Structural modeling of the human erythrocyte bisphosphoglycerate mutase

Craescu, Constantin T.; Schaad, Olivier; Garel, Marie-Claude; Rosa, R.J. Della; Edelstein, Stuart J.

doi:10.1016/0300-9084(92)90149-9

Cited by 6 publications

(11 citation statements)

References 22 publications

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“…coli-In the human, murine, and rabbit BPGMs, the Cys 22 and Ser 23 residues are strictly conserved (Table I), however, at the position of Ser 23 in BPGMs there is always a Gly in the MPGMs from human muscle and brain and from yeast. In contrast, whereas Cys 22 is conserved in human muscle MPGM, it is substituted by Ser in human brain MPGM and by Thr in …”

Section: Purification Of Wild-type and Mutant Bpgms Expressed In Ementioning

confidence: 99%

“…We have constructed a three-dimensional model of human BPGM based on crystallographic data from yeast MPGM since in human BPGM and yeast MPGM about 50% of residues are identical (22). The BPGM model shows specific charge configuration near the postulated substrate position, in the active site, which differs from MPGM.…”

mentioning

confidence: 99%

“…The BPGM model shows specific charge configuration near the postulated substrate position, in the active site, which differs from MPGM. In particular Ser 11 , Thr 20 , and Gly 21 in yeast MPGM are replaced by Gly 13 , Cys 22 , and Ser 23 , respectively, in BPGM.…”

mentioning

confidence: 99%

“…Initially we focused on Cys 22 as sulfhydryl treatment of human BPGM is known to inhibit the different catalytic activities to various degrees (29,30). The position of Cys 22 , in the threedimensional protein model appears to be in the putative active site (Fig.…”

mentioning

confidence: 99%

“…The catalytic properties of several BPGM variants, obtained by substitution of Cys 22 and Ser 23 are reported here. Further enzymatic studies on the variant R89K described previously (24) are also reported.…”

mentioning

confidence: 99%

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Critical Role of Human Bisphosphoglycerate Mutase Cys22 in the Phosphatase Activator-binding Site

Ravel

Craescu

Arous

et al. 1997

Journal of Biological Chemistry

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The enzymatic activities catalyzed by bisphosphoglycerate mutase (BPGM, EC 5.4.2.4) have been shown to occur at a unique active site, with distinct binding sites for diphosphoglycerates and monophosphoglycerates. The physiological phosphatase activator (2-phosphoglycolate) binds to BPGM at an undetermined site. BPGM variants were constructed by site-directed mutagenesis of three amino acid residues in the active site to identify residues specifically involved in the binding of the monophosphoglycerates and 2-phosphoglycolate. Substitution of Cys 22 by functionally conservative residues, Thr or Ser, caused a great decrease in 2-phosphoglycolate-stimulated phosphatase activity and in the K a value of the activator, whereas it caused no change in other catalytic activities or in the K m values of 2,3-diphosphoglycerate (2,3-DPG) and glycerate 3-phosphate (3-PG, EC 1.1.1.12), indicating that Cys 22 is specifically involved either directly or indirectly in 2-phosphoglycolate binding.Kinetic experiments showed that the K a of the cofactor and the K m of 3-PG were affected by the substitution of Ser 23 indicating that this residue is necessary for the fixation of both 3-PG and 2-phosphoglycolate. The R89K variant has previously been shown to have a modified K m value for monophosphoglycerates, however, its affinity for 2-phosphoglycolate is unaltered, suggesting that Arg 89 is specifically involved in monophosphoglycerates binding.CD spectroscopic studies of substrates and cofactor binding showed that 2,3-DPG induced structural modifications of normal and mutated enzymes which could be due to protein phosphorylation. Addition of 2-phosphoglycolate to phosphorylated proteins with normal affinity for the cofactor produced spectra with the same characteristics as unphosphorylated species.In summary, monophosphoglycerates and 2-phosphoglycolate have partially distinct binding sites in human BPGM. The specific implication of the Cys 22 residue in 2-phosphoglycolate binding is of great significance in the design of analogs of therapeutic benefit.

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Section: Purification Of Wild-type and Mutant Bpgms Expressed In Ementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Critical Role of Human Bisphosphoglycerate Mutase Cys22 in the Phosphatase Activator-binding Site

Ravel

Craescu

Arous

et al. 1997

Journal of Biological Chemistry

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Erythrocytosis due to bisphosphoglycerate mutase deficiency with concurrent glucose‐6‐phosphate dehydrogenase (G‐6‐PD) deficiency

et al. 2004

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A 28-year-old asymptomatic male of Iranian Jewish (Meshadi) heritage was found on routine exam to have an erythrocytosis (RBC = 6.22 · 10 12 /l, Hgb = 19.2 g/dl, Hct = 58.9%). Splenomegaly was absent on physical exam. There was no family history of erythrocytosis. His oxygen dissociation curve was left-shifted with a p 50 of 19 mmHg (normal = 25-32 mmHg). Hemoglobin electrophoresis showed no abnormalities. DNA sequencing of the hemoglobin b globin gene and both a globin genes did not reveal a mutation. A 2,3-bisphosphoglycerate (BPG) level was markedly decreased at 0.3 mmol/g Hb (normal = 11.4-19.4 mmol/g Hb). The patient's bisphosphoglycerate mutase (BPGM) enzyme activity was also markedly decreased at 0.16 IU/g Hb (normal = 4.13-5.43 IU/g Hb). A red cell enzyme panel revealed a markedly decreased G-6-PD level (0.3 U/g Hb, normal = 8.6-18.6 U/g Hb). His parents and a brother were also available for evaluation. Both parents showed normal 2,3-BPG levels but BPGM activity approximately 50% of normal. Paradoxically, the brother showed normal BPGM activity but a slightly decreased 2,3-BPG level. All family members had markedly decreased G-6-PD activity. DNA sequencing of the BPGM gene showed the propositus to be homozygous for 185 GfiA, Arg 62 Gln in exon 2. Thus, the erythrocytosis in this patient is secondary to low 2,3-BPG levels, due to a deficiency in BPG mutase. This appears due to consanguinity within this family. Am.

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Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia

Bruggen

Gualtieri

et al. 2020

Cell Reports

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Structural modeling of the human erythrocyte bisphosphoglycerate mutase

Cited by 6 publications

References 22 publications

Critical Role of Human Bisphosphoglycerate Mutase Cys22 in the Phosphatase Activator-binding Site

Critical Role of Human Bisphosphoglycerate Mutase Cys22 in the Phosphatase Activator-binding Site

Erythrocytosis due to bisphosphoglycerate mutase deficiency with concurrent glucose‐6‐phosphate dehydrogenase (G‐6‐PD) deficiency

Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia

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