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PubMed2001

Arg-302 facilitates deprotonation of Glu-325 in the transport mechanism of the lactose permease from Escherichiacoli.

A mechanistic model for lactose/H(+) symport via the lactose permease of Escherichia coli proposed recently indicates that the permease must be protonated to bind ligand with high affinity. Moreover, in the ground state, the symported H(+) is shared between His-322 (helix X) and Glu-269 (helix VIII), whereas Glu-325 (helix X) is charge-paired with Arg-302 (helix IX). Substrate binding at the outer surface induces a conformational change that leads to transfer of the H(+) to Glu-325 and reorientation of the binding site to the inner surface. After release of the substrate, Glu-325 is deprotonated on the inside because of rejuxtapositioning with Arg-302. To test the role of Arg-302 in the mechanism, the catalytic properties of mutants Arg-302-->Ala and Arg-302-->Ser were studied. Both mutants are severely defective in active lactose transport, as well as in efflux or influx down a concentration gradient, translocation modes that involve net H(+) movement. In marked contrast, the mutants catalyze equilibrium exchange of lactose and bind ligand with high affinity. These characteristics are remarkably analogous to those of permease mutants with neutral replacements for Glu-325, a residue that plays a direct role in H(+) translocation. These observations lend strong support for the argument that Arg-302 interacts with Glu-325 to facilitate deprotonation of the carboxylic acid during turnover.

Arginine↗
PubMed1986

A stochastic model of gene-culture coevolution suggested by the "culture historical hypothesis" for the evolution of adult lactose absorption in humans.

A stochastic model of gene-culture coevolution, suggested by the "culture historical hypothesis" of Simoons and McCracken, is presented. According to this hypothesis, adult lactose absorption, believed to be an autosomal dominant trait, attained a high frequency in some human populations due to the positive selection pressure induced by culturally determined milk use in those populations. Two-dimensional Kolmogorov backward equations with appropriate boundary conditions are derived for the ultimate fixation probability of milk users, of the gene for adult lactose absorption, and of both jointly, and for the average time until fixation of the gene. These boundary value problems are solved numerically by the Gauss-Seidel method. I define a theoretical measure of the correlation between gene and culture in terms of the three ultimate fixation probabilities. Monte Carlo simulations are conducted to check and extend the numerical results and also to obtain the first arrival time at gene frequency 0.70, which is approximately the highest observed frequency in any population. Two results that pertain to the culture historical hypothesis are obtained. First, the incomplete correlation observed between adult lactose absorption and milk use does not necessarily constitute evidence against the hypothesis. Second, for the postulated genetic change to have occurred within the 6000-year period since the advent of dairying, either the effective population size was of the order of 100, or, if it was of larger order, the selection coefficient probably had to exceed 5%.

Animals↗
PubMed1992

Insertional mutagenesis of hydrophilic domains in the lactose permease of Escherichia coli.

The lactose permease of Escherichia coli is a membrane transport protein postulated to contain a hydrophilic N terminus (hydrophilic domain 1), 12 hydrophobic transmembrane alpha-helices that traverse the membrane in zigzag fashion connected by hydrophilic domains, and a hydrophilic C terminus (hydrophilic domain 13). To test whether the hydrophilic domains are important for function, each domain was independently disrupted by insertion of two or six contiguous histidine residues, and the mutants were characterized with respect to initial rate of lactose transport and steady-state level of accumulation. Remarkably, histidine insertions into 10 out of 13 hydrophilic domains result in molecules that catalyze lactose accumulation effectively, although the initial rate of transport is compromised in certain cases. In contrast, insertions into hydrophilic domain 3, 9, or 10 cause a marked decrease in transport activity. As judged by immunoblots and [35S]methionine pulse-chase experiments, diminished activity is not due to decreased expression of the mutated permeases, defective insertion into the membrane, or increased rates of proteolysis after insertion. The results (i) suggest that most of the hydrophilic domains in the permease do not play an essential role in the transport mechanism and (ii) focus on the region of the permease containing putative helices IX and X as being particularly important for activity.

