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Biomedical subjects

K Sandhoff

Publications and source records attributed to K Sandhoff.

At least 235 records · Page 13Linked to original sources
PubMed1980

[Lipid-protein interactions: mechanisms of enzymatic glycolipid catabolism and their genetic restrictive escapes].

Investigations of the genetic basis of ganglioside catabolism have led to the characterisation of two types of lipid-enzyme interaction: a) Breakdown of membrane-bound glycolipids as far as catalysed by membrane-bound enzymes is regulated by the membrane itself. b) The degradation of micelle-forming glycolipids by water-soluble lysosomal enzymes is facilitated by cofactors known as activator proteins. A genetic defect in an activator protein can be just as fatal as the lack of the enzyme itself.

Animals↗
PubMed1980

Wolman's disease: clinical, biochemical and ultrastructural studies in an unusual case without striking adrenal calcification.

A case of Wolman's disease is described in a German infant who died at the age of 4 months. Hepatosplenomegaly, abdominal distention, gastrointestinal symptoms, dyserythropoietic changes in the bone marrow, but not adrenal calcification on X-ray were present. Stored lipid material could be demonstrated in liver, spleen, intestine, adrenals, thymus, kidneys, blood cells, but not in the central nervous system. Cholesterylesters and triglycerides were markedly increased in liver and spleen. Lysosomal acid lipase was found to be decreased in leucocytes and liver to less than 10% of normal, when measured with synthetic and natural substrates.

Adrenal Glands↗
PubMed1979

Biochemistry and genetics of gangliosidoses.

The gangliosidoses comprise an-ever increasing number of biochemically and phenotypically variant diseases. In most of them an autosomal recessive inherited deficiency of a lysosomal hydrolase results in the fatal accumulation of glucolipids (predominantly in the nervous tissue) and of oligosaccharides. The structure, substrate specificity, immunological properties of and genetic studies on the relevant glycosidases, ganglioside GM1 beta-galactosidase and beta-hexosaminidase isoenzymes, are reviewed in this paper. Contrary to general expectation, only a poor correlation is observed between the severity of the disease and residual activity of the defective enzyme when measured with synthetic or natural substrates in the presence of detergents. For the understanding of variant diseases and for their pre- and postnatal diagnosis, the necessity of studying the substrate specificity of normal and mutated enzymes under conditions similar to the in vivo situation, e.g., with natural substrates in the presence of appropriate activator proteins, is stressed. The possibility that detergents may have adverse affects on the substrate specificity of the enzymes is discussed for the beta-hexosaminidases. The significance of activator proteins for the proper interaction of lipid substrates and water-soluble hydrolases is illustrated by the fatal glycolipid storage resulting from an activator protein deficiency in the AB variant of GM2-gangliosidosis. Recent somatic complementation studies have revealed the existence of a presumably post-translational modification factor necessary for the expression of ganglioside GM1 beta-galactosidase activity. This factor is deficient in a group of variants of GM1-glangliosidosis. Among the possible reasons for the variability of enzyme activity levels in heterozygotes and patients, allelic mutations, formation of hybrid enzymes, and the existence of patients as compound heterozygotes are discussed. All these may result in the production of mutant enzymes with an altered specificity for a variety of natural substrates.

Adolescent↗
PubMed1979

Purification and characterization of an activator protein for the degradation of glycolipids GM2 and GA2 by hexosaminidase A.

The activator protein for the degradation of glycolipids GM2 and GA2 by hexosaminidase A was purified some 2 500-fold from normal human kidney. It has a molecular weight of approximately 25 000 is heat-stable up to 60 degrees C, possesses an isoelectric point of pH 4.8 and is digestible by proteases. Enzymic degradation of the lipid substrates in the presence of this activator proceeds optimally at pH 4.2. The mode of action of the activator was also studied: the protein most probably complexes lipid molecules and presents them to the enzyme which otherwise cannot attack the aggregates formed by the lipids in aqueous solution. The hydrolysis of water-soluble synthetic substrates is not affected by the activator protein. The activator is highly specific for hexosaminidase A: hydrolysis of glycolipids GA2 and GM2 by the hexosaminidase B isoenzyme is almost not enhanced by this protein. The isoenzymes' lipid substrate specificity measured in the presence of the activator is entirely different from that obtained with detergents and can satisfactorily account for the lipid storage pattern observed in patients with variant forms of infantile GM2- gangliosidosis.

Binding Sites↗
PubMed1978

Prenatal diagnosis of Tay-Sachs disease in cell-free amniotic fluid.

The diagnosis of 6 known Tay-Sachs cases was confirmed by isoelectric focusing of the cell-free amniotic fluid. The presence of an additional--hitherto unknown--heatstable, acid hexosaminidase X in normal and pathological amniotic fluids must be taken into account especially when the heat denaturation method of detecting Tay-Sachs disease is applied. Hexosaminidase X shows some properties similar to those of hexosaminidase B.

Amniotic Fluid↗
PubMed1978

Studies on bovine brain membrane-bound neuraminidase (sialidase).

