Nucleotides deficiency

Decker K, Keppler D. Galactosamine hepatitis key role of the nucleotide deficiency period in the pathogenesis of cell injury and cell death. Rev Physiol Biochem Pharmacol 1974 71 77-106. 

It was observed that the adenine sensitivity of the double mutant could be overcome by adding guanosine to the medium (78). This and other data demonstrated that the double mutant was starved for GMP in the presence of excess AMP. The implication for wild-type cells was that any regulatory mechanisms operating at the IMP branchpoint could be overridden by a high concentration of adenine nucleotides, even under conditions of guanine nucleotide deficiency. 

The consequence of ADA deficiency is accumulation of adenosine and 2 -deoxyadenosine, substances toxic to lymphocytes, important cells in the immune response. 2 -Deoxyadenosine is particularly toxic because its presence leads to accumulation of its nucleotide form, dATP, an essential substrate in DNA synthesis. Elevated levels of dATP actually block DNA replication and cell division by inhibiting synthesis of the other deoxynncleoside 5 -triphosphates (see Chapter 27). Accumulation of dATP also leads to selective depletion of cellular ATP, robbing cells of energy. Children with ADA SCID fail to develop normal immune responses and are susceptible to fatal infections, unless kept in protective isolation. 

Riboflavin was first isolated from whey in 1879 by Blyth, and the structure was determined by Kuhn and coworkers in 1933. For the structure determination, this group isolated 30 mg of pure riboflavin from the whites of about 10,000 eggs. The discovery of the actions of riboflavin in biological systems arose from the work of Otto Warburg in Germany and Hugo Theorell in Sweden, both of whom identified yellow substances bound to a yeast enzyme involved in the oxidation of pyridine nucleotides. Theorell showed that riboflavin 5 -phosphate was the source of the yellow color in this old yellow enzyme. By 1938, Warburg had identified FAD, the second common form of riboflavin, as the coenzyme in D-amino acid oxidase, another yellow protein. Riboflavin deficiencies are not at all common. Humans require only about 2 mg per day, and the vitamin is prevalent in many foods. This vitamin... 

Dutartre H, Bussetta C, Boretto J, Canard B (2006) General catalytic deficiency of hepatitis C virus RNA polymerase with an S282T mutation and mutually exclusive resistance towards 2 -modified nucleotide analogues. Antimicrob Agents Chemother 50 4161 169 Elferink RO, Groen AK (2002) Genetic defects in hepatobiliary transport. Biochim Biophys Acta... 

Since the end products of pyrimidine catabolism are highly water-soluble, pyrimidine overproduction results in few clinical signs or symptoms. In hypemricemia associated with severe overproduction of PRPP, there is overproduction of pyrimidine nucleotides and increased excretion of p-alanine. Since A, A -methyl-ene-tetrahydrofolate is required for thymidylate synthesis, disorders of folate and vitamin Bjj metabofism result in deficiencies of TMP. 

The RBC contains certain enzymes of nucleotide metabolism (eg, adenosine deaminase, pyrimidine nucleotidase, and adenylyl kinase) deficiencies of these enzymes are involved in some cases of hemolytic anemia. 

M. Ju.szczuk and A. M. Rychter, Changes in pyridine nucleotide levels in leaves and roots of bean plants Phaseolus vtilgans L.) during phosphate deficiency. J. Plant Physiol. 151 399 (1997). 

Deficiencies of enzymes involved in glycolysis, the hexose monophosphate pathway, the closely related glutathione metabolism and synthesis, and nucleotide metabolism have emerged as causes of hereditary nonspherocytic hemolytic anemias (Table 1) (F10, Fll, M27). Some enzyme deficiencies, such as diphospho-glycerate mutase deficiency, lactate dehydrogenase deficiency, and NADH cy-... 

Up to now, 101 different mutations have been identified (Fig. 11) (B29, H18). Most of the variant enzymes are produced by one or two missense mutations in the structural gene. G6PD Vancouver is caused by three nucleotide substitutions (M4). Although nucleotide deletions or nonsense mutations are common molecular abnormalities that may cause a variety of genetic disorders, they are rare in G6PD deficiency cases. Nucleotide deletions have been found in only five variants... 

