Molecular abnormality of phosphoglycerate kinase-uppsala
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1 Proc. Natl. Acad. Sci. USA Vol. 77, No. 9, pp , September 1980 Medical Sciences Molecular abnormality of phosphoglycerate kinase-uppsala associated with chronic nonspherocytic hemolytic anemia (amino acid substiution/genetic disease) HISAICHI FUJII AND AKIRA YOSHIDA Department of Biochemical Genetics, City of Hope Research Institution, Duarte, California Communicated by Ernest Beutler, June 3,1980 ABSTRACT Inherited deficiency of phosphoglycerate kinase (PGK,- ATP3-phosphoglycerate 1-phosphotransferase, EC ) is associated with chronic nonspherocytic hemolytic anemia and mental disorders in man. One such variant, PGK- Uppsala, was purified to homogeneity. PGK-Uppsala had a lower-than-normal specific activity (30% of normal in the backward reaction and about 20% o normal in the forward reaction) and higher-han-normal Michaelis constants for ATP, ADP, 3-phosphoglycerate and 1,3-diphosphocerate. Peptide mapping analysis revealed that the structural abnormality of PGK-Uppsala is a single amino acid substitution from arginine to proline at the 206th position. Based on the known complete amino acid sequence of the normal human PGK and the threedimensional model deduced from horse PGK, correlations between the structural and functional abnormalities of PGK- Uppsala are discussed. Structural abnormalities of PGK-II, which is an electrophoretic variant not associated with enzyme deficiency, and PGK-Munchen, which is associated with enzyme deficiency and heat instability but not associated with hemolytic anemia, are also discussed. Except for hemoglobin abnormalities, precise molecular detail of abnormal enzymes and proteins related to genetic disorders have not been elucidated. Recent determination of the complete amino acid sequence of normal human phosphoglycerate kinase (PGK; ATP:3-phosphoglycerate 1-phosphotransferase, EC ) in this laboratory (1, 2) and the x-ray crystallographic study of horse PGK (3) have opened the way towards elucidating the molecular abnormalities of PGK variants. PGK is a key enzyme for ATP generation in the glycolytic pathway. Inherited deficiency of PGK is associated with chronic nonspherocytic hemolytic anemia and often with mental disorders in man. At the present time, 11 unrelated families with PGK deficiency have been reported (4). Besides these deficient variants, several other electrophoretic variants, which are not associated with enzyme deficiency, also have been reported (4). The mode of inheritance of an electrophoretic variant (PGK-I) indicated that the structural gene for PGK is located on an X chromosome (5). This paper reports the enzymatic and molecular abnormality of PGK-Uppsala, which is associated with chronic nonspherocytic anemia. Clinical and hematologic observations of the subject have been briefly reported (6, 7). MATERIALS AND METHODS Blood Sample. Glycerated erythrocytes from a PGK-Uppsala subject were stored in liquid nitrogen and used for the study. Assay of Enzyme Activity. The forward (1,3-diphosphoglycerate + ADP 3-phosphoglycerate + ATP) and backward The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C solely to indicate this fact A a b B a h..71r pg. -*1 t, to FIG. 1. Polyacrylamide gel electrophoresis of the normal and variant PGK. A piece of metal wire was inserted to mark the front dye position. Electrophoresis in 7.5% (wt/vol) gel with Tris/glycine, ph 8.3, in the absence of sodium dodecyl sulfate (A) and in 10% (wt/vol) gel with Tris/glycine, ph 8.3, in the presence of sodium dodecyl sulfate (B). Lanes: a, normal PGK; b, PGK-Uppsala. (3-phosphoglycerate + ATP -- 1,3-diphosphoglycerate + ADP) reactions of the enzyme were measured as described (8, 9). Peptide Mapping. S-Carboxymethylation and tryptic digestion of the normal and variant enzymes were carried out as described (10). Peptide mapping of the tryptic digests on microscale thin-layer cellulose was carried out as described (10). Acrylamide Gel Electrophoresis. Electrophoresis was performed in the absence and presence of sodium dodecyl sulfate as described (11, 12). Protein was assayed by Lowry's method with bovine serum albumin as the standard (13). The source of chemicals has been described (10; 14). Abbreviation: PGK, phosphoglycerate kinase (ATP: 3-phosphoglycerate I-phosphotransferase, EC ).
