Red Cell Enzyme Deficiencies Research Articles

A single amino acid substitution (Asp leads to Asn) in a phosphoglycerate kinase variant (PGK München) associated with enzyme deficiency.

The structural abnormality of the phosphoglycerate kinase variant, PGK München, associated with red cell enzyme deficiency and heat instability, was elucidated by a microscale peptide-mapping method. A single amino acid substitution, from aspartic acid in the normal enzyme to asparagine in the variant enzyme, was found. From the known amino acid sequence of normal human phosphoglycerate kinase, the substitution is in the aspartic acid residue located at 268th position from the NH2-terminal of the protein.

Structure and function of normal and variant human phosphoglycerate kinase.

Complete amino acid sequence of normal human phosphoglycerate kinase (PGK) was determined. The enzyme consists of 417 amino acid residues with acetylserine at the NH2-terminal and isoleucine at the COOH-terminal. The structural abnormality of PGK-II, which is fairly common in Southern Pacific populations, is a single amino acid substitution from threonine in the normal enzyme to asparagine in the variant enzyme at the 352nd position. The substitution induced no change in the enzyme activity, but induced strong binding of the variant enzyme with citrate. The structural abnormality of PGK-München is a single amino acid substitution from aspartic acid in the normal enzyme to asparagine in the variant enzyme at the 267th position. PGK-München is associated with red cell enzyme deficiency (about 20% of normal), and substantial heat instability. Therefore, the negative charge of an aspartyl residue at the 267th position must play a role in maintaining the stability of the enzyme molecule. Possible mechanisms of hemolysis due to hereditary deficiency of PGK are discussed.

Associated Red Cell Enzyme Deficiencies and Their Significance in a Case of Congenital Enzymopenic Methemoglobinemia

Examination of the red cell enzyme profile in a case of congenital methemoglobinemia has shown associated deficiencies of glutathione reductase (GR) and glutathione peroxidase (GSHPx) in addition to NADH-methemoglobin reductase deficiency. Contrary to expectations, GR and GSHPx deficiencies do not seem to have contributed to the methemoglobinemia in this case. The lack of symptoms in spite of a high methemoglobin (Hi) level (35%) appears to be due to the restriction of Hi to a small percentage of red cells.

Metabolism of Human Erythrocytes

Deficiency states have been well established in nine enzymes of anaerobic glycolysis and suggested, but inadequantely confirmed, in others. In additon, hemolytic anemia has been defined in glucose-6-phosphate dehydrogenase deficiency, in certain enzymes glutathione metabolism of importance to the function of the oxidative hexsemonophosphate shunt, and in certain enzymes of nucleotide metabolism. In heterogeneous dyserythropoietic states with ineffective erythropoiesis, enzyme ratios are grossly distorted and differ greatly from those of either normal or reticullocyte-rich blood. Red blood cell (RBC) enzyme deficiencies show noticeable genetic polymorphism, most apparently recessively transmitted anemias actually resulting from inheritance of two different mutant, allelic genes. In addition to causing hemolytic syndromes in selected instances, deficiencies of enzymes more important to other tissues than to the RBC itself are detectable by assay of hemolystates.

Haemolytic anaemia with hereditary pyruvate kinase instability developing acute leukaemia.

The case of a 27-year-old woman with pancytopenia, revealing acute monocytic leukaemia and haemolytic anaemia, is described in detail. The underlying cause for the red cell destruction was found to be a pyruvate kinase (PK) instability. Further investigation into three generations of her family (n = 12) disclosed a hereditary PK instability. This was proven by performing biochemical studies to elucidate mutants representing a structurally defective enzyme. Since conversions of pancytopenia with acquired red cell enzyme deficiency into leukaemia have been described, our observation emphasizes that hereditary red cell enzymopathy might also be associated with adult acute leukaemia.

Congenital hemolytic anemias and red cell enzyme deficiencies

Congenital hemolytic anemias and red cell enzyme deficiencies

The Hereditary Hemolytic Anemias: Membrane and Enzyme Defects

Similar clinical syndromes may be produced by a variety of red cell membrane abnormalities or enzyme deficiencies. Those disorders so far identified and characterized are reviewed and their similarities and differences are noted.