Amino Acid Sequence↗
PubMed1995

Cooperative binding of lactose and the phosphorylated phosphocarrier protein HPr(Ser-P) to the lactose/H+ symport permease of Lactobacillus brevis.

Lactobacillus brevis accumulates lactose and nonmetabolizable lactose analogues via sugar/H+ symport, but addition of glucose to the extracellular medium results in rapid efflux of the free sugar from the cells due to the uncoupling of sugar transport from proton transport. By using vesicles of L. brevis cells, we recently showed that these regulatory/effects could be attributed to the metabolite-activated ATP-dependent protein kinase-catalyzed phosphorylation of serine-46 in the phosphocarrier protein HPr [HPr(Ser-P)] of the phosphotransferase system and that a mutant form of HPr with the serine-46-->aspartate replacement ([S46D]HPr) is apparently locked in the seryl phosphorylated conformation. We here demonstrate that [S46D]HPr binds directly to inside-out membrane vesicles of L. brevis that contain the lactose permease. Sugar substrates of the permease markedly and specifically stimulate binding of [S46D]HPr to the membranes while certain transport inhibitors such as N-ethylmaleimide block binding. The pH dependency for binding follows that for transport. Wild-type HPr and the [S46A]HPr mutant protein did not appreciably compete with [S46D]HPr for binding to the permease. These results provide evidence for the direct interaction of HPr(Ser-P) with an allosteric site on the lactose/proton symporter of L. brevis for the purpose of regulating sugar accumulation in response to the metabolic needs of the cell.

Allosteric Regulation↗
PubMed2000

Close approximation of putative alpha -helices II, IV, VII, X, and XI in the translocation pathway of the lactose transport protein of Streptococcus thermophilus.

The lactose transport protein (LacS) of Streptococcus thermophilus belongs to a family of transporters in which putative alpha-helices II and IV have been implicated in cation binding and the coupled transport of the substrate and the cation. Here, the analysis of site-directed mutants shows that a positive and negative charge at positions 64 and 71 in helix II are essential for transport, but not for lactose binding. The conservation of charge/side-chain properties is less critical for Glu-67 and Ile-70 in helix II, and Asp-133 and Lys-139 in helix IV, but these residues are important for the coupled transport of lactose together with a proton. The analysis of second-site suppressor mutants indicates an ion pair exists between helices II and IV, and thus a close approximation of these helices can be made. The second-site suppressor analysis also suggests ion pairing between helix II and the intracellular loops 6-7 and 10-11. Because the C-terminal region of the transmembrane domain, especially helix XI and loop 10-11, is important for substrate binding in this family of proteins, we propose that sugar and proton binding and translocation are performed by the joint action of these regions in the protein. Indeed, substrate protection of maleimide labeling of single cysteine mutants confirms that alpha-helices II and IV are directly interacting or at least conformationally involved in sugar binding and/or translocation. On the basis of new and published data, we reason that the helices II, IV, VII, X, and XI and the intracellular loops 6-7 and 10-11 are in close proximity and form the binding sites and/or the translocation pathway in the transporters of the galactosides-pentosides-hexuronides family.

Amino Acid Sequence↗
PubMedDate not supplied

Persistent high intestinal lactase activity in Papua New Guinea. Lactose absorption curves in two populations.

Thirty adolescent males, aged 16-19 years, all of Huli, Mendi or Dunai descent, sampled at Tari in Southern Highlands of Papua New Guinea, and 29 children aged between 9 and 15 years, all speakers of Daga and sampled at Agaun in the Milne Bay Province, have been tested for persistent high intestinal lactase activity. Three persons at Tari and five at Agaun were found to be lactose absorbers. There is reasonably convincing evidence that all five absorbers at Agaun descend from a common ancestor five generations ago, but there is no such suggestion for those tested at Tari. Gene flow from Caucasoids who penetrated both areas is possible. The presence of lactose absorbers in peoples who are not traditional users of fresh milk suggests that the culture historical hypothesis may not give a completely adequate explanation for the establishment and conservation of the lactose polymorphism in man.

Adolescent↗
PubMed1990

The response to dietary treatment of patients with chronic post-infectious diarrhea and lactose intolerance.

