title: Metabolic biology of 3-methylglutaconic acid-uria: a new perspective.
abstract: Over the past 25 years a growing number of distinct syndromes/mutations associated with compromised mitochondrial function have been identified that share a common feature: urinary excretion of 3-methylglutaconic acid (3MGA). In the leucine degradation pathway, carboxylation of 3-methylcrotonyl CoA leads to formation of 3-methylglutaconyl CoA while 3-methylglutaconyl CoA hydratase converts this metabolite to 3-hydroxy-3-methylglutaryl CoA (HMG CoA). In "primary" 3MGA-uria, mutations in the hydratase are directly responsible for the accumulation of 3MGA. On the other hand, in all "secondary" 3MGA-urias, 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-associated 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-specific metabolic conditions, 3-methylglutaconyl CoA hydratase converts HMG CoA into 3-methylglutaconyl 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-methylcrotonyl CoA carboxylase. Instead, hydrolysis of the CoA moiety of 3-methylglutaconyl 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.
authors.affiliation: Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA, 94609, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Su
authors.forename: Robert O
authors.initials: RO
authors.lastname: Ryan
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D002308:Cardiolipins / Q000737:chemistry; D002819:Chorea / Q000378:metabolism; D002952:Citric Acid Cycle; D005977:Glutarates / Q000652:urine*; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009896:Optic Atrophy / Q000378:metabolism; D010715:Phosphatidylglycerols / Q000378:metabolism; D019082:Smith-Lemli-Opitz Syndrome / Q000378:metabolism; D015419:Spastic Paraplegia, Hereditary / Q000378:metabolism; D013729:Terpenes / Q000378:metabolism
chemical_list: D000214:Acyl Coenzyme A; D002308:Cardiolipins; D005977:Glutarates; D024101:Mitochondrial Proteins; D010715:Phosphatidylglycerols; D013729:Terpenes; C010667:acetoacetyl CoA; C022034:3-methylglutaconic acid; D000105:Acetyl Coenzyme A