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PubMed2006

D-Galactose induces cellulase gene expression in Hypocrea jecorina at low growth rates.

Lactose (1,4-O-beta-d-galactopyranosyl-d-glucose) is a soluble and economic carbon source for the industrial production of cellulases or recombinant proteins by Hypocrea jecorina (anamorph Trichoderma reesei). The mechanism by which lactose induces cellulase formation is not understood. Recent data showed that the galactokinase step is essential for cellulase induction by lactose, but growth on d-galactose alone does not induce cellulases. Consequently, the hypothesis was tested that d-galactose may be an inducer only at a low growth rate, which is typically observed when growing on lactose. Carbon-limited chemostat cultivations of H. jecorina were therefore performed at different dilution rates with d-galactose, lactose, galactitol and d-glucose. Cellulase gene expression was monitored by using a strain carrying a fusion between the cbh2 (encoding cellobiohydrolase 2, Cel6A) promoter region and the Aspergillus niger glucose oxidase gene and by identification of the two major cellobiohydrolases Cel7A and Cel6A. The results show that d-galactose indeed induces cbh2 gene transcription and leads to Cel7A and Cel6A accumulation at a low (D=0.015 h(-1)) but not at higher dilution rates. At the same dilution rate, growth on d-glucose did not lead to cbh2 promoter activation or Cel6A formation but a basal level, lower than that observed on d-galactose, was detected for the carbon-catabolite-derepressible Cel7A. Lactose induced significantly higher cellulase levels at 0.015 h(-1) than d-galactose and induced cellulases even at growth rates up to 0.042 h(-1). Results of chemostats with an equimolar mixture of d-galactose and d-glucose essentially mimicked the behaviour on d-galactose alone, whereas an equimolar mixture of d-galactose and galactitol, the first intermediate of a recently described second pathway of d-galactose catabolism, led to cellulase induction at D=0.030 h(-1). It is concluded that d-galactose indeed induces cellulases at low growth rate and that the operation of the alternative pathway further increases this induction. However, under those conditions lactose is still a superior inducer for which the mechanism remains to be clarified.

Artificial Gene Fusion↗

PubMed2006

Galactose transport in Kluyveromyces lactis: major role of the glucose permease Hgt1.

In Kluyveromyces lactis, galactose transport has been thought to be mediated by the lactose permease encoded by LAC12. In fact, a lac12 mutant unable to grow on lactose did not grow on galactose either and showed low and uninducible galactose uptake activity. The existence of other galactose transport systems, at low and at high affinity, had, however, been hypothesized on the basis of galactose uptake kinetics studies. Here we confirmed the existence of a second galactose transporter and we isolated its structural gene. It turned out to be HGT1, previously identified as encoding the high-affinity glucose carrier. Analysis of galactose transporter mutants, hgt1 and lac12, and the double mutant hgt1lac12, suggested that Hgt1 was the high-affinity and Lac12 was the low-affinity galactose transporter. HGT1 expression was strongly induced by galactose and insensitive to glucose repression. This could explain the rapid adaptation to galactose observed in K. lactis after a shift from glucose to galactose medium.

Base Sequence↗

PubMed1992

Mechanism of delayed hepatic glycogen synthesis after an oral galactose load vs. an oral glucose load in adult rats.

We have compared the effects of administration of oral galactose or glucose (1 g/kg) to 24-h fasted rats to examine the mechanism by which galactose regulates its own incorporation into liver glycogen in vivo. Liver glycogen increased to a maximum more slowly after galactose than after glucose administration (0.14 vs. 0.29 mumol.g liver-1.min-1). Glycogen accumulation after the galactose load was 70% of that after the glucose load (149 vs. 214 mumol), and the net increase in liver glycogen represented the same proportion (24 vs. 22%) of added carbohydrate after urinary loss of galactose was accounted for. Slower glycogen accumulation after galactose vs. glucose loading could not be explained by galactosuria, by differences in the active forms of synthase or phosphorylase, by end product (glycogen) inhibition of synthase phosphatase, or by different concentrations of the known allosteric effectors of synthase R plus I and phosphorylase a. Similar increases in glucose 6-phosphate were observed after both hexoses. AMP and ADP increased only transiently after galactose administration, and ATP, UTP, and Pi concentrations were unchanged. The UDP-glucose concentration decreased, whereas the UDP-galactose concentration increased two- to threefold after galactose but not glucose administration. The UDP-glucose pyrophosphorylase reaction is inhibited competitively by UDP-galactose. This could explain the decreased UDP-glucose concentration and the reduced rate of glycogen synthesis after galactose was given.