Fig. 12. Absorption spectra of perchloric acid extracts of whole blood from normal subject and a patient with pyrimidine 5 -nucleotides (P5N) deficiency. Absorption peak shift occurs in P5N deficiency, reflecting intracellular accumulation of pyrimidine nucleotides.

Low levels or absence of adenosine deaminase (ADA) is associated with one form of severe combined immunodeficiency disease (SCID) characterized by B-andT-lymphocyte dysfunction due to toxic effects of deoxyadenosine (HI9). Most patients present as infants with failure to thrive, repeated infections, severe lymphopenia, and defective cellular and humoral immunity. Disease severity is correlated with the degree of deoxyadenosine nucleotide pool expansion and inactivation of S-adenosylhomocysteine hydrolase in red blood cells. Up to now, more than 40 mutations have been identified (A4, H20, S5, S6). The majority of the basic molecular defects underlying ADA deficiency of all clinical phenotypes are missense mutations. Nonsense mutations, deletions ranging from very large to single nucleotides, and splicing mutations have also been reported. It is likely that severe... 

Acatalasemia is a rare hereditary deficiency of tissue catalase and is inherited as an autosomal recessive trait (03). This enzyme deficiency was discovered in 1948 by Takahara and Miyamoto (Tl). Two different types of acatalasemia can be distinguished clinically and biochemically. The severe form, Japanese-type acatalasemia, is characterized by nearly total loss of catalase activity in the red blood cells and is often associated with an ulcerating lesion of the oral cavity. The asymptomatic Swiss-type acatalasemia is characterized by residual catalase activity with aberrant biochemical properties. In four unrelated families with Japanese-type acatalasemia, a splicing mutation due to a G-to-A transition at the fifth nucleotide in intron 4 was elucidated (K20, W5). We have also determined a single base deletion resulting in the frameshift and premature translational termination in the Japanese patient (HI6). 

A4. Arredondo-Vega, F. X., Santisteban, I., Kelly, S., Schlossman, C., Umetsu, D and Hershfield, M. S., Correct splicing despite a G- A mutation at the invariant first nucleotide of a 5 splice site A possible basis for disparate clinical phenotypes in siblings with adenosine deaminase (ADA) deficiency. Am. J. Hum. Genet. 54,820-830 (1994). 

Eighty distinct mutations in type I AT deficiency, ranging from single nucleotide substitutions, to deletion or insertion of a small number of nucleotides of 22 base pairs or less, to major deletions of either a part of or the entire AT gene, have been recognized (83). 

Paglia DE, Valentine WN, Fink K. 1977. Lead poisoning Further observations on erythrocyte pyrimidine-nucleotidase deficiency and intracellular accumulation of pyrimidine nucleotides. J Clin Invest 60 1362-1366. 

Thiopurine S-methyltransferase deficiency two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am J Hum Genet 1996 58 694-702. 

Calcium oxalate monohydrate responsible for the formation of most kidney stones significantly increased mitochondrial superoxide production in renal epithelial cells [42], Recombinant human interleukin IL-(3 induced oxygen radical generation in alveolar epithelial cells, which was suppressed by mitochondrial inhibitors 4 -hydroxy-3 -methoxyacetophe-none and diphenylene iodonium [43]. Espositio et al. [44] found that mitochondrial oxygen radical formation depended on the expression of adenine nucleotide translocator Anti. Correspondingly, mitochondria from skeletal muscle, heart, and brain from the Antl-deficient mice sharply increased the production of hydrogen peroxide. 

Deficiency of the muscle-specific myoadenylate deaminase (MADA) is a frequent cause of exercise-related myopathy and is thought to be the most common cause of metabolic myopathy. MADA catalyzes the deamination of AMP to IMP in skeletal muscle and is critical in the purine nucleotide cycle. It is estimated that about 1-2% of all muscle biopsies submitted to medical centers for pathologic examination are deficient in AMP deaminase enzyme activity. MADA is 10 times higher in skeletal muscle than in any other tissue. Increase in plasma ammonia (relative to lactate) after ischemic exercise of the forearm may be low in this disorder, which is a useful clinical diagnostic test in patients with exercise-induced myalgia... 

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