2- Hydroxyisovaleric acid

Mock NI, Malik MI, Stumbo PJ, Bishop WP, and Mock DM (1997) Increased urinary excretion of 3-hydroxyisovaleric acid and decreased urinary excretion of biotin are sensitive early indicators of decreased biotin status in experimental biotin deficiency. American Journal of Clinical Nutrition 65, 951-8. 

Identification of the compounds that gave rise to the significant descriptors has not been conclusively proven. However, close examination of spectra from samples from the various classes using both 600 MHz and 750 MHz H NMR spectroscopy suggested that these were 3-hydroxyisovaleric acid, A -acetylated glycoproteins, TMAO, hippuric acid and a molecule related to A -methylnicotinamide. 

An example of a search for unusual metabolites related to a human disorder is well illustrated with the case of hereditary progressive deafness in a large Norwegian family, studied by Jellum et al. [164]. While no other obvious clinical symptoms were associated with the deafness cases, capillary GC/MS demonstrated the presence of two unusual metabolites, 3-hydroxyisovaleric acid and 3-methylcrotonylglycine. Both compounds appear to be intermediates in the metabolism of leucine, and as Fig. 3.13 demonstrates, a metabolic loading experiment with leucine revealed an enzymatic deficiency in patients with hereditary progressive deafness. 

Fig. 3.13. Organic acid urinary profiles of a patient with hereditary progressive deafness and a control patient both individuals were administered orally 20 g of leucine. 3-HIVA, 3-hydroxyisovaleric acid 3-MCG, 3-methyl-crotonylglycine. Reproduced from [164].

Fig. 3.22. GC separation of keto and hydroxy acids from the urine of a patient with maple syrup urine disease. Top chromatogram, the patient before dietary treatment middle chromatogram, the same patient after two days on a diet bottom chromatogram, a mixture of reference compounds. Peaks 1, lactic acid 2, 2-hydroxyisobutyric acid 3, 2-hydroxybutyric acid 4, pyruvic acid 5, 3-hydroxyisobutyric acid 6, 3-hydroxybutyric acid 7, 2-hydroxyisovaleric acid 8, 2-ketobutyric acid 9, malonic acid (internal standard) 10, 2-methyl-3-hydroxybutyric acid 11, 2-hydroxy-n-valeric acid 12. methylmalonic acid 13, 3-hydroxyisovaleric acid 14a and b, 2-ketoisovaleric acid IS, acetoacetic add 16, 2-hydroxyisocaproic acid 17, 2-hydroxy-3-methylvaleric acid 18a, L-2-keto-3-methylvaleric add 18b, D-2-keto-3-methyl-valeric acid 19, 2-ketoisocaproic acid. Reproduced from [386],...

IVA was initially described in 1966 and became the first organic acidemia described. IVA is caused by a deficiency of the enzyme isovaleryl-CoA dehydrogenase, an enzyme important in leucine catabolism and also important in the transfer of electrons to the respiratory chain [7, 13]. The consequent accumulating metabolites include isovaleric add, isovalerylglydne, 3-hydroxyisovaleric acid, and isovalerylcamitine (C5) [7, 13] (Fig. 17.3). These are easily identified on urine organic acid analysis and acylcamitine profile. The excretion of isovalerylglydne and 3-hydroxyisovaleric acid is diagnostic. 

The anticonvulsants primidone and carbamazepine inhibit biotin uptake into brush-border membrane vesicles from human intestine (Zempleni et al. 2009). Long-term therapy with anticonvulsants increases both biotin catabolism and urinary excretion of 3-hydroxyisovaleric acid. These eifects might be due to displacement of biotin from biotinidase by anticonvulsants, thereby aifecting plasma transport, renal handling or cellular uptake of biotin. 

Reduced activities of carboxylase enzymes can cause a metabolic block of certain substrates and a use of alternative pathways for catabolism. Therefore, 3-hydroxyisovaleric acid and 3-methylcrotonyl glycine are formed consequently to a shunt of 3-methylcrotonyl carboxylase counterbalancing its activity decrease. Marginal biotin deficiency experimentally induced by 20 days of free biotin diets in human increased 3-hydroxyisovaleric acid excretion in urine above the upper limit of normal. The normal urinary excretion of 3-hydroxyisovaleric acid in healthy adults is 112 38 pmol per 24 hours (Mock et al. 1997). This suggests that 3-hydroxyisovaleric acid urinary excretion is a good indicator of marginal biotin deficiency. 

Cat urine 3-Hydroxyisovaleric acid 3-Methylcrotonylglycinuria Multiple carboxylase deficiency... 

Mock DM, Henrich CL, Camell N, Mock Nf. Indicators of marginal biotin deficiency and repletion in humans validation of 3-hydroxyisovaleric acid excretion and a leucine challenge. Am J Clin Nutr 2002 76 1061—1068. 

MHz H NMR spectroscopy suggested that these were 3-hydroxyisovaleric acid, N-acetylated glycoproteins, TMAO, hippuric acid and a molecule related to N-methylnicotinamide. 

Odd-chain fatty acid accumulation is also a marker of biotin deficiency. The accumulation of odd-chain fatty acid is thought to result from PCC deficiency (Figure 3) the accumulation of propionyl-CoA likely leads to the substitution of a propionyl-CoA moiety for acetyl-CoA in the ACC reaction and to the incorporation of a three- (rather than two-) carbon moiety during fatty acid elongation. However, in comparison to lymphocyte PCC activity and urinary excretion of 3-hydroxyisovaleric acid, odd-chain fatty acids accumulate in blood lipids more slowly during biotin deficiency and return to normal more gradually after biotin repletion. 

Landaas, S. (1974), Increased urinary excretion of 3-hydroxyisovaleric acid in patients with ketoacidosis. Clin. Chim. Actay 54,39. 

Possible errors due to the methods used have been referred to in the sections of Part I and include the dehydration of hydroxy acids, for example 3-methyl-crotonic acid from 3-hydroxyisovaleric acid, crotonic acid from 3-hydroxy-butyric acid, either on acid steam distillation or alkaline treatment, decarboxylation of 2-oxo acids, for example phenylpyruvic acid to phenylacetic acid (Thompson et al., 1975b) and similar effects with branched-chain oxo acids, during sample preparation, particularly by solvent extraction. Derivatization artefacts produced during methylation have been detailed in Part I, and decarboxylation of free non-volatile acids during the analysis of volatile acids, for example, methylmalonic acid to propionic acid, are also detailed elsewhere. 

Isovaleric acidaemia Isovaleric and 3-hydroxyisovaleric acids and isovalerylglycine Isovaleryl-CoA dehydrogenase 10.3.1... 

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