Absorption↗

PubMed1978

Kinetic properties of galactose influx across the mucosal border of guinea pig ileum.

By using everted sac preparations of guinea pig ileum, properties of galactose influx across the mucosal border were studied under various ionic conditions of the media. Mannitol was used as a marker of the extracellular space on the mucosal surface. In the absence of Na+ in the mucosal medium, the "galactose space" was almost the same as mannitol space, indicating the lack of uptake of galactose through the specific carrier mechanism. Galactose influx obeyed Michaelis-Menten kinetics at any Na+ concentration and it was also a Michaelis-Menten type function of Na+ concentration in the medium when examined at a constant galactose concentration. The observed kinetic properties were well explained on the basis of the kinetic model in which galactose was assumed to be transported only in the form of galactose-Na-carrier complex. The increase in Na+ influx associated with galactose influx was not significantly different from galactose influx. Na+ concentration of the serosal medium had no effect on galactose influx across the mucosal border. Choline and Tris, as well as mannitol, had no stimulating or inhibitory effect on galactose influx.

Animals↗

PubMed1989

The effects of 5% and 25% galactose diets on lens polyols, glutathione and protein glycation in male and female pigs.

The cataractogenic effect of a galactose diet was studied in male and female pigs in relation to the daily galactose intake. Two experiments were performed. In the first, 10 male and 10 female pigs were maintained on a 5% galactose diet for 30 days; galactose was given either as pure sugar or as hydrolyzed whey. In the second experiment, 18 castrated male and 21 female pigs were fed a 25% galactose diet for 49 days. Galactose was given as whey, hydrolyzed whey or as an alternating diet. Lenses were analyzed for sugar-alcohols, glutathione and protein glycation, and compared to lenses of pigs on a control standard diet. The 5% galactose diet induced large accumulation of dulcitol in the lens, which was similar whether galactose was ingested alone or as hydrolyzed whey. Glutathione and inositol contents were slightly below control values only in males on the galactose alone diet, perhaps indicating initiation of a cataractogenic process. No change was observed in females. The lenses of females on control diet were different from those of control males: having decreased glutathione, inositol and sorbitol contents and higher protein glycation. The 25% galactose diet resulted in an approximately 10 times higher lens dulcitol accumulation and advanced lens damage as measured by loss of inositol and increase in protein glycation. These changes were more severe in males than in females. The data indicate that there is a relationship between total galactose intake and dulcitol accumulation.

Animals↗

PubMed1992

Cell surface and intracellular functions for ricin galactose binding.

