Diversion of Acetyl CoA to 3-Methylglutaconic Acid Caused by Discrete Inborn Errors of Metabolism

Abstract

A growing number of inborn errors of metabolism (IEM) have been identified that manifest 3-methylglutaconic (3MGC) aciduria as a phenotypic feature. In primary 3MGC aciduria, IEM-dependent deficiencies in leucine pathway enzymes prevent catabolism of trans-3MGC CoA. Consequently, this metabolite is converted to 3MGC acid and excreted in urine. In secondary 3MGC aciduria, however, no leucine metabolism pathway enzyme deficiencies exist. These IEMs affect mitochondrial membrane structure, electron transport chain function or ATP synthase subunits. As a result, acetyl CoA oxidation via the TCA cycle slows and acetyl CoA is diverted to trans-3MGC CoA, and then to 3MGC acid. Whereas the trans diastereomer of 3MGC CoA is the only biologically relevant diastereomer, the urine of affected subjects contains both cis- and trans-3MGC acids. Studies have revealed that trans-3MGC CoA is susceptible to isomerization to cis-3MGC CoA. Once formed, cis-3MGC CoA undergoes intramolecular cyclization, forming an anhydride that, upon hydrolysis, yields cis-3MGC acid. Alternatively, cis-3MGC anhydride can acylate protein lysine side chains. Once formed, cis-3MGCylated proteins can be deacylated by the NAD+-dependent enzyme, sirtuin 4. Taken together, the excretion of 3MGC acid in secondary 3MGC aciduria represents a barometer of defective mitochondrial function.

Characterization of trans-3-Methylglutaconyl CoA-Dependent Protein Acylation

“…The results obtained support the concept that trans -3MGC CoA has unique chemical properties. Thus, when metabolic dysfunction occurs as a result of inherited mutations in leucine catabolic enzymes, or genes that affect aerobic respiration [ 1 , 5 ], trans -3MGC CoA is redirected to form an organic acid waste product (3MGC acid) or it acylates substrate proteins. Based on these findings, it is conceivable that characterization of tissue homogenates obtained from animal models or subjects with primary or secondary 3MGC aciduria will reveal the extent and diversity of protein 3MGCylation in these disorders.…”

“…In these enzyme deficiencies, as trans -3MGC CoA accumulates, it is subject to three sequential non-enzymatic chemical reactions, generating the organic acid, cis -3MGC acid ( Figure 2 ), which is excreted in urine (3MGC aciduria). These reactions include: (1) Isomerization of trans -3MGC CoA to cis -3MGC CoA; (2) intramolecular cyclization to cis -3MGC anhydride and free CoA; and (3) hydrolysis of the anhydride to yield cis -3MGC acid [ 1 ]. This reaction sequence provides an explanation for the massive excretion of 3MGC acid in subjects harboring these enzyme deficiencies [ 2 , 3 ].…”

“…When considering the various gene mutations that lead to secondary 3MGC aciduria, a previously unknown metabolic route to trans -3MGC CoA has been proposed. The “acetyl CoA diversion pathway” is initiated by IEMs in genes that participate, directly or indirectly, in aerobic energy metabolism [ 1 ]. In this process, mutations that adversely affect electron transport chain function result in inhibition of the TCA cycle.…”

“…Thus, each leucine molecule yields three acetyl CoAs that can enter the TCA cycle to produce ATP. Interest in the pathway intermediate, trans-3MGC CoA, has increased with the knowledge that inborn errors of metabolism (IEM) which affect AUH, encoded by the AUH gene or HMG CoA lyase (encoded by HMGCL), result in urinary excretion of large quantities of 3MGC acid [1]. In these "primary" 3MGC acidurias, leucine catabolism is blocked due to an inability to either hydrate trans-3MGC CoA (AUH deficiency) or cleave HMG CoA into acetoacetate and acetyl CoA (HMGCL deficiency).…”

Organic Acidemias: Clinical Presentation in Neonates

“…3-MCG has a good prognosis for survival and neurodevelopment. [120][121][122] There are five types of 3-MGA. 12 Type I: A rare AR condition caused by 3-methylglutaconyl-CoA hydratase deficiency.…”