Propionic acid deficiency

Reducing the availability of GABA by blocking the synthesising enzyme GAD also promotes convulsions. This may be achieved by substrate competition (e.g. 3-mercapto propionic acid), irreversible inhibition (e.g. allylglycine) or reducing the action or availability of its co-factor pyridoxal phosphate (e.g. various hydrazides such as semi-carbazide). In fact pyridoxal phosphate deficiency has been shown to be the cause of convulsions in children. 

Valine, methionine, isoleucine, and threonine are all metabolized through the propionic acid pathway (also used for odd-carbon fatty acids). Defidency of either enzyme results in neonatal ketoacidosis from failure to metabolize ketoacids produced from these four amino adds. The defidendes may be distinguished based on whether meth)dmalonic adduria is present. A diet low in protein or a semisynthetic diet with low amounts of valine, methionine, isoleudne, and threonine is used to treat both deficiencies. 

Breakdown of isoleucine, valine, threonine, and methionine results in the production of propionyl-CoA. Propionyl-CoA, in turn, is catabolized to succinyl-CoA via the intermediate methylmalonyl-CoA. Methylmalonyl-CoA is a compoimd of imusual interest to nutritional scientists. This compound accumulates in the cell during a vitamin B12 deficiency. Vitamin B12 deficiency is not a rare disease, as it appears in a common autoimmune disease called pernicious anemia. Vitamin B12 deficiency also occurs in strict vegetarians who avoid meat, fish, poultry, and dairy products. Methylmalonyl-CoA can also build up with rare genetic diseases that involve the production of defective, mutant forms of methylmalonyl-CoAmutase. Most of the methylmalonyl-CoAthat accumulates to abnormally high levels in the cell is hydrolyzed to methylmalonic acid (MMA), which leaves the cell for the bloodstream and eventual excretion in the urine. Some of the MMA is converted back to propionyl-CoA, resulting in the production and accumulation of propionic acid in the cell. The measurement of plasma and urinary MMA has proven to be a method of choice for the diagnosis of vitamin B12 deficiency, whether induced by pernicious anemia or by dietary deficiency. 

The buildup of methylmalonyl-CoA in the cell may lead to reversal of the reaction of propionyl-CoA carboxylase and, as a consequence, an increase in the levels of propionyl-CoA. Increased levels of propionyl-CoA can lead to its use, in place of acetyl-CoA, by fatty acid sjmthase. Use of the 3-carbon propionyl group, rather than the 2-carbon acetyl group, by this enzyme can result in the production of small amoimts of odd-chain fatty acids. These fatty acids contain an odd number of carbons, that is, 15,17, or 19 carbons. The addition of large amounts of propionic acid to the diet during B12 deficiency can be used to artificially enhance the production of odd-chain fatty acids. 

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). 

The answer is d. (Murray, pp 238-249. Scriver, pp 2165-2194. Sack, pp 121-144. Wilson, pp 287-324.) Propionic acidemia (232000) results from a block in propionyl CoA carboxylase (PCC), which converts propionic to methylmalonic acid. Excess propionic acid in the blood produces metabolic acidosis with a decreased bicarbonate and increased anion gap (the serum cations sodium plus potassium minus the serum anions chloride plus bicarbonate). The usual values of sodium (-HO meq/L) plus potassium ( 4 meq/T) minus those for chloride (-105 meq/L) plus bicarbonate (—20 meq/L) thus yield a normal anion gap of -20 meq/L. A low bicarbonate of 6 to 8 meq/L yields an elevated gap of 32 to 34 meq/L, a gap of negative charge that is supplied by the hidden anion (propionate in propionic acidemia). Biotin is a cofactor for PCC and its deficiency causes some types of propionic acidemia. Vitamin B deficiency can cause methylmalonic aciduria because vitamin Bn is a cofactor for methylmalonyl coenzyme A mutase. Glycine is secondarily elevated in propionic acidemia, but no defect of glycine catabolism is present. 