Red Cell Enzyme Deficiencies as a Cause of Hemolytic Disorders

The human red cell, biologically speaking, is intriguingly but deceptively simplistic. Freely floating, separable from contaminating cell types, devoid of a nucleus and cellular organelles, restricted in its energy needs and in the mechanisms for meeting them, it can be biopsied repeatedly with safety and offers many lures to the investigator. In recent years its enzymatic machinery has been explored with increasing intensity, and a variety of genetically determined inborn errors have been demonstrated (Valentine, 1, 2; Jaffe, 3). Some have been associated etiologically with hereditary hemolytic disease, and some have clarified mechanisms of what formerly were regarded as idiosyncratic reactions to drugs. Some have provided a convenient diagnostic tool for defining diseases not characterized by he­ matopoietic abnormalities. In still others, the definition of genetically de­ termined enzymopathy has been a curiosity with no counterpart in clinical disease.

HEMATOLOGIC ABNORMALITIES IN TUBERCULOUS PATIENTS

<h3>To the Editor.</h3> —I would like to add a note concerning the retrospective study of hematologic abnormalities in tuberculous patients by Glasser and co-workers (<i>Arch Intern Med</i><b>125</b>:691-695, 1970). There are four possible relationships of tuberculosis to hematologic disease. These are (1) the hematologic disease predisposes to tuberculosis reactivation, (2) the tuberculosis "causes" or is associated with hematologic abnormalities, (3) antituberculous drugs cause hematologic abnormalities, and (4) the hematologic disease and tuberculosis are coincidental. Of these, they neglected to mention the third listed above:<i>antituberculous drugs</i>causing hematologic abnormalities. These drugs may cause idiosyncratic reactions, malabsorption, interference with iron metabolism, and hemolysis in patients with red blood cell enzyme deficiencies. Idiosyncratic reactions manifested by depression of any or all of the three cellular blood elements may be caused by any of the antituberculous drugs. Of the usual three drugs, aminosalicylic acid and streptomycin are most often responsible. Evidence of

Glucose-6-phosphate dehydrogenase deficiency.

It has long been recognized that certain ordinarily salutary drugs may produce an acute hemolytic anemia in some susceptible individuals. The 8-aminoquinoline antimalarial, pamaquine (plasmoquine), was such a medication. It was the investigation of the hemolytic effect of pamaquine and its derivatives which led to the recognition that hereditary red cell enzyme deficiencies could produce hemolytic disease.

Athens Variant of Glucose-6-Phosphate Dehydrogenase

A variant of glucose-6-phosphate dehydrogenase (G6PD), characterized by slower than normal electrophoretic migration and associated with mild deficiency of G6PD in the red cells, was detected in two unrelated Greek males. Electrophoretic, chromatographic, and enzymologic study indicated that the new mutant is structurally different from normal G6PD (B+) and from the Mediterranean variant associated with red-cell enzyme deficiency (B-). Convincing electrophoretic separation of the new variant from the normal B+ and the Mediterranean B- enzymes was achieved only by detailed electrophoretic study in different buffer systems and conditions.

Distribution pattern of an inherited trait, red cell enzyme deficiency, in New Guinea and New Britain.

Distribution pattern of an inherited trait, red cell enzyme deficiency, in New Guinea and New Britain.

Contribution of red cell enzyme deficiency trait to an understanding of genetic relationships between Melanesian and other populations.

Contribution of red cell enzyme deficiency trait to an understanding of genetic relationships between Melanesian and other populations.

Absence of red cell enzyme deficiency in Australian Aborigines.

THE geographical distribution of erythrocyte glucose-6-phosphate dehydrogenase deficiency is now-known to be widespread. Thus, this genetically determined enzyme defect has been shown to be present in parts of Africa, Asia and Europe, and in some Indian groups in South America. Marked variations in the incidence of the defect have been observed between different populations and in some instances between different groups in the same population. In south-east Asia recent work has shown the trait to be present in Thais, Malays, Indonesians (Lie-Injo, L. E., personal communication), Filipinos and Melanesians.