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Defects of Glycosyltransferase Activities in Human Fibroblasts of Pk and P Blood Group Phenotypes

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Defects of Glycosyltransferase Activities in Human Fibroblasts of Pk and P Blood Group Phenotypes Proc. Nati. Acad. Sci. USA Vol. 74, No. 12, pp. 5407-5410, December 1977 Biochemistry Defects of glycosyltransferase activities in human fibroblasts of pk and p blood group phenotypes (trihexosyl ceramide/globoside/net synthesis of P antigens/glycolipid contents/glycosidases) SHIGEKO KIJIMOTO-OCHIAI*, MASAHARU NAIKIt, AND AKIRA MAKITA* * Biochemical Laboratory, Cancer Institute, School of Medicine, and t Department of Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060, Japan Communicated by Herman M. Kalckar, September 21, 1977 ABSTRACT We demonstrate that human fibroblasts of Present investigations were undertaken to determine the the rare pk phenotype lack globoside, which was identified as cause of genetic defects of the antigens in pk and p fibroblasts the blood group P antigen, and that p cells possess neither glo- by chemical analysis of glycolipids, incorporation of radioactive boside nor trihexosyl ceramide, which was identified as pk an- tigen. Our investigations indicate also that these glyco- galactose into glycolipids, and assays of specific glycosyltrans- sphingolipid patterns are most likely caused by inherited pref- ferase and glycohydrolase activities. erential biosynthetic pathways in the abnormal phenotypes rather than by excess catabolism of the antigens. Evidence is MATERIALS AND METHODS presented that the fibroblasts of pk phenotype lack fl-N-acetyl- galactosaminyltransferase (globoside synthetase; UDP-N- Cell Lines and Culture. Fibroblasts from three donors whose acetylgalactosamine:trihexosylceramide fi-N-acetylgalactosa- phenotypes of P blood group were P2, Pi, and p were generously minyltransferase; EC 2.4.1.79) activity, and those of p are defi- donated by M. Fellous, Hopital Saint-Louis, Paris. Their anti- cient in a-galactosyltransferase (trihexosylceramide synthetase; genic and chemical properties are summarized in Table 1. The UDP galactose:lactosylceramide a-galactosyltransferase) and fibroblasts, obtained from skin biopsy were cultured in possibly also in globoside synthetase. The diminished globoside (5),, synthetase activity in p cells, however, is not caused by the de- Eagle's minimum essential medium containing 20% fetal calf fect in the gene coding for this enzyme. It appears, rather, to be serum. The fibroblasts were labeled with [14Clgalactose as caused by a failure in gene expression because one-third of pk follows: The cells at the 17th or 18th passage were grown to X p hybrids became able to express P antigenicity with a time confluence on glass bottles of 4 X 10 cm, and the medium was lag of 3X4 days after cell fusion [Fellous, M., Gerbal, A., Nobillot, changed to 10 ml of fresh medium containing 5 ACi of [U- G. & Weils, J. (1977) Vox Sang. 32, 262-2681. 14C]galactose (Radiochemical Center, Amersham, 95 Ci/mol). After 10 days, the cells were washed five times with Dulbecco's The human blood group P system was demonstrated originally phosphate-buffered saline (pH 7.0) and harvested by use of on erythrocytes (1-4) and subsequently on fibroblasts and trypsin. For analysis of glycolipid contents, the cells'were har- lymphocytes (5). This blood group system, which consists of vested after trypsin treatment and pooled (10th to; 20th pas- three antigens and five phenotypes, has been immunologically sages). For enzymatic assays, the cells were scraped with a and genetically established (reviewed in ref. 6). Recently the rubber policeman and suspended in 0.32 M sucrose:containing chemical structures of these antigens have been identified as 14 mM 2-mercaptoethanol and 1 mM EDTA, disrupted by glycosphingolipids (7, 8) (Table 1). sonication for 20 sec (Kontes sonicator), and used for the assay Confirmative evidence has come from studies on erythro- without fractionation. cytes of the rare abnormal phenotypes (9): the pk erythrocytes Glycolipid Substrates. LacCer from equine spleen, Hex3Cer lack globoside and possess an increased amount of trihexosyl from equine kidney, and globoside from pig spleen were pre- ceramide (Hex3Cer), and p erythrocytes, which are virtually pared as described (13). Radioactive Hex3Cer (5.4 X 105 deficient in both globoside and Hex3Cer, accumulate lactosyl cpm/,gmol), supplied by S. Handa, University of Tokyo, and ceramide (LacCer), thus suggesting a genetic block in formation globoside (5.2 X 105 cpm/Amol) were prepared by labeling of globoside in pk individuals and of both Hex3Cer and glob- with tritium at their nonreducing terminal sugars by the oside in p persons. method of Suzuki and Suzuki (14), and used as substrates in the The biosynthesis of the carbohydrate moiety of glycolipids hydrolase studies. proceeds by the sequential addition of monosaccharide units Isolation and Analysis of Glycolipids. The fibroblasts were from their sugar nucleotide donors to growing acceptors by freeze-dried and extracted with a suitable volume of chloro- specific