2 5462 Medical Sciences: Fujii and Yoshida Proc. Nati. Acad. Sci. USA 77 (1989) Table 1. Purification of phosphoglycerate kinase from normal and variant erythrocytes Normal erythrocytes PGK-Uppsala erythrocytes Total Total Total Specific Total Total Total Specific vol, protein, activity, activity, vol, protein, activity, activity, Step ml mg unit unit/mg ml mg unit unit/mg Hemolysate 1, ,500 16, , Affinity chromatography , Sephadex gel filtration , CM-Sephadex chromatography Enzyme activity (unit) is expressed as micromoles of 1,3-diphosphoglycerate produced per min in the backward reaction under the assay conditions (9). RESULTS Purification of the Normal and Variant Enzymes. The enzyme was purified by affinity chromatography with ATPribosyl-adipoyldihydrazo-Sepharose 4B and gel filtration with Sephadex G-75 as described (15). Further purification of PGK-Uppsala by carboxymethyl-sephadex chromatography was required to obtain a homogeneous preparation (14). The results of the purification are summarized in Table 1. The purified preparation showed a single protein band in acrylamide gel electrophoresis in the absence and presence of sodium dodecyl sulfate (Fig. 1 A and B). PGK-Uppsala moved faster toward the anode than the normal enzyme. Kinetic Properties. The specific activity of PGK-Uppsala was about 30% of the activity of the normal enzyme (Table 1). Because the recovery of enzyme activity after the purification was almost identical in the normal and variant enzymes, a more severe inactivation of PGK-Uppsala during the purification can be ruled out. It can be concluded that PGK-Uppsala has an intrinsically lower specific enzyme activity than the normal enzyme has-i.e., 30% of normal in the backward reaction and about 20% of normal in the forward reaction (Table 2). Michaelis constants of PGK-Uppsala were higher than that of the normal enzyme (Table 2), indicating reduced affinity of PGK-Uppsala with ATP, ADP, 3-phosphoglycerate and 1,3- diphosphoglycerate. However, the ph-optimum of the variant enzyme was similar to that of the normal enzyme, both being at ph The rate of heat inactivation of PGK-Uppsala was approximately 3 times higher than that of the normal enzyme at 45 C and at ph 7.5. Amino Acid Substitution. The peptide maps of the tryptic digests obtained from the normal and the variant enzymes are shown in Fig. 2. Comparison of their peptide maps showed that one peptide (marked I) of the normal enzyme was replaced by a peptide (marked II) in the variant enzyme. Other spots appearing on the peptide map of the variant enzyme corresponded to the spots of the normal enzyme. The amino acids found in peptide I, peptide II, and a closely located peptide III, after acid hydrolysis, are shown in Table 3. The results indicate that peptide III was common in both enzymes, and that arginine in peptide I was replaced by proline in peptide II. From its amino acid composition and the known amino acid sequence of normal PGK (Fig. 3) (1, 2), peptide I should be H2N-Ala-Leu-Glu-Ser-Pro-Glu-Arg-Pro-Phe-Leu-Ala-Ile- Leu-Gly-Gly-Ala-Lys-COOH (positions ). In fact, it has been demonstrated that this is the tryptic peptide (T-29) located at the corresponding spot on two-dimensional paper chromatography-electrophoresis with the same solvent system as that of the present system (1). It can be concluded that arginine at the 206th position of the normal enzyme was replaced by proline in PGK-Uppsala. From its amino acid composition and location on the peptide map, peptide III should be tryptic peptide