The response to dietary treatment of patients with chronic post-infectious diarrhea and lactose intolerance was prospectively studied in 29 infants less than 1 year of age. All had gastroenteritis with diarrhea which persisted for more than 3 weeks. In the hospital, diarrhea continued and lactose intolerance was documented while being fed half-strength cow's milk formula. They were given dietary treatment with one of three formulas used for treatment of diarrhea in infancy. Improvement of diarrhea was more frequently achieved with Pregestimil when given as the initial therapy than with the other two formulas. With Pregestimil nine of 10 patients improved whereas only four of nine infants fed Portagen and one of 10 patients initially treated with soy formula improved. Pregestimil was also effective in three of five patients who initially failed to improve with Portagen and in four of eight patients tried with soy formula with or without carbohydrate. Additionally, in the patients who improved, recovery was more rapidly achieved with Pregestimil than with the other two formulas. Formula failures were due to intolerance to glucose polymers in three patients, possibly to protein in seven infants, and an intolerance to all nutrients in five patients. The improvement of the diarrhea was slower in patients who had evidence of colitis in rectal biopsies regardless of the dietary treatment given, but was not correlated with other variables, i.e., etiology of diarrhea, jejunal histology, or duration of diarrhea prior to treatment. However, as a group, the patients who failed to respond to Pregestimil were younger (less than 3 months of age), had more formula changes and associated infections, and were given more antibiotics; they also had more prolonged diarrhea before treatment and more severe jejunal mucosal lesions and jejunal bacterial overgrowth. The data suggests that Pregestimil seems to be the most effective formula for the treatment of infants with chronic post-infectious diarrhea and lactose intolerance.

Age Factors↗
PubMed1999

Modification of electrostatic charge on inhaled carrier lactose particles by addition of fine particles.

Triboelectrification affects particle adhesion and agglomeration and hence the formulation, manufacture, and use of dry powder inhaler (DPI) devices. Electrostatic charge measurement of two component mixes of spray-dried or crystalline lactose fine particles (< 10 microns) 0, 5, 10, 15, 20, and 30% w/w with spray-dried or crystalline lactose 63-90 microns, respectively, has been undertaken using a system incorporating pneumatic transport of the mixed powders to a stainless steel cyclone charging device. The magnitude of charge on the mixes was shown to decrease with increased fine particle content, and there was no significant difference in charge for each concentration between spray-dried and crystalline lactose. Both the variation of charge and powder adhesion to the cyclone surface increased with increase in fine particle content. The proportion of fine particles in carrier systems in DPIs may thus have an important role where triboelectrification is involved.

Adhesiveness↗
PubMed1979

Lactose synthetase activity in mouse mammary glands is controlled by thyroid hormones.

Epithelial cells in explants from the mammary glands of euthyroid mature virgin mice are proliferatively dormant. They must undergo DNA synthesis and traverse the cell cycle in vitro before they are able to differentiate fully in response to insulin, hydrocortisone, and prolactin, and synthesize enzymatically active alpha-lactalbumin (measured as lactose synthetase activity). In contrast, glands from hyperthyroid mature virgin mice do not require DNA synthesis in vitro to differentiate. Explants from the euthyroid virgin tissue overcome their dependence on DNA synthesis when 10(-9) M 3,5,3'-triiodo-L-thyronine is added directly to the cultures in addition to the other three hormones. Explants from involuted mammary glands from euthyroid primiparous mice do not require DNA synthesis in vitro to make the milk protein even though they, like explants from mature euthyroid virgin tissue, are proliferatively dormant and do not contain detectable lactose synthetase activity in vivo. Glands from primiparous animals made mildly hypothyroid by ingestion of 0.1% thiouracil in drinking water during 7 wk of involution remain morphologically indistinguishable from glands of their euthyroid counterparts. However, explants from the glands of these hypothyroid animals revert to a state of dependence on DNA synthesis to differentiate functionally. These observations suggest that the dependence on DNA synthesis and cell cycle traversal for hormonal induction of lactose synthetase activity in the mouse mammary gland is controlled by thyroid hormones.

Animals↗
PubMed1982

Quantitation of two endogenous lactose-inhibitable lectins in embryonic and adult chicken tissues.

