Propionate metabolism disorder

Figure 7.12 show the results of a validation study. The task was to identify bioisosteric replacements for fragments in known PPAR (peroxisome pro-liferator-activated receptor) ligands. Fibrates are therapeutic agents for the treatment of metabolic disorders and activate PPARoc, a member of the PPAR family.It has been demonstrated that the 2-methyl-propionic acid moiety 7.6 is responsible for the selectivity of fibrates toward PPARa. SQUIRRELnovo suggests bioisosteric replacement for this group. These groups have been patented for action on PPARoc. ... 

Sometimes a test for more than one protein is needed and mass spectrometry is the method of choice for that purpose. A good example for this would be the use of tandem mass spectrometry to screen neonates for metabolic disorders such as amino acidemias (e.g., phenylketonuria—PKU), organic acidemias (e.g., propionic acidemia—PPA), and fatty acid oxidation disorders (e.g.. Medium-chain acyl-CoA Dehydrogenase deficiency—MCAD) [9]. Although the price of this capital equipment could be high, costs of using it as a sensor is quite low (usually < U.S. 50.00 to screen for more than 20 metabolic disorders), and many states in the United States provide the service to newborns during the first week of life. 

FeiUet F, et al. Resting energy expenditure in disorders of propionate metabolism. J Pediatr. 2000 136(5) 659-63. 

Zinc is used for a variety of indications. Zinc acetate (8.102) or, rarely, zinc sulfate (8.103) have been used orally to treat Wilson s disease, a recessively inherited disorder of copper metabolism, characterized by brain and liver dysfunction arising from excessive deposits of copper. Zinc pyrithione (8.104) is used in shampoos to treat seborrhea. Zinc propionate (8.105) and zinc caprylate (8.106) have been used as topical antifungal agents. 

Lenton WA, Gravel RA, Rosenblatt DS (2001) Disorders of propionate and methylmalonic acid metabolism. In Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, 8th edn. McGraw-Hill, New York, NY, pp 2165-2193... 

Unknown compounds are detected frequently, and laboratories eventually develop some level of comfort in recognizing them as artifacts that are not significant clinically, at least for the purpose of ruling out a possible inborn error of metabolism [21]. However, there are instances when an unknown compound is found in multiple specimens from the same patient and cannot be associated with ongoing drug and known dietary intake. This was the set of circumstances that led to the identification of 2-octenylsuccinic acid as the compound referred to by some laboratories as pseudo-orotic acid [11, 18]. On the other hand, the spectrum shown in Fig. 3.1.10, tentatively identified as 4-hydroxy 2-hexenoic acid by GC-MS/MS, belongs to a compound that appears in the urine of patients with disorders of propionate me-... 

In known metabolic states and disorders, the nature of metabolites excreted at abnormal levels has been identified by GC-MS. Examples of this are adipic and suberic acids found in urine from ketotic patients [347], 2-hydroxybutyric acid from patients with lactic acidosis [348], and methylcitric acid (2-hydroxybutan-l,2,3-tricarboxylic acid) [349] in a case of propionic acidemia [350,351]. In the latter instance, the methylcitric acid is thought to be due to the condensation of accumulated propionyl CoA with oxaloacetate [349]. Increased amounts of odd-numbered fatty acids present in the tissues of these patients due to the involvement of the propionyl CoA in fatty acid synthesis, have also been characterised [278]. A deficiency in a-methylacetoacetyl CoA thiolase enzyme in the isoleucine pathway prevents the conversion of a-methylacetoacetyl CoA to propionyl CoA and acetyl CoA [352,353]. The resultant urinary excretion of large amounts of 2-hydroxy-3-methylbutanoic acid (a-methyl-/3-hydroxybutyric acid) and an excess of a-methylacetoacetate and often tiglyl glycine are readily detected and identified by GC-MS. 

