Duarte) is associated with diminished activity, while the other (LA) is associated with greater than normal activity. Therefore, although the concordance rates between N314D and both of these phenotypes are compelling, the question remains as to whether N314D alone is sufficient to cause either or both variants. To address the question of precisely what properties of variant GALT can be attributed to the N314D substitution alone, we have modeled both the wildtype and N314D-GALT alleles in a previously defined yeast expression system, and characterized each with respect to activity, abundance, subunit interaction, and mobility on isoelectric focusing gels. Our results indicate that the N314D subunit dimerizes well both with wildtype GALT and with itself and that the N314D substitution is sufficient to confer the expected shift of IEF banding pattern associated with both the Duarte and LA variant proteins isolated from human cells. However, our results also suggest that N314D-GALT retains full specific activity, thereby calling into question the suggestion that N314D encodes the Duarte variant of GALT.

Alleles↗
PubMed1996

A mouse model of galactose-1-phosphate uridyl transferase deficiency.

Galactose-1-phosphate uridyl transferase (GALT) deficiency causes classical galactosemia in humans. Mice deficient in this enzyme were created by gene targeting. GALT-deficient mice develop biochemical features similar to those seen in humans with GALT deficiency, but fail to develop the pattern of acute toxicity seen in newborns with classical galactosemia. This study suggests that alternative routes of galactose metabolism are important in the pathogenesis of galactosemia.

Animals↗
PubMed2001

Functional analysis of the human galactose-1-phosphate uridyltransferase promoter in Duarte and LA variant galactosemia.

Human galactose-1-phosphate uridyltransferase (hGALT) is an evolutionarily conserved enzyme central to D-galactose metabolism. The impairment of hGALT causes galactosemia. One missense mutation, an aspartate to asparagine substitution at amino acid 314 (N314D), impairs 50% activity in the homozygous state in some patients but gives near normal activity in others. The former condition is called Duarte (D) and the latter, Los Angeles (LA). The D allele is linked to hGALT polymorphisms including a deletion 5'to the translation start site (-119 to -116delGTCA), g1391G --> A and g1105G --> C. The LA allele is linked to a g1721C --> T transition. To investigate possible mechanisms for differences in hGALT activity between the D and LA alleles, we sequenced 3951 nucleotides of genomic DNA 5' to the hGALT translation start site. Using a dual-luciferase reporter system to express deletion constructs of the hGALT promoter, we noted both positive and negative regulatory regions. Two putative positive regulatory domains overlap with the naturally occurring -119 to -116delGTCA linked to Duarte. One is an E-box motif (CACGTG) at -117 to -112 bp. The second is an AP-1 motif (TCAGTCAG) at -124 to -119 bp. The delGTCA mutation confers reduced luciferase activity to transfected cell lines derived from human ovarian and liver neoplasms. Additionally, human lymphoblasts derived from patients with the Duarte allele have reduced GALT mRNA. We conclude that the human GALT gene is regulated in the first -165 bp of its promoter region by positive regulators of GALT gene expression. The -119 to -116delGTCA reduces hGALT transcription resulting in reduced GALT activity in the Duarte allele.

Alleles↗
PubMed1995

Characterization of two stop codon mutations in the galactose-1-phosphate uridyltransferase gene of three male galactosemic patients with severe clinical manifestation.

Classical galactosemia, which is caused by deficiency of galactose-1-phosphate uridyltransferase, is characterized by acute problems of hepatocellular dysfunction, sepsis, cataracts and failure to thrive. Galactose limitation reverses these symptoms immediately; however, the long-term complications, such as mental retardation and ovarian failures are major problems in most of these patients. In order to investigate the molecular basis for phenotype variation in galactosemia, we have screened the most common mutation in the GALT gene, Q188R. We have further examined those patients who are heterozygous for Q188R or negative for this mutation by SSCP analysis and direct sequencing. In three male patients, we have identified, for the first time, two stop-codon mutations in the GALT gene, G212X (exon 7) and E340X (exon 10). Two patients of 8 and 28 years of age, respectively, who are compound heterozygotes for Q188R and G212X, have severe mental retardation and their general clinical condition is more severe than that of patients with missense mutations. The third patient, who is 8 years of age and who is homozygous for E340X, the N314D polymorphism and a silent substitution L218L, presents with a relatively normal physical and mental condition to date.

