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In the leucine degradation pathway, carboxylation of 3\u2010methylcrotonyl CoA leads to formation of 3\u2010methylglutaconyl CoA while 3\u2010methylglutaconyl CoA hydratase converts this metabolite to 3\u2010hydroxy\u20103\u2010methylglutaryl CoA (HMG CoA). In \u201cprimary\u201d 3MGA\u2010uria, mutations in the hydratase are directly responsible for the accumulation of 3MGA. On the other hand, in all \u201csecondary\u201d 3MGA\u2010urias, no defect in leucine catabolism exists and the metabolic origin of 3MGA is unknown. Herein, a path to 3MGA from mitochondrial acetyl CoA is proposed. The pathway is initiated when syndrome\u2010associated mutations\/DNA deletions result in decreased Krebs cycle flux. When this occurs, acetoacetyl CoA thiolase condenses two acetyl CoA into acetoacetyl CoA plus CoASH. Subsequently, HMG CoA synthase 2 converts acetoacetyl CoA and acetyl CoA to HMG CoA. Under syndrome\u2010specific metabolic conditions, 3\u2010methylglutaconyl CoA hydratase converts HMG CoA into 3\u2010methylglutaconyl CoA in a reverse reaction of the leucine degradation pathway. This metabolite fails to proceed further up the leucine degradation pathway owing to the kinetic properties of 3\u2010methylcrotonyl CoA carboxylase. Instead, hydrolysis of the CoA moiety of 3\u2010methylglutaconyl CoA generates 3MGA, which appears in urine. If experimentally confirmed, this pathway provides an explanation for the occurrence of 3MGA in multiple disorders associated with compromised mitochondrial function.<\/jats:p>","DOI":"10.1007\/s10545-013-9669-0","type":"journal-article","created":{"date-parts":[[2014,1,9]],"date-time":"2014-01-09T13:30:57Z","timestamp":1389274257000},"page":"359-368","source":"Crossref","is-referenced-by-count":34,"title":["Metabolic biology of 3\u2010methylglutaconic acid\u2010uria: a new perspective"],"prefix":"10.1002","volume":"37","author":[{"given":"Betty","family":"Su","sequence":"first","affiliation":[{"name":"Children's Hospital Oakland Research Institute 5700 Martin Luther King Jr. Way Oakland CA 94609 USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert O.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Children's Hospital Oakland Research Institute 5700 Martin Luther King Jr. Way Oakland CA 94609 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