Two lactose-binding lectins from chicken tissues, chicken-lactose-lectin-1 (CLL-1) and chicken-lactose-lectin-11 (CLL-11) were quantified with a radioimmunoassay in extracts of a number of developing and adult chicken tissues. Both lectins could be measured in the same extract without separation, because they showed not significant immunological cross-reactivity. Many embryonic and adult tissues, including brain, heart, intestine, kidney, liver, lung, muscle, pancreas, and spleen, contained one or both lectins, although their concentrations differed markedly. For example, embryonic muscle, the richest source of CLL-1 contained only traces of CLL-11 whereas embryonic kidney, a very rich source of CLL-11 contained substantial CLL-1. In both muscle and kidney, lectin levels in adulthood were much lower than in the embryonic state. In contrast, CLL-1 in liver and CLL-11 in intestine were 10-fold to 30-fold more concentrated in the adult than in the 15-d embryo. CLL-1 and CLL-11 from several tissues were purified by affinity chromatography and their identity in the various tissues was confirmed by polyacrylamide gel electrophoresis, isoelectric focusing, and peptide mapping. The results suggest that these lectins might have different functions in the many developing and adult tissues in which they are found.

Animals↗
PubMed2006

Lactose intolerance revealed by severe resistance to treatment with levothyroxine.

The most common cause of apparent ineffectiveness or resistance to treatment with oral levothyroxine (LT(4)) is the result of noncompliance, known as pseudomalabsorption. However, an abnormality in the bioavailability of LT(4) should also be considered in patients requiring large doses of LT(4) to achieve euthyroidism. The incidence of lactose intolerance in Caucasian adult patients is 7%-20%, but the association with resistance to treatment with oral LT(4) is unusual. We report a 55-year-old woman in whom treatment LT(4) for hypothyroidism was found related to a previously undiagnosed oligo-symptomatic lactose intolerance, an unusual association. Although rare, intolerance to lactose should be considered in the differential diagnosis of gastrointestinal diseases that can cause malabsorption of LT(4). The possibility of correcting this disorder with simple dietary measures justifies its consideration.

Drug Resistance↗
PubMed1975

Effects of dietary lactose and lactase preparation on the intestinal absorption of calcium and magnesium in normal infants.

Effects of dietary lactose and a lactase preparation on the intestinal absorption of calcium and magnesium were studied in 3 groups under 8 months of age; infants on a proprietary milk, infants on a lactose-free milk, and infants on a proprietary milk to which a lactase preparation was added. The intestinal absorption of both elements was reduced in infants on a lactose-free milk and enhanced in infants who were fed on a proprietary milk and given a lactase preparation.

Animals↗
PubMed1979

Lactose intolerance in the Lebanese population and in "Mediterranean lymphoma".

Lactose tolerance tests were performed on 75 healthy Lebanese volunteers, 12 patients with "Mediterranean lymphoma" and 15 American and West European Caucasians. Small intestinal biopsies were done on 10 intolerant and five tolerant subjects for histological evaluation and lactase assay. Lactose malabsorption was present in 78% of the Lebanese subjects, in all patients with Mediterranean lymphoma and in five of the 15 Caucasians. Two of the five intolerant Caucasians had giardiasis. There was no difference in the prevalence rate among the various Lebanese groups nor among males and females. Symptoms occurred in 91% of the 58 intolerant Lebanese subjects: diarrhea in 71%, abdominal distension in 67%, and cramps in 48%. The increased prevalence of lactose intolerance with Mediterranean lymphoma is probably secondary to the pathological changes in the intestinal mucosa and protein depletion.

Adolescent↗
PubMed1985

Lactose malabsorption in Australian Aboriginal children.

The purpose of this study was to determine the prevalence of lactose malabsorption in healthy full-blood Australian Aboriginal children. Sixty-three Aboriginal subjects and forty-six non-Aboriginal controls ranging in age from six to 14 years were tested using the breath hydrogen method. Seventy percent of the Aboriginal subjects were found to be lactose malabsorbers and 9% of the controls. The results provide strong evidence that the majority of full-blood Aboriginal children are lactose malabsorbers and that the characteristic is well-established by 6-7 years of age, in common with most other non-Western populations.