The role of the two galactose binding sites of ricin B chain in ricin toxicity was evaluated by studying a series of ricin point mutants. Wild-type (WT) ricin and three ricin B chain point mutants having mutations in either 1) the first galactose binding domain (site 1 mutant, Met in place of Lys-40 and Gly in place of Asn-46), 2) the second galactose binding domain (site 2 mutant, Gly in place of Asn-255), or 3) both galactose binding domains (double site mutant containing all three amino acid replacements formerly stated) were expressed in Xenopus oocytes and then reassociated with recombinant ricin A chain. The different ricin B chains were mannosylated to the same extent. Cytotoxicity of these toxins was evaluated when cell entry was mediated either by galactose-containing receptors or through an alternate receptor, the mannose receptor of macrophages. WT ricin and each of the single domain mutants was able to kill Vero cells following uptake by galactose containing receptors. Lactose blocked the toxicity of each of these ricins. Site 1 and 2 mutants were 20-40 times less potent than WT ricin, and the double site mutant had no detectable cytotoxicity. WT ricin, the site 1 mutant, and the site 2 mutant also inhibited protein synthesis of mannose receptor-containing cells. Ricin can enter these cells through either a cell-surface galactose-containing receptor or through the mannose receptor. By including lactose in the cell medium, galactose-containing receptor-mediated uptake is blocked and cytotoxicity occurs solely via the mannose receptor. WT ricin, site 1, and site 2 mutants were cytotoxic to macrophages in the presence of lactose with the relative potency, WT greater than site 2 mutant greater than site 1 mutant. The double site mutant lacked cytotoxicity either in the absence or presence of lactose. Thus, even for mannose receptor-mediated toxicity of ricin, at least one galactose binding site remains necessary for cytotoxicity and two galactose binding sites further increases potency. These results are consistent with the model that the ricin B chain galactose binding activity plays a role not only in cell surface binding but also intracellularly for ricin cytotoxicity.

Animals↗

PubMed1982

A new method of screening for inherited disorders of galactose metabolism.

A method has been developed for detecting elevated levels of galactose and galactose-1-phosphate in routine blood samples of newborns and has been successfully applied as a screening procedure for galactosemia in several laboratories. The procedure utilizes a strain of Escherichia coli that becomes resistant to bacteriophage C21 in the presence of galactose. The presence of galactose or galactose-1-phosphate is detected as a zone of bacterial growth around blood spots placed on a dish in which the bacteria are otherwise killed by phage. The diameter of the growth zone is proportional to the concentration of total blood galactose. The procedure has the potential of detecting all metabolic abnormalities that can lead to the accumulation of galactose or galactose-1-phosphate. Over a million newborn infants have now been tested by this procedure in three countries. In the New England Regional Screening Program, 12 galactosemic children were detected in 825,403 live births. One additional case, a sibling of a previously diagnosed galactosemic, was not allowed any milk feeding and was detected by an enzymatic test of cord blood. The combined frequency was 1:63,000. No problems of interference by antibiotics were apparent. Use of the test in Switzerland and in Japan also allowed the discovery of infants with UDP galactose 4-epimerase deficiency. Our experience suggests that the test provides an efficient and reliable means of detecting congenital defects of galactose metabolism with a very low frequency of errors. It can also be used to monitor blood galactose levels in the management of galactosemic children.

Bacteriophages↗

PubMed1996

The galactose elimination capacity test: a study of the technique based on the analysis of 868 measurements.

OBJECTIVES: Our objective in this study was to analyze the correspondence of galactose concentration-on-time-decay curve to theoretical assumptions and the confidence limits of the determination of galactose elimination capacity. METHODS: We analyzed a retrospective series of 868 galactose elimination tests, performed on subjects with and without liver disease. Zero-order kinetics of galactose elimination was tested by comparison of the residual variance of linear regression with that obtained after quadratic transformation. The uncertainty in determination of galactose elimination capacity was calculated on the regression line by computing the 95% confidence limits of the estimate. RESULTS: The time-course of galactose concentration suggested an initial uneven distribution, and the first (20-min) data point deviated significantly from the regression. The galactose decay curve in plasma rejected linearity in 13% of tests; after exclusion of the first data-point, linearity was rejected in only 3% of cases. The 95% confidence interval of galactose elimination capacity was on average +/- 16%, but in individual tests it was as large as +/- 60-80%. The uncertainty of the test was not affected by linearity. It was larger, with poor fitting of the experimental data on the regression of galactose concentration on time, low number of data points, and low galactose elimination. It was maintained within +/- 20% only when residual variance was > or = 2% of total variance (nearly 50% of tests). CONCLUSION: The methodology for the determination of galactose elimination capacity leads to considerable uncertainty as to the final result, which must be considered whenever the test is used for clinical purposes in the decision-making process. It tends to be larger in patients with advanced disease and can be accurately calculated so as to contribute to a proper evaluation of the test result.