Adult↗
PubMed1994

On the molecular nature of the Duarte variant of galactose-1-phosphate uridyl transferase (GALT).

Galactosemia is an inborn error of galactose metabolism secondary to deficiency of galactose-1-phosphate uridyl transferase (GALT). GALT is a polymorphic enzyme and Duarte (D) is the most common enzyme variant. This variant is characterized by faster electrophoretic mobility and reduced activity. Duarte/galactosemia compound heterozygotes (D/G) are commonly identified in galactosemia newborn screening programs. However, these patients do not generally require treatment. By using a "candidate mutation" approach to define the molecular basis of the Duarte variant of GALT, a close association between the previously reported N314D polymorphism and the Duarte variant of GALT was found. We suggest that N314D encodes the D variant of GALT and that molecular testing for N314D might be useful to confirm a biochemical diagnosis of Duarte variant of GALT.

Alleles↗
PubMed1989

Streptomyces species with madurose (3-O-methyl-D-galactose) as a whole-cell sugar.

Madurose, an actinomycete whole-cell sugar, was found in the strains of the genus Streptomyces: three strains of S. platensis, one strain each of S. platensis subsp. malvinus, and S. albus subsp. albus. The sugar was isolated from the hydrolysate of S. platensis IFO 14008 cells, and was identified as madurose (3-O-methyl-D-galactose) by chromatographic analyses, 1H-NMR spectrometry, mass spectrometry as its alditol acetate, and demethylation with boron trichloride. Cell walls of the strain contained peptidoglycan and teichoic acids. LL-Diaminopimelic acid, glycine, glutamic acid, and alanine were present in the peptidoglycan fraction in molar ratios of 1.0:1.3:1.2:2.3. Madurose was detected in the teichoic acid fraction, which was composed of phosphorus, glycerol, galactose, and madurose in molar ratios of 9.3:8.5:2.9:1.0. Thus, madurose was found in the glycerol teichoic acid moiety of the cell walls of this strain.

Carbohydrates↗
PubMed1995

Purification, properties, and immunological characterization of GalT-3 (UDP-galactose: GM2 ganglioside, beta 1-3 galactosyltransferase) from embryonic chicken brain.

A beta 1-3 galactosyltransferase (GalT-3; UDP-Gal; GM2 beta 1-3 galactosyltransferase) was purified over 5100-fold from 19-day-old embryonic chicken brain homogenate employing detergent solubilization, alpha-lactalbumin Sepharose, Q-Sepharose, UDP-hexanolamine Sepharose, and GalNAc beta 1-4Gal beta-Synsorb column chromatography. The purified enzyme was resolved into two bands on reducing gels with apparent molecular weights of 62 kDa and 65 kDa, respectively. GalT-3 activity was also localized in the same regions by activity gel analysis and sucrose-density gradient centrifugation of a detergent-solubilized extract of 19-day-old embryonic chicken brain. Purified GalT-3 exhibited apparent Kms of 33 microM, and 14.4 mM with respect to the substrates GM2, UDP-galactose, and MnCl2, respectively. Substrate specificity studies with the purified enzyme and a variety of glycosphingolipids, glycoproteins, and synthetic substrates revealed that the enzyme was highly specific only for the glycosphingolipid acceptors, GM2 and GgOse3Cer (asialo-GM2). Ovine-asialo-agalacto submaxillary mucin inhibited the transfer of galactose to GM2 but did not act as an acceptor in the range of concentrations tested. Polyclonal antibodies raised against purified GalT-3 inhibited GalT-3 activity in vitro and Western-immunoblot analysis of purified GalT-3 showed immunopositive bands at 62 and 65 kDa.

Animals↗