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ABSTRACT Extract: 2-Methylcitrate was tested _in vitro_ on enzymes which interact with citrate and isocitrate. It was found to inhibit citrate synthase, aconitase, the NAD+- and NADP+-linked

isocitrate dehydrogenase. This inhibition was competitive in nature except in the case of aconitase, and the Ki for all the enzymes was in the range of 1.5-7.6 mM. Phosphofructokinase was

also inhibited by 2-methylcitrate with 50% inhibition achieved at 1 mM. ATP-citrate lyase and acetyl-CoA carboxylase were not inhibited by this compound. 2-Methylcitrate was not a substrate

for ATP-citrate lyase. Acetyl-CoA carboxylase was activated by 2-methylcitrate with a Ka of 2.8 mM. The apparent Km (3.3 mM) for 2-methylcitrate for the mitochondrial citrate transporter was

about 10-fold higher than the apparent Km (0.26 mM) for citrate. The tricarboxylate carrier can also be inhibited by low concentrations (0.2 mM) of 2-methylcitrate when the concentration of

citrate is close to the apparent Km. Accumulation of 2-methylcitrate inside the mitochondrion, therefore, might lead to inhibition of enzymes in the citric acid cycle and thereby contribute

to the ketogenesis and hypoglycemia seen under these conditions. Speculation: Treatment of patients with propionic aciduria and methylmalonic aciduria with alkali therapy would be

advantageous with respect to the acidemia but also would cause a more rapid exit of 2-methylcitrate from the mitochondrion. Alkalinization with sodium citrate might be even more beneficial

if this citrate could enter the liver and allow more rapid removal of 2-methylcitrate and methylmalonate from liver mitochondria since increased cytosolic levels of these intermediates would

facilitate more rapid diffusion to the extracellular space and eventual excretion in the urine. This therapy does not exclude the low protein diet and for the vitamin-responsive form of

methylmalonic aciduria, B12 treatment. SIMILAR CONTENT BEING VIEWED BY OTHERS ASSOCIATION OF THE MALATE DEHYDROGENASE-CITRATE SYNTHASE METABOLON IS MODULATED BY INTERMEDIATES OF THE KREBS

TRICARBOXYLIC ACID CYCLE Article Open access 21 September 2021 ALLOSTERIC ROLE OF THE CITRATE SYNTHASE HOMOLOGY DOMAIN OF ATP CITRATE LYASE Article Open access 19 April 2023 STRUCTURAL

INSIGHT INTO SYNERGISTIC ACTIVATION OF HUMAN 3-METHYLCROTONYL-COA CARBOXYLASE Article 02 September 2024 ARTICLE PDF AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Medicine,

University of Toronto, Toronto Surinder Cheema-Dhadli, Clifford C Leznoff & Mitchell L Halperin * Department of Chemistry, York University, Downsview, Ontario, Canada Surinder

Cheema-Dhadli, Clifford C Leznoff & Mitchell L Halperin Authors * Surinder Cheema-Dhadli View author publications You can also search for this author inPubMed Google Scholar * Clifford C

Leznoff View author publications You can also search for this author inPubMed Google Scholar * Mitchell L Halperin View author publications You can also search for this author inPubMed 

Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Cheema-Dhadli, S., Leznoff, C. & Halperin, M. Effect of 2-Methylcitrate on Citrate

Metabolism: Implications for the Management of Patients with Propionic acidemia and Methylmalonic aciduria. _Pediatr Res_ 9, 905–908 (1975). https://doi.org/10.1203/00006450-197512000-00008

Download citation * Issue Date: 01 December 1975 * DOI: https://doi.org/10.1203/00006450-197512000-00008 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

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KEYWORDS * Hypoglycemia * ketoacidosis * ketotic hypoglycemia * 2-methylcitrate * methylmalonic aciduria * propionic aciduria