T-37, H2N-Ile- Thr-Leu-Pro-Val-Asp-Phe-Val-Thr-Ala-Asp-Lys-Phe-Asp- Glu-Asn-Ala-Lys-COOH (positions ), which was characterized in a previous paper (1). DISCUSSION The functional abnormalities of many human hemoglobin variants and the clinical symptoms they cause can now be understood on the basis of well-defined structural abnormalities. However, molecular details of other abnormal enzymes and proteins associated with genetic disorders have not been elucidated; full clarification requires: (i) determination of the complete amino acid sequence of the normal molecule, (if) construction of a three-dimensional structure based on x-ray crystallography, and (iii) determination of the amino acid substitution (or deletion, or elongation) of the mutant enzyme. The complete amino acid sequence of normal human PGK was recently determined (1, 2). Moreover, a three-dimensional model of horse PGK was proposed based on the x-ray crystallographic study (3). The amino acid sequences of horse PGK and human PGK are similar, and there seem to be only 14 differences among a total of 417 amino acid residues between the two proteins (2, 3). The real structural differences between the Table 2. Enzymatic properties of normal PGK and PGK-Uppsala Kmin um Vm, units/mg 1,3-Disphospho- 3-Phospho- PGK Forward Backward ADP glycerate ATP glycerate Normal Uppsala The forward reaction was assayed in 50 mm phosphate buffer, ph 6.9, containing 8 mm MgCl2, 0.4 mm NAD, 0.4 mm ADP, 1.2 mm D,L-glyceraldehyde 3-phosphate and 0.7 units of glyceraldehyde 3- phosphate dehydrogenase at 25 C. In measurements for the Km of 1,3-diphosphoglycerate, the concentration of D,L-glyceraldehyde 3-phosphate ranged from 1.25 to 40,uM, and for the Km of ADP the concentration of ADP ranged from 0.01 to 1 mm. The backward reaction was assayed in 80 mm Tris-HCl, ph 7.5, containing 8 mm MgCl2, 10 mm 3-phosphoglycerate, 5 mm ATP, 0.2 mm NADH and 0.7 units of glyceraldehyde 3-phosphate dehydrogenase at 25 C. In measurements for the K. of 3-phosphoglycerate, the concentration ranged from to 10 mm, and for the Km of ATP the concentration ranged from 0.03 to 5 mm. Km was determined from a Lineweaver-Burk plot.
3 ~~~~~~~~~~~~~~~~~~~~~~ Medical Sciences:-, Fuiii and Yoshida Proc. Natl. Acad. Sci. USA 77 (1980) 5463 A B bc 42) x x ElIectroph(oresis FIG. 2. Mficroscale peptide maps of tryptic digests of reduced, S-carboxymethylated phosphoglycerate kinase on two-dimensional thin-layer cellulose. (A) Normal enzyme. (B) PGK-Uppsala. First dimension: chromatography in n-butanol/acetic acid/water (4:1:5) for 12 hr. Second dimension: electrophoresis in pyridine/acetic acid/water (1:10:289, ph 3.6) at 900 V for 40 min. two proteins could be even smaller (2). Therefore, the three- Thus far, specific amino acid substitutions have been deterdimnsinalstructure of human PGK should be almost identical mined in two PGK variants-i.e., PGK-11 and PGK-Mtinchen to that of the horse enzyme. (16, 17). PGK-II is an electrophoretic variant found in New N-Acety1-ser-Leu-ser-Asn-ILys-Iau-7th-iLe-Asp-I~ys-ILeu-Asp-va1-Lys-Gly-Lys-Arg-va1-va1-4e~t Arg-val-Asp-Phe-Asnk-va1-Pro-Met--Lys-Asn-Asn-Gln-Ile-Thr-Asn-Asn-Gln-Arg-ILys-Ile Is-'Ala-Ala-Val-Pro-Ser~-Ile-Lys-Phe-Cys-LIApApGy- -y-e-a-val-ieu Met-Ser-His-Lai-Gly-Arg-Pro-sp-Gly-Val-Pro-Met-Pro-As-Lys-4yr-Ser-L~eu-Glu-Pro Gly-ProGMu-Val- -y-~-sa~-s-r-~-~ -Gly-Ser-Val-Ile-Leu-Ieau-Glu Agn-LI~-Arg--Ph-His-Val-Glu-GluGlu-Gly-Lys-Gly~-ILs-Asp-Ala-Ser-Gly-Asn-Lys-Val Lys-Ala-.Glu-Pr-Ala-Lys-IleGMu-Ala-Phe-Arg-Ala-Ser-I~eu-Ser-Lys-Leu-Gly~--Asp--Val E (PElectro) AIca-Piempor-Pth-c igys-tae-i e-asn-asn-m et-glu-ile-gly-th t-ser-lieu-p ot-asp-gdul Glu-GMy-Ala-ILys-Ile-Va1-Lys-Asp.