glycosyltransferases (10). The synthesis of Hex3Cer (11) form/methanol (2:1, vol/vol), and the solvent was removed by and globoside (12) occurs as follows: evaporation. The total lipids were acetylated with 1 ml of pyridine/acetic anhydride (3:2, vol/vol) overnight at 600. The UDP Gal UDP acetylated glycolipids were fractionated on a column of Florisil LacCer Hex3Cer (pk antigen) (15). The acetylated glycolipids were deacetylated by incu- Ilex3Cer synthetase bation with 0.5 ml of 0.1 M methanolic NaOH for 3 hr at room UDP-Ga1NAc UDP temperature followed by neutralization with Dowex 50 (H+ form). Analytical thin-layer chromatography was carried out Hex 3Cer Globoside (P antigen) Globoside synthetase Abbreviations: GicCer, glucosyl ceramide; LacCer, lactosyl ceramide; Hex3Cer, trihexosyl ceramide; ganglioside GM3 (hematoside), sialo- The costs of publication of this article were defrayed in part by the syl(a2 o 3)Gal(l1 - 4)Glc(#l - 1)ceramide; Hex3Cer synthetase, payment of page charges. This article must therefore be hereby marked UDPgalactose:lactosylceramide a-galactosyltransferase; globoside "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate synthetase, UDP-N-acetylgalactosamine:trihexosylceramide f3-N- this fact. acetylgalactosaminyltransferase (EC 2.4.1.79). 5407 Downloaded by guest on September 28, 2021 5408 Biochemistry: Kijimoto-Ochiai et al. Proc. Natl. Acad. Sci. USA 74 (1977) Table 1. Expression of blood group P antigens on erythrocytes, lymphocytes, and fibroblasts Frequency, Antigens on Antibodies Phenotype % cells in serum GLcCer - Pi 75 p1,p,pk* None P2 25 p, pk* Anti-P1 p Very rare None Anti-Pi, -P, pk Pk Very rare Pi, pk Anti-P Ik Very rare Anti-P Pk antigen (Hex3Cer), Gal(al - 4)Gal(ll - 4)Glc(f31 - 1)cer- amide; P antigen (globoside), GalNAc(B1 - 3)Gal(al - 4)Gal(fll 4)Glc(f1 - 1)ceramide; P1 antigen, Gal(al -* 4)Gal(#1 - 4)- GlcNAc(01 - 3)Gal(f1 - 4)Glc(,B1 - 1)ceramide. * k antigenic activity is detected only in cultured lymphocytes and fibroblasts. HexCerC on coated Silica-gel H-60 plates (Merck) which were developed with chloroform/methanol/water (60:35:8, by volume) and :M<030 _ _ visualized with anthrone-sulfuric acid reagent. Gangliosides F:,Gw*. were detected with resorcinol-HCI reagent. Radioactivity was detected by a radio-thin-layer scanner (Aloka JTC-202B) and by autoradiography, i.e.,-exposing the plates on x-ray film (Fuji KX Safety Film) for 18 days. SpSG 001. Glycosyltransferase Assays. The activities of Hex3Cer synthetase (UDP galactose:lactosylceramide a-galactosyl- transferase) (16) and globoside synthetase (UDP-N-acetylga- lactosamine:trihexosylceramide fl-N-acetylgalactosaminyl- transferase; EC 2.4.1.7b) (12) were assayed as described, with some modifications. Complete incubation mixture contained the following components in a final volume of 100 gl. For 1 {2 3 4 Hex3Cer synthetase assay: 50 Mig of LacCer, 300. jAg of Triton X-100, 0.1 M Hepes (N-2-hydroxethylpiperazine-N'-2-etha- FIG. 1. Thin-layer chromatogram of glycolipids in fibroblasts nesulfonic buffer 6.55), 10 mM MnCl2, 70 of whole from P2 and Pk donors. Total glycolipids (approximately 50 1Ag each acid) (pH ,l as hexose) from P2 and pk cells were applied to lanes 3 and 4, respec- cell homogenates (112-395 Ag of protein), and 250 nCi of tively. Lanes 1 and 2, standard glycolipids. GlcCer, glucosyl ceramide; UDP[l-3HJgalactose (New England Nuclear; 25 Ci/mol for GLOBO, globoside; PG, paragloboside, Gal(j1- 4)GlcNAc(#1 - Exps. 1 and 2 and 5 Ci/mol for Exp. 3 in Table 2). For globoside 3)Gal(O1 - 4)Glc(01 - 1)ceramide; SPG, sialosyl paragloboside, synthetase assay: 50 jig of Hex3Cer, 300. Mg of sodium tauro- N-acetylneuraminyl (A2 - 3)Gal(O1 - 4)GlcNAc(f1 - 3)Gal(O1 cholate, 50 nCi of UDP-N-acetyl[l-'4C]galactosamine (New 4)Glc(j31 - 1)ceramide. England Nuclear, 51.2 Ci/mol), and- other components (buffer, MnCl2, and cell homogenates) as described for the Hex3Cer and globoside 3-N-acetylgalactosaminidase were determined synthetase assay. The mixture was incubated for 2 hr at 370, and with [3H]Hex3Cer and [3H]globoside as the substrates under the reaction was terminated by adding 2.5 ,mol of EDTA and the same conditions as the glycosyltransferase assays but without 5 ,mol of KCI in 20 Ml of water, followed by 0.6 ml of chloro- the labeled nucleotide sugars, respectively. After incubation form/methanol (2:1, vol/vol). After vigorous mixing and cen- for 2 hr at 370, the radioactive sugars released were determined trifugation, the lower layer was chromatographed on a thin- as described (17, 18). layer plate of Silica gel H (merck) in chloroform/methanol/ The a-galactosidase (EC 3.2.1.22) and fl-N-acetylgalactos- water (65:35:8, lower phase) and (58:35:8, by volume) for aminidase (EC 3.2.1.53) activities toward 4-methylumbellif- Hex3Cer and globoside synthetase assays, respectively. The eryl-a-galactoside (Seikagaku Kogyo) and 4-methylumbellif- radioactivity of the silica gel corresponding to each glycolipid eryl-,B-N-acetylgalactosaminide (Koch-Light Labs.), respec- was measured in toluene cocktail with a liquid scintillation tively, were determined as described (19, 20).
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