3-Hydroxyisovaleric Acid (3-HIA) is formed from the metabolism of the branched-chain amino acid leucine. Methylcrotonyl-CoA carboxylase catalyzes an essential step in this pathway and is biotin dependent. Reduced activity of this enzyme leads to an alternate pathway of metabolism resulting in 3-hydroxyisovaleric acid. 3-Hydroxyisovaleric Acid (3-HIA) is formed from the metabolism of the branched-chain amino acid leucine. Methylcrotonyl-CoA carboxylase catalyzes an essential step in this pathway and is biotin dependent. Reduced activity of this enzyme leads to an alternate pathway of metabolism resulting in 3-hydroxyisovaleric acid.
The urinary excretion of 3-HIA has been shown to be an early and sensitive indicator for marginal biotin deficiency. Elevated levels of 3-HIA in pregnant women reflect reduced or marginal biotin status. Smoking and anticonvulsant medication can also increase this metabolite as a reflection of accelerated biotin metabolism and therefore marginal deficiency.
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Biotin deficiencies, certain lifestyle habits (smoking), or specific genetic conditions can reduce methylcrotonyl-CoA carboxylase activity. This reduction can lead to a buildup of 3-methylcrotonyl-CoA, which is converted into 3-hydroxyisovaleryl-CoA by the enzyme enoyl-CoA hydratase. Increased concentrations of 3-methylcrotonyl-CoA and 3-hydroxyisovaleryl-CoA can lead to a disruption of the esterified CoA:free CoA ratio, and ultimately to mitochondrial toxicity. Detoxification of these metabolic end products occur via the transfer of the 3-hydroxyisovaleryl moiety to carnitine forming 3-hydroxyisovaleric acid-carnitine or 3HIA-carnitine, which is then transferred across the inner mitochondrial membrane where 3-hydroxyisovaleric acid is released as the free acid.
3-Hydroxyisovaleric acid has been found to be elevated in smokers and in subjects undergoing long-term anticonvulsant therapy with carbamazepine and/or phenytoin. These levels are elevated due to impairment of renal reclamation of biotin. Levels may also be increased from prolonged consumption of raw egg-whites. When present in sufficiently high levels, 3-hydroxyisovaleric acid can act as an acidogen and a metabotoxin. An acidogen is an acidic compound that induces acidosis, which has multiple adverse effects on many organ systems. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels.
Chronically high levels of 3-hydroxyisovaleric acid are associated with at least a dozen inborn errors of metabolism, including 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, 3-methylglutaconic aciduria type I, biotinidase deficiency and isovaleric aciduria, dihydrolipoamide dehydrogenase deficiency, 3-methylcrotonyl-CoA carboxylase 1 deficiency, 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, late-onset multiple carboxylase deficiency, holocarboxylase synthetase deficiency, and 3-methylcrotonyl-CoA carboxylase 2 deficiency.
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2-Hydroxyphenylacetic Acid, 3-Hydroxyisovaleric Acid, 3-Hydroxyphenylacetic Acid, 3-Hydroxypropionic Acid, 3-Methyl-4-OH-phenylglycol, 4-Hydroxyphenylacetic Acid, 5-OH-indoleacetic Acid, a-Hydroxyisobutyric Acid (from MTBE), a-Keto-b-Methylvaleric Acid, a-Ketoadipic Acid, a-Ketoglutaric Acid (AKG), a-Ketoisocaproic Acid, a-Ketoisovaleric Acid, a-Ketophenylacetic Acid (from Styrene), Adipic Acid, Arabinose, B-OH-B-Methylglutaric Acid (HMG), Benzoic Acid, Beta-OH-Butyric Acid (BHBA), Cis-Aconitic Acid, Citramalic Acid, Citric Acid, Dihydroxyphenylpropionic Acid (DHPPA), Formiminoglutamic Acid (FIGlu), Glutaric Acid, Hippuric Acid, Homogentisic Acid, Homovanillic Acid, Indoleacetic Acid (IAA), Isocitric Acid, Isovalerylglycine, Kynurenic / Quinolinic Ratio, Kynurenic Acid, Lactic Acid, Malic Acid, Methylmalonic Acid, Orotic Acid, Phenylacetic Acid (PAA), Pyroglutamic Acid, Pyruvic Acid, Quinolinic Acid, Suberic Acid, Succinic Acid, Tartaric Acid, Vanilmandelic Acid, Xanthurenic Acid