Pyruvic acid metabolic disorders

On the other hand, organic acids are more difficult to measure in the labs. Usually, these are measured by GC or HPLC. However, CE offers speed, precision, and specificity over other methods. Organic acids are important in inborn errors of metabolism, in infection, and different metabolic disorders. Many of these compounds have been measured by CE directly, or by indirect UV absorbency after addition of a UV absorbing compound such as benzoate, naphthalene sulfonate, imidazole, or benzylamine. For example, oxalate and citrate, which are important in stone formation, have been measured after urine dilution by both direct and indirect detections. Lactate, pyruvate, ascorbate, and oxalate were measured by CE in the CSF of patients in 10 min. Methylmalonic acid, which is a sensitive measure of vitamin Bi2 deficiency preceding any clinical symptoms or changes in the serum, has been determined in m-ine by CE after sample extraction and concentration. 

Amino acid changes can be of a secondary nature and a clue to other types of metabolic disorders such as galactosemia, organic acidopathies and pyruvate metabolic disorders. 

The most widely known metabolic disorders are those which result in impairment of the intermediary metabolism of nutrients such as proteins, carbohydrates and lipids. For example, phenylketonuria is due to a genetic deficiency of phenylalanine hydroxylase, an enzyme involved in the conversion of phenylalanine to tyrosine. As a result, when ingested in amounts normally encountered in the diet, phenylalanine accumulates in blood and cerebrospinal fluid along with its pyruvate, lactate and acetate derivatives. (See review by McBean and Stephenson. ) The toxic response takes the form of severe mental retardation, neural and dermal lesions and premature death. But phenylalanine is an essential dietary amino acid and cannot be rigorously excluded from the diet, even of sufferers from phenylketonuria, though fortunately they do respond to reduced dietary intakes. Clearly, phenylalanine hydroxylase deficiency narrows the gap between the required intake and that which elicits a toxic response because this pathway is more readily overloaded . 

Tryptophan is metabolized by several different pathways (Fig. 1) each yielding biologically important substances such as tryptamine and in particular serotonin (5-hydroxytryptamine), which seems to be involved in certain mental disorders. Indole-3-acetic acid is a plant growth hormone its precursor is tryptamine or indole-3-pyruvic acid. In humans, the microorganisms of the large intestine can further degrade indole-3-acetic acid to yield indole, skatole (3-methyl-indole) and other substances. 

With such an extensive knowledge base, what is the present state of our understanding of the mechanisms of this disorder Not unexpectedly, initial studies, primarily in experimental animal models, focused on the known metabolic pathways which involve thiamine. Indeed, the classical studies of Peters in 1930 (Peters, 1969) showed lactate accumulation in the brainstem of thiamine deficient birds with normalization of this in vitro when thiamine was added to the tissue. This led to the concept of the biochemical lesion of the brain in thiamine deficiency. The enzymes which depend on thiamine are shown in Fig. 14.1. They are transketolase, pyruvate and a-ketoglutarate dehydrogenase. Transketolase is involved in the pentose phosphate pathway needed to form nucleic acids and membrane lipids, including myelin. The ketoacid dehydrogenases are key enzymes of the Krebs cycle needed for energy (ATP) synthesis and also to form acetylcholine via Acetyl CoA synthesis. Decrease in activity of this cycle would result in anaerobic metabolism and lead to lactate formation (i.e., tissue acidosis) (Fig. 14.1). 

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