Animal and human studies have shown that an elevated concentration of ammonia (hyperammonemia) exerts toxic effects on the central nervous system. There are several causes, both inherited and acquired, of hyperammonemia. The inherited deficiencies of urea cycle enzymes are the major cause of hyperammonemia in infants. The two major inherited disorders are those involving the metabolism of the dibasic amino acids lysine and ornithine and those involving the metabolism of organic acids, such as propionic acid, methylmalonic acid, isovaleric acid, and others (see Chapter 55). 

Inborn errors of metabolism may be due to propionyl-CoA carboxylase deficiency, defects in biotin transport or metabolism, methylmalonyl-CoA mutase deficiency, or defects in adenosylcobalamin synthesis. The former two defects result in propionic acidemia, the latter two in methylmalonic acidemia. All cause metabolic acidosis and developmental retardation. Organic acidemias often exhibit hyperammonemia, mimicking ureagenesis disorders, because they inhibit the formation of N-acetylglutamate, an obligatory cofactor for carbamoyl phosphate synthase (Chapter 17). Some of these disorders can be partly corrected by administration of pharmacological doses of the vitamin involved (Chapter 38). Dietary protein restriction is therapeutically useful (since propionate is primarily derived from amino acids). Propionic and methylmalonyl acidemia (and aciduria) results from vitamin B12 deficiency (e.g., pernicious anemia Chapter 38). 

The answer is b. (Murray, pp 238-249. Scriver, pp 2165-2194. Sack, pp 121—144. Wilson, pp 287—324.) In treating inborn errors of metabolism that present acutely in the newborn period, aggressive fluid and electrolyte therapy and caloric supplementation are important to correct the imbalances caused by the disorder. Calories spare tissue breakdown that can increase toxic metabolites. Since many of the metabolites that build up in inborn errors ol metabolism are toxic to the central nervous system, hemodialysis is recommended for any patient in stage II coma (poor muscle tone, few spontaneous movements, responsive to painful stimuli) or worse. Dietary therapy should minimize substances that cannot be metabolized—in this case fatty acids, since the oxidation of branched-chain fatty acids results in propionate. Antibiotics are frequently useful because meta-bolically compromised children are more susceptible to infection. 

Propionic acidemia (PROP) and methylmalonic acidemia (MMA) are inherited disorders of the metabolism of the propiogenic amino acids valine, isoleucine, threonine, and methionine and odd-chain fatty acids (Figs. 20.1 and 20.2,... 

Unlike many routine clinical chemistry tests, clinical analyses of lEM almost always involve a multiple metabolite analysis. The results form the basis of a metabolic profile in which both individual concentrations of metabolites and their relationship to each other can be viewed either in tabular form or in a graphical display. Perhaps the most comprehensive and historically significant test in lEM studies is gas chromatography/mass spectrometry (GC/MS) of a derivatized extract of urine. Figure 2 is a chromatogram from an infant with propionic acidemia, an organic acid disorder of leucine metabolism. Hundreds of volatile compounds of carbohydrate, amino acid, fatty acid, and nucleic acid metabolism are separated in 40 min using capillary GC. Addition... 

Studies on Congenital Disorders in Propionic Acid Metabolism Using Gas Chromatography and Mass Spectrometry GC-MS News 5(4) 2-3 (1977) CA 88 185472p... 

MacFabe DF, Cain NE, Boon F, Ossenkopp KP, Cain DP. Effects of the enteric bacterial metabolic produd propionic add on object-directed behavior, sodal behavior, cognition, and neuroinflammation in adolescent rats Relevance to autism spectrum disorder. Behav Brain Res. 2011 217 47-54. 

Rollman N and Sjostrom G (1946) The behavior of some propionic acid bacteria strains against NaCl, NaN03, and heating. Svenska Mejerit 38(19) 199-201 (20) 209-212 Romanskaya NN, Diment GS and Vorobjeva LI (1985) Method of production of dairy beverages. Avt svidet No 1184506 Bull No 38 Rosenberg LE (1983) Disorders of propionate, methylmalonate and cobalamin metabolism. 

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