-LIu-Met-Ser-Lys-Ala-Glu-Lys-Asp-Gly-Va1-ILys-Ile- (Ash) Thr-uau-Pro-Va(-ATh-Peo-Va-Tthre-Aa-Asp-Lysh-Psf-Asp-Gpu-Asn-Aca-Lys-Thr-Giy-Gluv Ala-4hr-Val-Ala-Ser-Gly-Ile-Pro-Ala-Gly-Trp-Mt-Gly-LIs-Asp-Cys-Gya-Pro-Glu-Ser Ser-Lys-Lys91yr-Ala-Glu-Ala-Val-Ptw-Arg-Ala-Lys-Gln-Ile-Val-rt-Ap-Gly-Pro-Va-l Gly-Va1-Val-PltS-Aya-Arg-G Ar s- Ala-t- G8Val-Va Lys-Ala-ThIrSer-Arg-Gly-Cys-Ile-Ttr-Ile-I1G1 -T s Ala-IAys-Trp-asn-Thry-Gln-ASp-Ly-al-Ser-His--Val-Ser-Thr-Gly-Gly-Gly-Ala-Ser-Ieu- 410 Gltiu- eu-glu-glv-lys-val-tlu-prougy-val-asp-ala-leu-ser-asry-ile-el FIG. 3. Complete amino acid sequence of normal human PGK. Specific amino acid substitutions of three PGK variants-i.e., PGK II (Thr -Asn at 352), PGK-Munchen (Asp - Asn at 268) and PGK-Uppsala (Arg - Pro at 206)-are also shown.
4 5464 Medical Sciences: Fujii and Yoshida Table 3. Amino acid composition of tryptic peptides I, II, and III Peptide II Peptide I from Peptide III from from PGK- Normal PGK- Amino acid normal PGK Uppsala PGK Uppsala Aspartic acid (4) 0.359(4) Threonine 0.188(2) 0.204(2) Serine 0.183(1) 0.109(1) 0.049(0) 0.024(0) Glutamic acid 0.441(2) 0.172(2) 0.126(1) 0.103(1) Proline 0.333(2) 0.219(3) 0.167(1) 0.112(1) Glycine 0.500(2) 0.211(2) 0.015(0) 0.051(0) Alanine 0.523(3) 0.214(3) 0.262(2) 0.198(2) Valine 0.245(2) 0.209(2) Methionine Isoleucine 0.245(1) 0.070(1) 0.165(1) 0.098(1) Leucine 0.642(3) 0.249(3) 0.123(1) 0.128(1) Tyrosine (0) 0.055(0) Phenylalanine 0.200(1) 0.107(1) 0.286(2) 0.171(2) Histidine Lysine 0.189(1) 0.109(1) 0.250(2) 0.157(2) Arginine 0.225(1) 0.010(0) The values are for amino acids (nmol) in the acid hydrolysates of the tryptic peptides extracted from a thin-layer plate. The numbers in parentheses are probable molar ratios of amino acids. Guinea populations and seems to be fairly common in southern Pacific populations (5). Erythrocyte enzyme activity and the specific enzyme activity of PGK-II are normal, and the kinetic properties of PGK-II are also normal (5, 16). However, PGK-II strongly binds with citrate and moves towards the anode much faster than the normal enzyme does on starch gel electrophoresis with the citrate buffer system (16). The structural abnormality of PGK-II is a single amino acid substitution from threonine to COOH-terminal domain Proc. Natl. Acad. Sci. USA 77 (1980) asparagine at the 352nd position (Figs. 3 and 4) (16). Consequently, the unusual interaction of PGK-II with citrate should be related to this substitution, directly or indirectly. PGK-Munchen is associated with erythrocyte enzyme deficiency (about 20% of normal), but this variant is not associated with hemolytic anemia and other clinical problems (18). The variant enzyme has normal Km for the substrates, normal specific activity, and slower than normal anodal electrophoretic mobility (17, 18). *However, the heat stability in vitro of PGK-Munchen is substantially lower than normal (i.e., 50% inactivation of the variant enzyme at 45 C and at ph 7.5 occurs in 3 min and that of the normal enzyme occurs in 160 min). The amino acid substitution of PGK-Munchen is asparagine for aspartic acid at the 268th position of the normal enzyme (Figs. 3 and 4) (17). It is conceivable that the aspartyl residue at the 268th position forms a hydrogen bond with a basic residue in a neighboring strand, stabilizing the molecule against heat denaturation. The variant, PGK-Uppsala, is associated with severe erythrocyte enzyme deficiency (5% to 10% of normal) and chronic nonspherocytic hemolytic anemia. PGK-Uppsala, compared with the normal enzyme, had lower affinity to all substrates (i.e., ATP, ADP, 3-phosphoglycerate, and 1,3-diphosphoglycerate), and it had lower specific activity for both forward and backward reactions (Table 2). The amino acid substitution of PGK-Uppsala was found to be at the 206th position, where arginine in the normal enzyme was replaced by proline in the variant enzyme (Figs. 3 and 4). The substitution is compatible with a single base substitution in the gene. The substitution Arg -* Pro is expected to reduce flexibility of the random coil at positions , because a Pro-Pro linkage causes difficulty in forming a flexible extended peptide bond. The strain at this portion is likely to induce a dislocation of the /-strand at posi- NH2-terminal domain. : ATP & ADP binding site a:e-helices - -:,BStrands * : PGK-Uppsala (Arg-Pro at 206) * : PGK-Munchen (Asp-Asn at 268) * : PGK-II (Thr-Asn at 352) I I : Random coil FIG. 4. Three-dimensional model of human phosphoglycerate kinase. This figure is based on the three-dimensional model of horse PGK published by Banks et al. (3). Positions of the amino acid substitutions of three variant enzymes are also shown.
5 Medical Sciences: Fujii and Yoshida tions , which constitutes the ATP and ADP binding site, resulting in lower affinity of PGK-Uppsala with the nucleotides. In contrast to the nucleotide binding site, the phosphoglycerate binding site of the enzyme has not yet been determined by x-ray crystallography. It has been tentatively speculated that the binding site could be located in the NH2-terminal domain (3). The reduced affinity of PGK-Uppsala for the phosphoglycerate substrates suggests that the binding site may be located in the COOti-terminal domain. Future study of molecular abnormalities of other human PGK variants associated with reduced affinities for the phosphoglycerate substrates will contribute towards elucidating the problem. We thank Professor C-H de Verdier, University Hospital, Uppsala, for providing us with PGK-Uppsala red blood cells. This work was supported by U.S. Public Health Service Grant HL Huang, I-Y., Rubinfien, E. & Yoshida, A. (1980) J. BMol. Chem. 255, Huang, I-Y., Welch, C. D. & Yoshida, A. (1980) J. Biol. Chem. 255, Banks, R. D., Blake, C. C. F., Evans, P. R., Haser, R., Rice, D. W., Hardy, G. W., Merrett, M. & Phillips, A. W. (1979) Nature (London) 279, Proc. Nati. Acad. Sci. USA 77(1980) Huang, I-Y., Fujii, H. & Yoshida, A. (1980) Hemoglobin, in press. 5. Chen, S-H., Malcolm, L. A., Yoshida, A. & Giblett, E. R. (1971) Am. J. Hum. Genet. 23, Hjelm, M. & Wadman, B. (1970) Abstracts, 13th International Congress of Hematology, Munich, p Yoshida, A., Hjelm, M. & Miwa, S. (1973) Am. J. Hum. Genet. 25, 89 (abstr.). 8. Buicher, T. (1955) Methods Enzymol. 1, Yoshida, A. (1975) Methods Enzymol. 42, Watanabe, S. & Yoshida, A. (1971) Biochem. Genet. 5, Davis, B. J. (1964) Ann. N.Y. Acad. Sol. 121, Laemmli, U. K. (1970) Nature (London) 227, Lowry, 0. H., Rosebrough, N. J., Farr, A. L. & Randall, R. J. (1951) J. Biol. Chem. 193, Yoshida, A. & Watanabe, S. (1972) J. Biol. Chem. 247, Kuntz, G. W. K., Eber, S., Kessler, W., Krietsch, H. & Krietsch, W. K. G. (1978) Eur. J. Biochem. 85, Yoshida, A. & Watanabe, S. (1972) J. Biol. Chem. 247, FuAi, H., Krietsch, W. G. K. & Yoshida, A. (1980) J. Biol. Chem. 255, Krietsch, W. K. G., Eber, S. W., Haas, B. & Kuntz, G. K. (1980) Am. J. Hum. Genet. 32,
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