3-methylglutaric acid is an organic acid classically associated with two distinct leucine pathway enzyme deficiencies.
3-methylglutaric acid is excreted in urine of individuals harboring deficiencies in 3-hydroxy-3-methylglutaryl (HMG) CoA lyase (HMGCL) or 3-methylglutaconyl CoA hydratase (AUH). Whereas 3MG CoA is not part of the leucine catabolic pathway, it is likely formed via a side reaction involving reduction of the α-ß trans double bond in the leucine pathway intermediate, 3-methylglutaconyl CoA. While the metabolic basis for the accumulation of 3MG acid in subjects with deficiencies in HMGCL or AUH is apparent, the occurrence of 3MG aciduria in a host of unrelated inborn errors of metabolism associated with compromised mitochondrial energy metabolism is less clear. Herein, a novel mitochondrial biosynthetic pathway termed "the acetyl CoA diversion pathway", provides an explanation. The pathway is initiated by defective electron transport chain function which, ultimately, inhibits acetyl CoA entry into the TCA cycle. When this occurs, 3MG acid is synthesized in five steps from acetyl CoA via a novel reaction sequence, providing a metabolic rationale for the connection between 3MG aciduria and compromised mitochondrial energy metabolism.
References:
Jones DE, Perez L, Ryan RO. 3-Methylglutaric acid in energy metabolism. Clin Chim Acta. 2020 Mar;502:233-239. doi: 10.1016/j.cca.2019.11.006. Epub 2019 Nov 12. PMID: 31730811; PMCID: PMC6994337.
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Signi ficant increase is due to a reduced ability to metabolize the amino acid leucine.
This abnormality is found in the genetic disease methylglutaconic aciduria and in mitochondrial disorders.
Possible treatment options:
Supplementation with the following may be useful:
- coenzyme Q10,
- niacin,
- L-carnitine and acetyl-L-carnitine,
- riboflavin,
- nicotinamide,
- biotin,
- and vitamin E
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I have been using Healthmatters.io since 2021. I travel all over the world and use different doctors and health facilities. This site has allowed me to consolidate all my various test results over 14 years in one place. And every doctor that I show this to has been impressed. Because with any health professional I talk to, I can pull up historical results in seconds. It is invaluable. Even going back to the same doctor, they usually do not have the historical results from their facility in a graph format. That has been very helpful.
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