Adolescent↗

PubMed1983

A process related to membrane potential involved in bacterial chemotaxis to galactose.

Attractants, in the presence of respiration and ATPase inhibitors, stimulate a hyperpolarization in Escherichia coli [Eisenbach, M. (1982) Biochemistry 21, 6818-6825]. In order to examine whether this hyperpolarization is correlated with chemotaxis, the effect of the attractant D-galactose and its analogues on the membrane potential of wild-type E. coli strains and some of their mutants was studied. The main observations were the following: (i) Wild-type cells became hyperpolarized by either galactose or its nonmetabolizable analogues, D-fucose and L-sorbose. (ii) A mutant defective in galactose metabolism became hyperpolarized by galactose. (iii) Inhibiting the galactose permease system did not prevent the hyperpolarization, rather it facilitated the observation of the hyperpolarization. (iv) Mutants unable to transport galactose via the methyl beta-galactoside (Mgl) transport system but having normal chemotaxis to galactose became normally hyperpolarized by D-fucose. (v) Mutants which cannot bind galactose were not hyperpolarized by galactose. (vi) The hyperpolarization in flaI mutants, in which the whole chemotaxis machinery is repressed, was reduced to 12-15% of the hyperpolarization in the parent strains. (vii) Nonattractant sugars did not stimulate hyperpolarization. It is concluded that the hyperpolarization is the consequence of neither galactose metabolism nor transport but rather is correlated with galactose taxis.

Calcium-Binding Proteins↗

PubMed1977

Comparative studies of glucose-fed and glucose-starved hamster cell cultures: responses in galactose metabolism.

The metabolic flow of trace amounts of D-[14C]-galactose was followed in cultures of transformed and untransformed hamster cells over a period ranging from five minutes to two hours. The results of chromatographic and enzymatic analyses of the soluble pools are described. Non-glycolytic cells(previously deprived of sugar periods of up to 24 hours) convert D-galactose to galactose-1-phosphate and uridine diphosphoglucuronic acid in 10 to 20 minutes. In the same short assay time, glycolytic cells which have been maintained for 24 hours in media containing glucose or galactose convert D-galactose to uridine diphsphogalactose and uridine diphosphoglucose (ratio 1.4:1). Long term diprivation of sugar also results in 3- to 4-fold increases in the uptake of galactose. In addition, the incorporation of galactose label into chloroformethanol soluble material appears to be influenced by the culture conditions of the untransformed cells while incorporation in the transformed cells appears unaffected. When cycloheximide is included in the maintenance medium for extended periods, the non-glycolytic cells also show increases in galactose uptake rates but the glucose-fed, glycolytic cells llose uptake ability. UDPhexose is the main galactose metabolic peak in the soluble pools of the cycloheximide-treated, glycolytic and the cycloheximide-treated, non-glycolytic cells. The results of these experiments suggests that uptake of galactose and its subsequent metabolism are under separate control.

Animals↗

PubMed1978

Galactose catabolism in Caulobacter crescentus.

Caulobacter crescentus wild-type strain CB13 is unable to utilize galactose as the sole carbon source unless derivatives of cyclic AMP are present. Spontaneous mutants have been isolated which are able to grow on galactose in the absence of exogenous cyclic nucleotides. These mutants and the wild-type strain were used to determine the pathway of galactose catabolism in this organism. It is shown here that C. crescentus catabolizes galactose by the Entner-Duodoroff pathway. Galactose is initially converted to galactonate by galactose dehydrogenase and then 2-keto-3-deoxy-6-phosphogalactonate aldolase catalyzes the hydrolysis of 2-keto-3-deoxy-6-phosphogalactonic acid to yield triose phosphate and pyruvate. Two enzymes of galactose catabolism, galactose dehydrogenase and 2-keto-3-deoxy-6-phosphogalactonate aldolase, were shown to be inducible and independently regulated. Furthermore, galactose uptake was observed to be regulated independently of the galactose catabolic enzymes.

