Erythrocytes enzyme disorders

G6PD deficiency (17a) is the most common erythrocyte enzyme disorder in the world, affecting more than 100 million people worldwide. This generic conchrion is very common in the populations of East and Central Africa, the areas round the Mediterranean, the Middle East and South East Asia. The conchrion is inherited in an X-hnked manner, and female carriers have some protection against infection by malaria. 

Another important reason for the significant deviation between calculated and X-ray structures can be the low resolution (2.9 A) of the X-ray structure. It is well known that X-ray structures may miss disordered water molecules inside the enzyme. The X-ray structure of the bovine erythrocyte GPx has a significantly higher resolution (2.0 A) and that structure contains two water molecules in the active site [63], Unfortunately that X-ray structure is not complete. In order to test for the presence of water molecules at the active site of the mammalian GPx, calculations were performed with two additional water molecules at the active site. This reduced the RMS deviation to from 0.97 to 0.19k for ONIOM(B3LYP/6-31G(d) Amber)-ME and suggests the presence of water molecules also in the active site of mammalian GPx. In our investigation of the reaction mechanism, these water molecules turns out to be critical. 

Excessive amounts of arsenic can cause skin, lung, and heart diseases, and gastrointestinal disorders, and it is known to have a carcinogenic influence. As" " compounds, which are bound by erythrocytes, affect the activity of numerous enzymes - especially those involved in respiratory processes (Cebrian et al., 1983 Done and Peart, 1971 National Academy of Sciences, 1977 WHO, 2001). 

The study of enzymes has immense practical importance. In some diseases, especially inheritable genetic disorders, there may be a deficiency or even a total absence of one or more enzymes. For other disease conditions, excessive activity of an enzyme may be the cause. Measurements of the activities of enzymes in blood plasma, erythrocytes, or tissue samples are important in diagnosing certain illnesses. Many drugs exert their biological effects through interactions with enzymes. And enzymes are important practical tools,... 

Deficiencies of any of these red cell enzymes may result in impaired ATP generation and consequently loss of function of the erythrocyte. By far the majority of these disorders are hereditary in nature, although acquired deficiencies have been described, mainly in malignant disorders involving the bone marrow. Hereditary enzymatic defects in these pathways disturb the erythrocyte s integrity, shorten its cellular survival, and produce chronic nonspherocytic hemolytic anemia (CNSHA). Deficiencies of some enzymes, however, do not lead to chronic hemolytic anemia, but to acute episodes of severe hemolysis when there is increased oxidative stress on the red cell (as in some types of glucose-6-phosphate dehydrogenase deficiency). 

A number of these enzymes are expressed in other tissues as well but cause a notable deficiency predominantly in red blood cells because of the life span of the erythrocyte after the loss of protein synthesis. Once an enzyme is degraded or otherwise becomes nonfunctional, it cannot be replaced by new or other compensating proteins because of the lack of nucleus, mitochondria, ribosomes, and other cell organelles in mature red cells. Disorders have been described in the EMP, HMP, Rapoport-Luebering cycle, the glutathione pathway (Figure 21-9), purine-pyrimidine metabolism and methemoglobin reduction. 

Pyrimidine-5 -nucleotidases are a group of enzymes dephos-phorylating pyrimidine nucleotides to the corresponding nucleosides. The pyrimidine bases diffuse out of the erythrocyte and the phosphates are retained. Pyrimidine phosphates are present on ribosomes of erythroblasts and reticulocytes, but there are normally no pyrimidines in mature RBCs. Two cytoplasmic forms of the enzyme were identified in the erythrocyte, P5 N-1 and P5 N-2. These enzymes are encoded by different genes and have different molecular properties and substrate specificities. Since there are no known disorders associated with deficiency of P5 N-2, this enzyme will not be further discussed here. 

The abnormality of this enzyme associated with hereditary nonspherocytic hemolytic anemia is an increase in activity in the erythrocyte. This results in the depletion of red cell ATP and hemolysis. Few cases with a thirtyfoid to seventyfold increase have been described. It is the only RBC enzymopathy that is inherited as an autosomal dominant disorder. The molecular mechanism of this disorder has not been identified. High levels of normal ADA mRNA were present, suggesting a mutation in an in cis transcriptional regulating element, which could not be identified. 

