Metabolic errors

The second method for mixture analysis is the use of specialized software together with spectral databases. We have developed a mixture analysis program AMIX for one- and multidimensional spectra. The most important present applications are the field of combinatorial chemistry and toxicity screening of medical preparations in the pharmaceutical industry. An important medical application is screening of newborn infants for inborn metabolic errors. 

People can suffer from a variety of inborn metabolic errors that can result in various amino acids exhibiting toxic effects if ingested above certain threshold levels. Specialty products, intended to be absent these amino acids, must be rigorously tested for verification that threshold levels are not exceeded. Examples of this situation include phenylketoneuria (intolerance of phenylalanine) and maple syrup urine disease (intolerance for leucine, isoleucine, and valine). 

J3. Jervis, G. A., Studies on phenylpyruvic oligophrenia. The position of the metabolic error. J. Biol. Chem. 169, 651-656 (1947). 

Van Sande, M. (1972). Hair amino acids Normal values and results in metabolic errors. Monographs Human Genetics 6,157. 

In this chapter, we indicate that the metabolic error (i.e., deficiency of phosphotransferase activity in I-cell disease) gives rise to a secondary phenotype of generalized diminished lysosomal enzyme activity. What other metabolic defects in the mannose 6-phosphate-mediated uptake system could result in such a phenotype, and how would you confirm the defect ... 

Uric acid is the chief end product of purine metabolism in primates, birds, lizards, and snakes. An inborn metabolic error in humans results in increased levels of uric acid and its deposition as painful crystals in the joints. This condition (gout) may be treated by the drug allopurinol which is also oxidized by xanthine oxidase to allo-xanthine (dashed line in Eq. 19.29). However, alloxanthine binds so tightly to the molybdenum that the enzyme is inactivated, the catalytic cycle broken, and uric acid formation is inhibited. The extra stability of the alloxanthine complex may be a result of strong N—H --N hydrogen bonding by the nitrogen in the 8-position ... 

However, not all the results in glycogen storage disease can be dismissed as resulting from imperfect laboratory technique. Enzyme deficiencies could occur if the mutation was in an operator gene controlling more than one adjacent gene (Jl), and it is not impossible that such a situation exists in the hereditary metabolic errors of urea formation. 

There have been reports in the literature of hypouricemia coincident with specific inborn metabolic errors, but many of these cases are attributable to defects in the kidney leading to failure of renal tubular reabsorption. It was mentioned above that the excretion of uric acid by the Dalmatian coach hound can be attributed to such a mechanism (Fll). Similarly, the hypouricemia found in the Fanconi syndrome (L4) and Wilson s disease (B12) can be attributed to kidney malfunction. These are not true examples of underproduction of oxypurines, including uric acid, since the daily output of uric acid is normal. The large number of healthy people who have extremely low serum urate values, however, may indicate that there are individuals who underproduce oxypurines but suffer no ill effects because of this. The one well-documented inborn error that results in underproduction of uric acid is xanthinuria. It has been reported in relatively few cases, probably because individuals with this metabolic abnormality who suffer no ill effects would not come to the attention of a physician. 

Capecitabine is a pyrimidine analog. It is an oral systemic prodrug that is enzymatically converted to 5-fluorouracil (5-FU). Healthy and tumor cells metabolize 5-FU to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-flu-orouridine triphosphate (FUTP). These metabolites cause cell injury by two different mechanisms. First, they inhibit the formation of thymidine triphosphate, which is essential for the synthesis of DNA. Second, nuclear transcriptional enzymes can mistakenly incorporate FUTP during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis. Capecitabine is indicated in the treatment of resistant metastatic breast cancer alone or in combination with docetaxel, and colorectal cancer. 

Urinary acids from patients with amino acid metabolic errors Strongly basic anion exchange resin extraction combination with GC after methylation Guarino et al. [420]... 

However, encephalopathies with a metabohc basis tend to be the most problanatic for infants or children, with functional outcomes dependent upon timely and pradent interventions. Three varieties of metabolic encephalopathy in children are discussed here. The first two are closely related. Inborn (genetic) errors of metabolism can present in the newborn as severe encephalopathy from hyperammonemia alone. When a metabolic error presents months to years later, a degree of hepatic insufficiency may complicate the metabolic derangement. In acute or fulminant hepatic failure of any etiology (i.e., infections, drug-induced, toxin-related), the rise in serum ammonia may be only moderate but other factors contribute to the ensuing encephalopathy, which may be devastating within days. 

Despite the relatively few steps in intermediary metabolism of the aromatic amino acids, a large number of metabolic errors have been reported. Some, like phenylketonuria, lead to dramatic clinical situations, whereas others, like alkaptonuria, are less clinically important, and still others, like tyrosinosis, have no clinical significance. The reasons for many errors in a given pathway are not understood. Metabolic errors may be as common in other metabolic pathways, but they are not observed either because they do not lead to clinical alterations or because they are lethal. However, the genes concerned with the appearance of each enzyme involved in a specific metabolic pathway may be located on adjacent loci in the chromosome, and these loci are perhaps more prone to spontaneous mutation. 

Clearly, a metabolic error, which would in a human favor the bird pathway, would make such humans more urecotelic [217]. 

However, even if there should be a defect of glutamate or of glutamine metabolism, such a metabolic error could not directly account for the isotopic data, for an increase in concentration of free glutamine in liver would result in greater dilution of newly synthesized labeled glutamine and reduced rather than increased labeling of N-3 and N-9 relative to N-7 or total uric acid. 

A similar separation of 50 physiological amino adds can be obtained with the highly efficient 3 pm cation exchanger from Hitachi (Tokyo, Japan) in about 2 h. The Hitachi column is characterized by an extremely low back pressure of 370-800 psi over the course of the run. In addition to key amino adds related to certain metabolic errors, less common amino acids such as homocysteine, homocitrulline, //o-isoleucine, argininosuccinic acid, cysteine-homocysteine mixed disulfides, homocystine, and argininosuccinic acid anhydride can also be separated under similar chromatographic conditions. 

Mineral metabolism Errors causing serious intoxication continue to be reported, because of confusion between disodium edetate (which has a strong affinity for calcium) and calcium disodium edetate (which can be used in lead poisoning) [53" ]. If chelation therapy is required in children, calcium disodium edetate, not disodium edetate, should be used, because of the risk of hypocalcemia. 

Consideration of a primary defect in cerebroside metabolism calls for answers to the following questions 1) is there only a quantitative disturbance, i.e. a balance problem between cerebroside synthesis and breakdown, or 2) is there a qualitative abnormahty of cerebroside metabolism, evidenced by a) the finding of an abnormal cerebroside and/or b) an abnormal relation between various cerebrosides which are defined by their sugar and fatty acid moieties respectively, and 3) is the presumed metabolic error limited to certain cells, i.e. cells which are to become GC, or is it a general feature of all cells with the ability to synthesize and metabolize cerebrosides. 

Among the unexplained features is the storage of glycolipid by the infantile brain in same cases of GD. Here the possiblity of an additional metabolic error exists. A case (Jervis et al. 1962) where cytoside was the main splenic lipid instead of glucocerebroside (Rosenberg 1962) may represent a variant of GD where the enzymetic defect is localized to the site of cleavage of cytoside to cerebroside (see figure 7). 

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