Aldehyde-Lyases↗

PubMed1976

Transport and phosphorylation of D-galactose in renal cortical cells.

An improved analytical procedure for the extraction and determination of total, free and phosphorylated tissue sugar is described. This method, employing ZnSO4 plus Ba(OH)2 for the precipitation of sugar phosphates, yields values identical with those obtained by the more laborious separation of free and phosphorylated sugar by ion-exchange chromatography. Erroneous values for free sugar due to the action of a Zn2+ -activated phosphatase and/or the lability to acids of some sugar phosphates, are avoided. Using this technique for the sudy of transport and phosphorylation of D-galactose in rabbit renal cortical slices and tissue extracts, it was found: 1. The cellular uptake of D-galactose was associated with the appearance of both free and phosphorylated sugar whether or not external Na+ was present. At 1 mM sugar, galactose was accumulated in the cells against a modest concentration gradient of 1.445 +/- 0.097 (n = 17). Galactose phosphate appeared in the cells considerably faster than free sugar under conditions of net uptake as well as of steady-state exchange (pulse-labelling). 2. Increasing saline pH (6-8) increased the cellular levels of sugar phosphate without affecting the steady-state values of free sugar. With tissue extracts, increasing pH also stimulated the activity of galactokinase and the dephosphorylation of galactose 1-phosphate by a Zn2+ -activated phosphatase. 3. 0.5 mM phlorizin inhibited the tissue uptake of galactose and its subsequent oxidation to CO2 only to a minor degree (30 and 10%, respectively). The absence of external Na+ further depressed the phlorizin effect. Preincubation of the tissue with phlorizin and subsequent washing in part abolished the inhibitory effect. The data suggest that a major portion of the galactose uptake by the tissue proceeds by a mechanism with a low affinity for phlorizin. 4. Efflux studies showed that the wash-out of free galactose from slices was associated with a net decrease of both free and phosphorylated tissue sugar. 5. The above results suggest the possibility that phosphorylation may represent a step in the Na+ -independent, phloretin-sensitive transfer of D-galactose across the antiluminal cell membrane. The participation of intracellular galactokinase and a Zn2+ -activated alkaline phosphatase in the maintenance of the steady state of free and phosphorylated galactose in the cells has been demonstrated.

Animals↗

PubMed1991

In utero and milk-mediated effect of aldose reductase inhibitor on galactose cataracts.

Our previously reported investigations showed that cataracts could be induced in fetal lenses through the maternal feeding of galactose during pregnancy. We also reported that the lens opacity present at birth reverses completely by 30 days of age if there is no further post-natal exposure to galactose. This investigation was designed to investigate if an aldose reductase inhibitor (ARI) has any cross-placental effect in preventing galactose-induced cataracts in fetuses. We have also evaluated if there are any milk-mediated effects of galactose on cataract induction and of galactose and ARI on the maintenance or reversal of opacities induced in utero. Pregnant Sprague-Dawley rats were fed either 50% galactose or rat chow with or without the ARI, (2R,4S)-6-fluoro-2-methyl spirochroman-4,4'-imidazolidine-2',5'-dione (Eisai compound E-0722). Following parturition, pups of mothers from the different dietary groups were either fed by their own mothers or foster fed by lactating females fed either rat chow or 50% galactose with or without the ARI. Lenses of the pups were examined at desired intervals with light and scanning electron microscopes. We observed that: (a) both galactose and the ARI had a cross-placental effect on the fetal lenses in the development and inhibition of cataracts, respectively; (b) galactose had very little, if any, milk-mediated effect on either the induction of cataracts in newborn pups that were born with transparent lenses or the maintenance of cataracts induced in utero; (c) the ARI appeared to have a milk-mediated effect, which accelerates the reversal of cataract associated alterations in lenses of pups with cataracts induced in utero, leading to further reinstatement of lens transparency; and (d) the presence of ARI in the diet of rats during pregnancy and/or post-parturition provided continued protection to the lenses of pups that were exposed to a galactose diet following birth.