NADH-cytochrome b5 reductase deficiency (OMIM 250800) is an autosomal recessive disorder, causing hereditary methemoglobinemia. There are three types. In type I, the enzyme is deficient only in erythrocytes. Patients are typically blue and/or gray and cyanotic, but not very sick. Type II is more severe, the enzyme being completely deficient, causing mental retardation and neurological impairment. In type III the enzyme is deficient in all blood cells. 

Erythrocyte GSH concentration is diminished in many people who have defects in the hexose monophosphate or GSH synthesis pathways. The GSH stability test, originally devised to permit identification of people susceptible to hemolysis from primaquine (later shown to be the result of G6PD deficiency), still remains a useful "stress test of the intactness of these closely hnked pathways. Because deficiencies of GSH synthetase and y-glutamyl cysteine synthetase are rare disorders, it is not practical for clinical laboratories to contemplate assays for these enzymes unless results of the easily performed GSH stability test are abnormal. 

Screening family members to identify asymptomatic individuals who have inherited AIP, VP, or HCP, and are therefore at risk for acute attacks, is an essential part of management of families with these disorders. Screening may be carried out by metabolite measurement, enzyme assay, DNA analysis, or a combination of these approaches. The most sensitive metabolite assays for the presymptomatic diagnosis of each disorder are listed in Table 32-7. These tests are almost always normal before puberty and therefore are not suitable for the investigation of children. In addition, urinary PEG excretion in AIP and the plasma fluorescence scan in VP may often be normal in asymptomatic adults shown by DNA analysis to be affected (Table 32-7). Measurement of the activity of the defective enzyme is more sensitive, but both sensitivity and specificity are limited by the overlap between activities in disease and in the normal population. Erythrocyte HMBS assay is widely used for the presymptomatic diagnosis of AIP. ... 

In Lesch-Nyhan patients, all tissues are devoid of HPRT. The disorder thus can be detected by an assay for HPRT in erythrocytes and by cultured fibroblasts. The former test has been used in detection of the heterozygous state. HPRT is a 217-amino-acid cytosolic enzyme coded for by a single gene on the X chromosome. 

Pyruvate kinase and other enzyme deficiency disorders of the erythrocyte, W. N. Valentine, K. R. Tanaka and D. 

Muscle is the only source of CK and by measuring the isoenzyme CK-MB one can determine whether or not cardiac muscle is involved. If the liver is involved then the serum yGT should be increased as this is one of the most sensitive indicators of liver disease. LDH isoenzyme analysis will help identify erythrocyte damage as a possible source for some of the LDH and AST activity. In haemolytic disorders, one would expect a reticulocytosis and intravascular haemolysis will lead to a low serum haptoglobin level. These investigations will help identify whether or not erythrocytes have contributed to the serum enzymes. 

C9H16N3O14P3 483.158 Prod, by Leishmania and Streptomyces griseus found in erythrocytes and lymphocytes. Enzyme inhibitor. Implicated in purine and pyrimidine metabolism disorders. Contracts arteries. Cryst. powder (as Na salt). 

The most studied of the genetic polymorphisms for blood components in potentially lead-exposed populations and relevant to Pb toxicokinetics is that for the erythrocyte heme pathway enzyme 6-ALAD (EC 4.2.1.24). This enzyme, also known as porphobilinogen synthase (PBG-S), participates in the heme biosynthesis pathway, catalyzing the cyclodehydration of two units of 6-ALA to PBG. Inhibition by lead leads to the accumulation of 6-ALA in plasma and urine. Excess substrate is neurotoxic in animals and may play a role in manifestations of lead poisoning (Audeskirk, 1985) and, presumably, in the genetic disorder acute intermittent porphyria (Bonkowsky, 1982). It is... 

In both these two immunodeficiency and haematological disorders particularly, but also in all other disorders diagnosed by enzyme assay in erythrocytes, if possible transfusion should be delayed until the confirmation (or elimination) of a diagnosis is made. Donor enzyme activity will take 6 months to disappear. 

In 1965 Japanese workers [128] identified a deficiency in muscle of phosphofructokinase, another glycolytic enzyme the symptoms were quite similar to those of muscle phosphorylase deficiency. The enzyme was also low in erythrocytes. Inheritance is probably autosomal recessive and a small number of other cases have since been reported. A late-onset muscle disorder in two brothers associated with a low activity of phosphohexoseisomerase in the muscle has been reported in another Japanese family [129]. 

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