Adolescent↗
PubMed1989

Effect of lactose or its component sugars on jejunal calcium absorption in adult man.

The effect of lactose vs glucose plus galactose on jejunal calcium absorption was studied in 10 subjects using a triple-lumen perfusion technique. In each, 30 cm of jejunum was perfused with two test solutions. The comparisons made were lactose (Lac) vs mannitol (Man), Lac vs glucose and galactose (GG), and Man vs GG. Compared with Man, Lac, and GG caused a significant increase in net water and sodium absorption and luminal calcium concentration. In subjects receiving both Lac and GG, water and sodium absorption were greater with GG. The only statistically significant increase in net calcium absorption occurred with Man vs GG in which water absorption increased from 16 to 350 mL.h-1.30 cm-1. However, by use of data from all test solutions, water and sodium absorption were found to be significantly correlated with calcium absorption (p less than 0.05). These results suggest that lactose or its component sugars enhance jejunal calcium absorption in proportion to their effect on fluid absorption.

Body Water↗
PubMed1980

An institutional outbreak of Salmonellosis due to lactose-fermenting Salmonella newport.

An institutional outbreak of salmonellosis predominantly due to a lactose-fermenting Salmonella newport is described. Control of the outbreak was hampered by delay in the initial recognition of the aberrant strain. On primary culture, salmonellae were detected on bismuth sulfite agar only; colonies that formed on MacConkey agar and Salmonella-Shigella agar could not be differentiated from lactose-fermenting nonpathogenic organisms. The reactions in triple sugar iron were atypical for Salmonella. The lactose-fermenting property was plasmid-mediated and was readily transferable. Phage typing suggested chicken as a possible source of the strain. The need for awareness of the occurrence of such strains of Salmonella that may not be recognized by cultural procedures in common use, the necessity of the routine use of bismuth sulfite agar in procedures for isolation of salmonellae, and the use of lysine iron agar in conjunction with the triple sugar iron agar are emphasized.

Aged↗
PubMed2002

Association of dairy products, lactose, and calcium with the risk of ovarian cancer.

Epidemiologic findings have been inconsistent regarding the association of dietary fat, dairy products, and lactose with risk of ovarian cancer. The authors conducted a case-control study in Hawaii and Los Angeles, California, to examine several dietary hypotheses regarding the etiology of ovarian cancer in a population with a broad range of dietary intakes. A total of 558 patients with ovarian cancer diagnosed in 1993-1999 and 607 controls were interviewed regarding their diet. Consumption of all dairy products, all types of milk, and low-fat milk, but not consumption of whole milk, was significantly inversely related to the odds of ovarian cancer. Similar inverse gradients in the odds ratios were obtained for intakes of lactose and calcium, although these nutrients were highly correlated (r = 0.77). The odds ratio for ovarian cancer was 0.46 (95% confidence interval: 0.27, 0.76) among women in the highest quartile of dietary calcium intake versus the lowest (p for trend = 0.0006). The significant dietary association was limited to dairy sources of calcium (p for trend = 0.003), although a nonsignificant inverse gradient in risk was also found in relation to calcium supplement intake. These results suggest that intake of low-fat milk, calcium, or lactose may reduce the risk of ovarian cancer.

Adult↗
PubMed1989

Selection and neutrality in lactose operons of Escherichia coli.

The kinetics of the permeases and beta-galactosidases of six lactose operons which had been transduced into a common genetic background from natural isolates of Escherichia coli were investigated. The fitnesses conferred by the operons were determined using chemostat competition experiments in which lactose was the sole growth-limiting factor. The cell wall is demonstrated to impose a resistance to the diffusion of galactosides at low substrate concentrations. A steady state model of the flux of lactose through the metabolic pathway (diffusion, uptake and hydrolysis) is shown to be proportional to fitness. This metabolic model is used to explain why an approximately twofold range in activity among the permease alleles confers a 13% range in fitness, whereas a similar range in activity among alleles of the beta-galactosidase confers a 0.5% range in fitness. This metabolic model implies that selection need not be maximized when a resource is scarce.

Binding, Competitive↗