Aldehyde Reductase↗

PubMed1988

Galactose clearance measurements and liver blood flow.

Galactose clearance, measured during low galactose infusion and calculated as infusion rate divided by peripheral galactose concentration (systemic clearance), has been proposed as a measure of liver blood flow. This requires nearly complete hepatic extraction as well as negligible extrahepatic elimination. The purpose of the study was to examine if these assumptions are fulfilled in subjects with no liver disease, and to compare the galactose clearance measurement with an independent measurement of liver blood flow. Liver blood flow was measured in 6 subjects by means of a constant indocyanine green infusion, indocyanine green concentration measurements in a peripheral artery and a hepatic vein, and calculation according to Fick's principle. The mean (+/- SEM) blood flow rate was 1.2 +/- 0.1 L/min. Galactose was given at a constant infusion rate of 142 +/- 10 mumol/min, and steady-state concentrations were measured in the peripheral artery (A) and the hepatic vein (V). The hepatic extraction fraction [(A - V)/A] was 0.91 +/- 0.03. The hepatic galactose elimination rate [(A - V) X flow] was 101 +/- 12 mumol/min; this is about two-thirds of the total elimination rate (viz., infusion rate). Urinary excretion was negligible. This indicates an extrahepatic galactose elimination of approximately 41 mumol/min. Systemic galactose clearance, calculated as mentioned above, was 1.5 +/- 0.1 L blood/min. It was significantly higher than the liver blood flow in each subject (paired t-test, each p less than 0.02), on average 133% of the flow. Thus the systemic galactose clearance value overestimates liver blood flow, probably due to a small, but in this context quantitatively important, extrahepatic galactose elimination.

Galactose↗

PubMed2004

Age dependence of endogenous galactose formation in Q188R homozygous galactosemic patients.

The age dependence of endogenous galactose formation was investigated in Q188R homozygous galactosemic patients (n=18; 4-38 years) using the primed continuous infusion approach with D-[1-13C]galactose as a substrate. Studies were conducted under postabsorptive conditions (fasting >10h) and good metabolic control. In the patients, the release of galactose from endogenous sources into plasma (R(a)) decreased with age and ranged from 4.6 to 2.0 micromol/kg body weight per h. Galactitol and galactonate release rates paralleled the galactose R(a) but at a lower level. The mean relation of galactose, galactitol, and galactonate release was 10:5:1. Statistically, there was a highly significant (p<0.0001) inverse correlation between total galactose release (i.e., sum of R(a) plus galactitol and galactonate release) and age. The data (total galactose=y, age=t) were best fitted to the simple exponential model y=y(0)+axexp(-bt) by non-linear regression analysis. The parameter estimates were y(0)=3.0+/-0.2, a=6.5+/-0.4, and b=0.11+/-0.02. The value of y(0) provides an estimate of total galactose release in adult patients (i.e., approximately 13 mg/kg body weight per day), summation operator (y(0)+a) provides an estimate for galactosemic newborns (i.e., approximately 41 mg/kg body weight per day). The data show that significant amounts of endogenous galactose are formed in galactosemic patients with release rates being several fold higher in infants than in adults. The present findings can explain the persistently elevated galactose-1-phosphate levels in erythrocytes-and its age dependence-in galactosemic patients even when under strict dietary treatment.

Adolescent↗

PubMed2005

Intracellular galactose-1-phosphate accumulation leads to environmental stress response in yeast model.