Propionic acid accumulation from amino acid degradation would result from a deficiency of which of the following vitamins ... 

This reaction has been modified by Alder and Longo by heating the mixture of pyrrole and aldehyde in propionic acid at 4 °C while open to air to give unhindered porphyrin derivatives. However, such modification often causes problems such as the formation of a high level of tar material that complicates the purification process, the incompatibility with certain functional groups on aldehydes, and the low batch-to-batch reproducibility. On the other hand, Lindsey has carried out the reaction in the presence of a catalytic amount of BF3 or TFA under equilibrium conditions, followed by oxidation with an electron-deficient quinone, such as DDQ. " In addition, this reaction has been extended to the preparation of corrole by the application of an excess amount of pyrrole. ... 

In propionic and methylmalonic aciduria, metronidazole, given orally, inhibits the production of propionic acid by gut bacteria. In isovaleric aciduria and methylcrotonyl-CoA carboxylase deficiency, glycine accompanied by carnitine supplementation inCTeases the elimination of toxic metabolites. In many severe conditions, empiric administration of substances that act as cofactors proves to be helpful, and this treatment option should not be neglected (Table 5.3) [19]. 

Pantothenic acid 3-(2, 4 -dihydroxy-3, 3 -dimethylbu-tyramido) propionic acid is a precursor of coenzyme A. It is a vitamin, and if pantothenic acid is synthesized at all by mammalian organisms, the amount synthesized in most animals is too small for adequate metabolic performance. Pantothenic acid is abundant in the diet, especially in egg yolk, fresh vegetables, and meats. The vitamin survives most methods of cooking and food storage. For these reasons, pantothenic acid deficiency is unknown in man. 

The metabolic pathway for propionic acid use in mammals involves the carboxylation of propionyl CoA in the presence of a specific carboxylase and ATP. The products of the reaction are methylmalonyl CoA and ADP. The ultimate product of propionate metabolism is succinate, which is oxidized via the Krebs cycle. These reactions all occur in the mitochondria. The ability of the mitochondria of biotin-deficient animals to use propionic acid is reduced. This metabolic defect of the deficient mitochondria cannot be corrected by adding biotin in vitro, but the rate of propionic acid use by mitochondria is restored to normal if the deficient animals are fed a normal diet containing biotin. 

Rapid Gas Chromatographic Method for the Quantitation of Volatile Fatty Acids in Urine. Propionic Acid Excretion in Vitamin B] 2 Deficiency J. Chromatogr. 81(1) 65-69 (1973) ... 

The reduced DNA synthesis observed in vitamin Bn-deficient cells is not only due to the low RNR activity responsible for the synthesis of deoxyribo-nucleotide triphosphates. It is known (Andreeva, 1974) that CHsCbl is involved in the synthesis of the thymine intermediate of DNA. In vitamin Bi2-deflcient cells the DNA content increased upon adding thymine to the medium, which had no effect in the case of Bn -cells (Fig. 5.9, Table 5.3) (Iordan et al, 1979a). It follows, then, that the DNA of propionic acid bacteria is linked with Bi2-coenzymes in two ways through the synthesis of deoxyribosides and through the synthesis of thymine. In addition, we suggest that there is a third type of this connection, mediated by DNA methylation. 

Let us consider other natural habitats of propionic acid bacteria. In grasses used as fodder for livestock the content of cobalt is often below a certain limit (0.08 ppm), so that if cobaltous salts are not added to feeds, animals will suffer from cobalamin deficiency. Animals are supplied with corrinoids mainly through the biosynthetic activity of bacteria. If 1 mg of cobalt a day is added to the feed, then the content of cobalamins in the dry residue of lignin matter in rumen is 0.59 to 1.0 jag/g. When no cobalt is added, the content of cobalamins is lowered by an order of magnitude, to 0.081-0.108 ig/g (Smith and Marston, 1970) correspondingly, the content of vitamin in all animal tissues and fluids is low. Therefore, the concentration of vitamin in meat, milk and other products obtained from the animal will depend on the content of cobalt in the feed. 