1) Lipophilic ganglioside GD1a (IV3NeuAc, II3NeuAc-GgOse4-Cer) is taken up by the cell membranes and hydrolyzed faster by membrane-bound neuraminidase than are water soluble substrates of the enzyme. 2) The enzymic breakdown of ganglioside GD1a is enhanced by general anesthetics whereas the degradation of the hydrophilic substrate sialyllactitol is reduced by these same agents. 3) General anesthetics lower the microviscosity of membranes as indicated by studies of fluorescence depolarisation with the indicator 1,6-diphenylhexatrien. Decreased microviscosity can result in a higher lateral diffusion of ganglioside GD1a, increasing its interaction with membrane-bound neuraminidase. 4) In vitro studies indicate that the activity of membrane-bound neuraminidase on gangliosides of brain membranes is regulated by the viscosity of these membranes and their monosialoganglioside content.

Animals↗
PubMed1978

Membrane-bound neuraminidase from calf brain: regulation of oligosialoganglioside degradation by membrane fluidity and membrane components.

The degradation of lipophilic ganglioside GD1a and hydrophilic sialyllactitol by membrane-bound neuraminidase (EC 3.2.1.18) from calf brain has been studied at substrate concentrations of 0.1 mM. Ganglioside GD1a taken up by cell membranes is hydrolyzed faster membrane-bound neuraminidase than are water-soluble substrates of the enzyme, sialyllactitol and des-GD1a. Availability and enzymic breakdown of the disialoganglioside are enhanced by general anesthetics such as N2O or halothane whereas the degradation of the hydrophilic substrate silayllactitol is not affected or even is decreased by these agents. General anesthetics lower the microviscosity of membranes as indicated by studies of fluorescence depolarization with the indicator 1,6-diphenylhexatriene. Increased fluidity can result in higher lateral diffusion of ganglioside GD1a, thus increasing its chances of presentation to, and interaction with, membrane-bound neuraminidase. Lipophilic derivatives of the disialoganglioside, gangliosides GM1 and GM2 and gangliotriaosylceramide GA2, are strong inhibitors of the ganglioside degradation whereas water-soluble derivatives des-GM1, des-GM2, N-acetylneuraminic acid, and sialyllactose are not. A model is presented that suggests that the activity of membrane-bound neuraminidase on gangliosides of brain membranes is regulated by the viscosity of these membranes and their monosialoganglioside content.

Anesthesia, General↗
PubMed1978

AB variant of infantile GM2 gangliosidosis: deficiency of a factor necessary for stimulation of hexosaminidase A-catalyzed degradation of ganglioside GM2 and glycolipid GA2.

Human kidney extracts heated to 60 degrees and devoid of hexosaminidase activity (2-acetamido-2-deoxy-beta-D-glucoside acetamidodeoxyglucohydrolase EC 3.2.1.30) stimulate more than 20-fold the hexosaminidase A-catalyzed degradation of ganglioside GM2 and of glycolipid GA2, the neuronal storage compounds of GM2 gangliosidosis. The stimulating factor of this extract, which is labile at temperatures above 60 degrees, is also present in kidney extracts from patients with infantile GM2 gangliosidosis having a deficiency of hexosaminidase A (Tay-Sachs disease, variant B) and a deficiency of hexosaminidases A and B (variant 0). Evidence is presented that this factor is defective in the AB-variant of infantile GM2 gangliosidosis which is characterized by an accumulation of glycolipids GM2 and GA2 despite the fact that the degrading enzymes, hexosaminidases A and B, retain normal activity levels. Thus, variant AB is an example of a fatal lipid storage disease that is caused not by a defect of a degrading enzyme but rather by a defective factor necessary for the interaction of lipid substrates and the water-soluble hydrolase.

Enzyme Activation↗
PubMed1978

Purification, biochemical and immunological characterisation of hexosaminidase A from variant AB of infantile GM2 gangliosidosis.

Variant AB of infantile GM2 gangliosidosis is a fatal disease leading invariably to death within the first few years of life, due to the excessive storage of the glycolipids GM2 and GA2 which occurs in the nervous tissue of the patient. Unlike other variants of this hereditary disease, where a deficiency of hexosaminidase A, the ganglioside-GM2-degrading enzyme, could be demonstrated, the variant AB is characterized by a normal or even elevated level of this enzyme. To examine the possibility of a mutant hexosaminidase A, well capable of hydrolyzing the fluorogenic synthetic substrates but unable to attack the ganglioside, the enzyme was isolated from a patients tissue and characterized biochemically and immunologically in comparison with an enzyme preparation from normal control tissue. No differences between hexosaminidase A from normal and variant AB tissue could be detected indicating that the defect involved in this disease is not at the genetic level of production of either alpha or beta chains of hexosaminidase A.

Child, Preschool↗
PubMed1977

Isoelectric focusing pattern of acid hydrolases in cultured fibroblasts, leucocytes and cell-free amniotic fluid.

The activities of 9 acid hydrolases were determined in cell-free amniotic fluid, leucocytes and cultured fibroblasts using fluorogenic substrates. The specific activities of beta-glucosidase, alpha-fucosidase, beta-hexosaminidase, and arylsulphatase A and B were found to be in the same range in cell-free amniotic fluid and in leucocyties. The isoenzyme pattern of these 5 hydrolases as well as that of acid phosphatase and alpha-mannosidase showed some similarities in all three specimens studied; the pattern of alpha- and beta-galactosidase obtained by isoelectric focusing was different in the 2 types of cells studied and in the cell-free amniotic fluid.

Acid Phosphatase↗