In humans, deficiency of galactose-1-phosphate uridyltransferase (GALT) can lead a metabolic disorder Classic Galactosemia. Although the biochemical abnormalities associated with this disease have been described in detail, few attempts have been made to characterize the pathogenic mechanisms of this disorder at the molecular level. Here we report the use of high-throughput DNA microarray to examine how galactose affects gene expression in isogenic yeast models that are deficient in either galactokinase (GALK) or GALT, two enzymes which are essential for normal galactose metabolism. We confirmed that the growth of our GALT-deficient, but not GALK-deficient yeast strain ceased 4 h after challenge with 0.2% galactose. Such inhibition was not associated with a reduction of ATP content and was reversible after removal of galactose from medium. We compared the gene expression profiles of the GALT-deficient and GALK-deficient cells in the presence/absence of galactose. We revealed that in the absence of galactose challenge, a subset of genes involved in RNA metabolism was expressed at a level 3-fold lower in the GALT-deficient cells. Upon galactose challenge, significantly more genes involved in various aspects of RNA metabolism and almost all ribosomal protein genes were downregulated in the GALT-deficient, but not GALK-deficient cells. Remarkably, genes involved in inositol biosynthesis and turnover were exclusively induced at high level in the galactose-intoxicated GALT-deficient cells. Our data thus suggested that RNA metabolism, ribosome biogenesis, and inositol metabolism were likely targets for galactose-1-phosphate, a toxic intermediate that is uniquely accumulated under GALT-deficiency.

Environment↗

PubMedDate not supplied

Galactose metabolism and ovarian toxicity.

Galactose is an energy-providing nutrient and also a necessary basic substrate for the biosynthesis of many macromolecules in the body. Metabolic pathways for galactose are important not only for the provision of these pathways but also for the prevention of galactose and galactose metabolite accumulation. Problems with galactose metabolism can cause a variety of clinical manifestations in animals and humans. It has been found that the mammalian ovary is particularly susceptible to damage from the accumulation of galactose and galactose metabolites. The galactose metabolites Gal-1-P, galactitol, and UDPgal are all considered to be important in this toxicity and proposed mechanisms include interference with ovarian apoptosis and gonadotrophin signaling. This review addresses the most recent scientific findings regarding the possible mechanisms of galactose-induced ovarian toxicity and also the possible protective role of hormonal and antioxidant therapy. In addition, the available epidemiologic and scientific evidence linking galactose intake with risk of ovarian cancer is discussed.

Animals↗

PubMed1994

Ligand size is a major determinant of high-affinity binding of fucose- and galactose-exposing (lipo)proteins by the hepatic fucose receptor.

Previous in vivo studies have demonstrated that small galactose-exposing particles are preferentially internalized by the asialoglycoprotein receptor on the parenchymal liver cell and large particles by the galactose-particle receptor on the Kupffer cell. In this study, we have investigated using in vitro binding studies whether the affinity for either receptor is affected by the ligand size. The asialoglycoprotein receptor appeared to bind and process lactosylated proteins irrespective of their size. In contrast, recognition of galactose-exposing proteins by the galactose-particle receptor on the Kupffer cell was strongly dependent on size. The affinity increased 3000-fold with protein sizes increasing from 5 to 15 nm, reaching its maximum at approx. 1 nM for ligands larger than 15 nm. Apparently, the preferential in vivo uptake of large galactose-exposing ligands by Kupffer cells does not result from an inability of the parenchymal liver cells to internalize these ligands, but from the high affinity of large ligands for the galactose-particle receptor and the strategic anatomical localization of the Kupffer cells in the liver. In the preceding paper [Kuiper, Bakkeren, Biessen and Van Berkel (1994) Biochem. J. 299, 285-290] the galactose-particle receptor on the Kupffer cell was suggested to be identical with the fucose receptor. 125I-Lac-LDL-binding studies clearly showed that the galactose-particle receptor exhibited high-affinity binding of fucose-exposing proteins also. The affinity of fucosylated proteins for the galactose-particle receptor was greatly affected by ligand size. The above data strongly support the hypothesis that the galactose-particle receptor is identical with the fucose receptor. The size of neoglycoproteins can be appreciated as a new major determinant of affinity for the fucose receptor.

Animals↗