Other natural habitats of propionic acid bacteria are represented by cheese and silage. If one recalls that there are at least 10 bacterial cells in 1 g of cheese, then it becomes clear that bacteria lead a cobalamin-deficient existence. The same is true of bacteria that live in silage, where the cobalamin content is about 0.1 to 2.0 xg per 100 g (Smith and Marston, 1970). In the rumen of ruminants, where cobalt is limited, the cobalamin content is in the range of 0.14-0.41 ng/ml (Dryden et al., 1962). It is clear that these bacteria live at a very low cobalamin level. Therefore, the conclusion is obvious—most propionic acid bacteria lead a vitamin B -deficient mode of life in nature, although they can readily attain high levels of corrinoids under favorable conditions. 

By adding propionic acid bacteria to leavens bread can be enriched in vitamin B this is especially important for vegetarians and persons suffering from various diseases arising from vitamin B deficiency (see above). Vitamin Bn content in bacterial cells is regulated by the availability of cobaltous salts in the medium (see Chapter 5). Hence, tiie vitamin Bn content of bread can be modified by using an appropriate leaven. 

All the library building blocks in this study are commercially available, with the exception of the diamino propionic acid Dp. This amino acid introduces an electron deficient aromatic ring that is absent from natural amino acids, and its Fmoc-protected form (the one needed for library synthesis) was prepared from commercially available A -benzyloxycarbonyl-L-asparagine (Fig. 3). 

Of these only the methylmalonyl-CoA mutase (E.C. 5.4.99.2) reaction takes place in mammalian metabolism and forms the link between the metabolism of odd-chain fatty acids, cholesterol, isoleucine, valine, threonine, methionine, and propionic acid on the one hand, and the tricarboxylic acid cycle through succinyl-CoA on the other (Fig. 5). The reaction is of special importance for ruminants in which propionate, arising from cellulose degradation, forms a major source of energy. The enzyme involved is located in the mitochondria and is composed of two nonidentical subunits, one of which binds adenosylcobalamin. A deficiency of adenosylcobalamin or the apoenzyme results in the accumulation of methylmalonic acid, which is secreted by the kidneys and gives rise to methylmalonic aciduria (42). 

Methylmalonic acid (MMA) is a metabolic intermediate in the biosynthesis of succinic acid from propionic acid, a step that involves the enzyme Methylmalonyl Coenzyme A mutase and a vitamin B12-derived cofactor. MMA concentrations increase when vitamin B12 is deficient hence, MMA can be used as a clinical biomarker of vitamin B12 status. In addition, mutations in the genes encoding the enzyme responsible for MMA metabolism or the enzymes responsible for vitamin B12 metabolism can lead to heritable disorders, known as methylmalonic acidemias. 

A compound which can be found in the urine of patients witl vitamin B,2 deficiency and in the very rare inborn error o metabolism, methylmalonic aciduria. It is an intermediate in th< metabolism of propionic acid (itself a metabolite of certaii amino acids, particularly valine and isoleucine). Vitamin B 2 is i cofactor in the enzymic step by which methylmalonyl coenzym A is converted to succinyl coenzyme A. In vitamin B,2 deficienc methylmalonate accumulates and passes out into the urine. It measurement in urine can therefore be used to diagnose deficier cy of this vitamin. It can be estimated colorimetrically by il reaction with diazotized p-nitroaniline to form a green con pound. 

Thiamin was first implicated in bacterial growth by Tatum, Wood, and Peterson (381) who observed that it had a marked growth-promoting effect on certain strains of propionic acid bacteria when added to a deficient basal medium. Not all the strains of propionic acid bacteria used required to be given thiamin some strains grew and fermented well on the basal medium alone still others did not respond to the addition of thiamin alone and evidently required an additional growth factor. 

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