Adipic acid deficiency

In animals, the production of CO2 from [ Cjpalmitate or octanoate is not consistendy affected by riboflavin deficiency, possibly as a result of increased activity of carnitine palmitoyl transferase, which is more a response to food deprivation than to riboflavin deficiency. However, the production of C02 from [ C] adipic acid is significandy reduced, and responds rapidly (with some overshoot) to repletion with the vitamin. It has been suggested that the abiUty to metabolize a test dose of [ Cjadipic acid may provide a sensitive means of investigating ribodavin nutritional status in human beings (Bates, 1989, 1990). 

Bates CJ (1989) Metabolism of [ C] adipic acid in riboflavin-deficient rats a test in vivo for fatty acid oxidation./owma/ of Nutrition 119, 887-91. 

Experiments made on pyridoxal-deficient animals suggested that pyridoxal phosphate and iron are required for the biosynthesis of porphyrin. It was later established that pyridoxal phosphate is required for the formation of -amino levulinic acid, probably by participating in the formation of active glycine. The condensation of succinate and glycine leads to the formation of a very labile a-amino-j -keto adipic acid. The participation of a-amino-jS-keto adipic acid as an intermediate in the reaction was established in experiments proving the acid to be an efficient precursor of porphyrin biosynthesis in vitro. An enzyme system capable of catalyzing the succinyl CoA-glycine condensation and the decarboxylation of the intermediate to yield amino levulinic acid has also been obtained from a particular fraction of chicken erythrocyte. In liver, an enzyme has been found in the mitochondria [132]. 

The polyhydroxy components of urethane sealants are mostly hydroxyl-terminated saturated polyesters or poly ethers. Most polyesters used in urethane sealants have been standard condensation products of dibasic acids (such as adipic acid or phthalic anhydride) with glycols and triols (such as propylene glycol, glycerin, or trimethylol propane). Polyester-based urethane sealants are hard and tough, have relatively good adhesion in joints, but are deficient in hydrolytic stability and exterior durability. 

A sixth case, occurring in a 15-year-old boy, was reported by Halvorsen etal. (1979). Their patient, who was the second son of unrelated parents, had a history of coma and/or acidosis with ketonuria between 1 and 4 years of age, developing later in childhood episodes headaches, but with normal physical and mental development to 15 years of age. Large quantitities of 3-hydroxy-butyrate, 2-methyl-3-hydroxybutyrate and tiglylglycine were found in his urine together with increased amounts of adipic acid. No methylacetoacetate or acetoacetate were observed. A probable partial deficiency of )8-ketothiolase was postulated. 

One of the most frequent defects of fatty acid oxidation is deficiency of a mitochondrial acyl-CoA dehydrogenase.50 If the long-chain-specific enzyme is lacking, the rate of P oxidation of such substrates as octanoate is much less than normal and afflicted individuals excrete in their urine hexanedioic (adipic), octanedioic, and decanedioic acids, all products of co oxidation.54 Much more common is the lack of the mitochondrial medium-chain acyl-CoA dehydrogenase. Again, dicarboxylic acids, which are presumably generated by 0) oxidation in the peroxisomes, are present in blood and urine. Patients must avoid fasting and may benefit from extra carnitine. 

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. 

Wallace Carothers shelved his aliphatic polyesters because of their low softening points. However, R.T. Winfield and J.T. Dickson were able to overcome this deficiency by using an aromatic dicarboagrlic acid (terephthalic acid) instead of the aliphatic adipic add. 

This chapter describes the case reports of these enzyme deficiencies and the underlying biochemistry of the disorders and their associations. It is not the intention to discuss keto acidosis associated with other diseases, for example juvenile diabetes, or ketogenesis and its control which are reviewed elsewhere (Wildenhoff, 1975, 1977 McGarry and Foster, 1976 Halperin, 1977). In addition to the common occurrence of 3-hydroxybutyrate and acetoacetate in body fluids of patients with keto acidosis, secondary organic acids have been observed in urine, including adipic and suberic acids (Pettersen et aL, 1972), 3-hydroxyisovaleric acid (Landaas, 1974), 3-hydroxyisobutyric acid and 2-methyl-3-hydroxybutyric acid (Landaas, 1975). The dicarboxylic acids occur as a result of initial co-oxidation of accumulating long-chain fatty acids followed by )8-oxidation (Pettersen, 1972), and metabolites of the branched-chain amino acids occur because of inhibition of their metabolic pathways by 3-hydroxybutyrate and acetoacetate (Landaas and Jakobs, 1977). 

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