Dicarboxylic acid/aciduria

Nevertheless, malonyl-CoA is a major metabolite. It is an intermediate in fatty acid synthesis (see Fig. 17-12) and is formed in the peroxisomal P oxidation of odd chain-length dicarboxylic acids.703 Excess malonyl-CoA is decarboxylated in peroxisomes, and lack of the decarboxylase enzyme in mammals causes the lethal malonic aciduria.703 Some propionyl-CoA may also be metabolized by this pathway. The modified P oxidation sequence indicated on the left side of Fig. 17-3 is used in green plants and in many microorganisms. 3-Hydroxypropionyl-CoA is hydrolyzed to free P-hydroxypropionate, which is then oxidized to malonic semialdehyde and converted to acetyl-CoA by reactions that have not been completely described. Another possible pathway of propionate metabolism is the direct conversion to pyruvate via a oxidation into lactate, a mechanism that may be employed by some bacteria. Another route to lactate is through addition of water to acrylyl-CoA, the product of step a of Fig. 17-3. Tire water molecule adds in the "wrong way," the OH ion going to the a carbon instead of the P (Eq. 17-8). An enzyme with an active site similar to that of histidine ammonia-lyase (Eq. 14-48) could... 

Yoshida, H. Araki, J. Sonoda, J. Nobta, H. Ishida, J. Hirose, S. Yamaguchi, M. Screening method for organic aciduria by spectrofluorometric measurement of total dicarboxylic acids in human urine based on intramolecular excimer-forming fluorescence derivatization. Anal. Chim. Acta 2005,534,177-183. 

Tsemg KY, Jin SJ, Kerr DS, Hoppel CL. Urinary 3-hydroxydicarboxylic acids in pathophysiology of metabolic disorders with dicarboxylic aciduria. Metab Clin Exp. 1991 40(7) 676-82. 

Carnitine acylcarnitine carrier deficiency (CAC, 14.3) has two forms, i.e. a severe form with a high incidence of sudden childhood death and a mild form. Both cardiomyopathic acid hepatopathic features occur. All patients have a very low plasma free carnitine and increased Cig-Cis acylcarnitines [4]. A subtle dicarboxylic aciduria may be present. A number of patients initially presented with coma and marked hyperammonemia. 

Three forms of VLCAD deficiency (14.5) are known, i.e. a (lethal) neonatal cardiomyopathic form, a childhood form with recurrent Reye-like episodes, and an adolescent/adult muscular form [6]. The latter may be accompanied by severe rhabdomyolysis and sometimes renal failure. Diagnostic criteria are the abnormal plasma acylcarnitine and organic acid profile (Ci4 i, Ci4 2 and Ci6 i) and the Cg-Cio dicarboxylic aciduria, especially in young patients. 

Genetically normal human subjects have not yet been shown to accumulate these abnormal urinary products but, in contrast, humans who bear an abnormal gene resulting in dicarboxylic aciduria do quite frequently respond to riboflavin supplements, showing a reduction in their excretion of abnormal fatty acid... 

Table 14.6 Concentrations of urinary organic acids (extracted by DEAE-Sephadex) in twin English siblings with non-ketotic dicarboxylic aciduria (after Chalmers et al, 1980). 

Chalmers, R. A. and Lawson, A.M. (1979), Identification of 5-hydroxyhexanoic acid in the urine of twin siblings with a Reye s-like syndrome associated with dicarboxylic aciduria and hypoglycaemia and with similarities to Jamaican Vomiting Sickness. Biomed. Mass Spectrom., 6,444. 

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