Oxaloacetate

Last Updated: September 28, 2022

Oxaloacetate is an intermediate of the Kreb's cycle that binds to acetyl-CoA in the formation of citrate. A depletion of oxaloacetate relative to acetyl-CoA is the key step for the production of ketone bodies within the liver.

Oxaloacetate is most often used for



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1.

Sources and Composition

1.1

Sources and Structure

Oxaloacetate, the common name for the molecule 3-carboxy-3-oxopropanoic acid and synonymous with oxaloacetic acid (depending on acidity),

1.2

Physicochemical Properties

One mouse study mixing oxaloacetate into chow found a time-dependent decrease in OAA content at 4°C after 22-28 weeks, where the initial concentration of 479-555ppm detected after 2-5 weeks was reduced to 281ppm (24 weeks) and then to 164ppm (28 weeks).[1]

1.3

Biological Significance

Oxaloacetate is an intermediate of the Kreb's cycle and the stage immediately prior to the formation of pyruvate (via pyruvate carboxylase) and immediately after the NAD+-consuming conversion from L-malate (via malate dehydrogenase).

2.

Pharmacology

2.1

Cellular Kinetics

Intracellular oxaloacetate can be taken up into the mitochondria in various organs.[2][3]

3.

Neurology

3.1

Glutaminergic Neurotransmission

Oxaloacetate is known to be a glutamate scavenger[4] alongside some other small molecules such as pyruvate,[5] where both small molecules are subject to enzymes (glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT) respectively) which convert glutamate into metabolites of 2-ketoglutarate, aspartate, and alanine.[6] Injections of large doses (1mM in rodents) of either oxaloacetate or pyruvate can reduce serum glutamate by 30-40%, causing glutamate to flow from cerebrospinal fluid into peripheral circulation (indicative of reduced glutamate retained in neural tissue).[6]

Oxaloacetate's effects on glutamate appear to be concentration dependent, with maximal effects at 1M (1,000mM) and no effects at 0.01M (10mM).[4] This property has been shown to be active following peripheral injections of oxaloacetate in rat models of tramautic brain injury.[7][5][7]

As an endogenous molecule, oxaloacetate can sequester glutamate and reduce its activities. This has been shown with injections of oxaloacetate in rats, but due to the high concentrations required it may not be a relevant mechanism for oral supplementation of oxaloacetate (studies using oral oxaloacetate currently do not exist on this topic)

3.2

Bioenergetics

Intraperitoneal injections of oxaloacetate (1-2g/kg) day subchronically appears to enhance mitochondrial biogenesis in the mouse brain.[8]

4.

Longevity and Life Extension

4.1

Rationale

Oxaloacetate is thought to promote longevity due to being an intermediate of the Kreb's cycle of energy production. Any increase in the NAD+/NADH ratio can promote longevity in yeast[9] (and is thought to be a major factor in caloric restriction[10][11]) hypothesized to be due to increased energy in the cell, since increased NAD+ availability can stimulate overall Kreb's cycle activity in c. elegans.[12]

In C. elegans, administration of oxaloacetate promoted average (13%) and median (25%) lifespan with similar effects at two tested concentrations (2mM and 8mM) and similar effects with the metabolite pyruvate.[13] This observation was noted to not alter food intake and appeared to be mediated by AMPK acting on the DAF-16 transcription factor, and not be related to Sir2.[13]

Similar functions on the lifespan of C. elegans have been noted with similarly structured Kreb's cycle intermediates fumarate and malate although succinate was ineffective.[14] This effect was also not present in c. elegans lacking the ability to convert malate to fumarate (lacking the fumarase enzyme) or fumarate to succinate (succinate dehydrogenase flavoprotein), suggesting that the byproducts produced in these reactions including FAD and NAD+ rather than the metabolites.[14] A higher NAD+/NADH ratio is known to activate AMPK.[15]

Providing intermediates to the Kreb's cycle (TCA cycle) seems to increase NAD+ concentrations in the cell, and possibly due to increased Kreb's cycle activity overall an increase in longevity follows in nonmammalian subjects

In mice, administration of varying concentrations of oxaloacetate in food (0.5-3.5g/kg dry weight) did not influence longevity although the authors noted that oxaloacetate may have degraded to a degree (thought to be no more than 25% the intended amount) when mixed in chow for a few weeks.[1]

One study using oral oxaloacetate failed to find an increase in longevity in mice, but also had stability issues with oxaloacetate in the feed; more research is required

References
1.^Strong R1, Miller RA, Astle CM, Baur JA, de Cabo R, Fernandez E, Guo W, Javors M, Kirkland JL, Nelson JF, Sinclair DA, Teter B, Williams D, Zaveri N, Nadon NL, Harrison DEEvaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium-chain triglyceride oil on life span of genetically heterogeneous miceJ Gerontol A Biol Sci Med Sci.(2013 Jan)
2.^Passarella S, Barile M, Atlante A, Quagliariello EOxaloacetate uptake into rat brain mitochondria and reconstruction of the malate/oxaloacetate shuttleBiochem Biophys Res Commun.(1984 Mar 30)
3.^Passarella S, Atlante A, Quagliariello EOxaloacetate permeation in rat kidney mitochondria: pyruvate/oxaloacetate and malate/oxaloacetate translocatorsBiochem Biophys Res Commun.(1985 May 31)
4.^Zlotnik A1, Gruenbaum SE, Artru AA, Rozet I, Dubilet M, Tkachov S, Brotfain E, Klin Y, Shapira Y, Teichberg VIThe neuroprotective effects of oxaloacetate in closed head injury in rats is mediated by its blood glutamate scavenging activity: evidence from the use of maleateJ Neurosurg Anesthesiol.(2009 Jul)
5.^Zlotnik A1, Gurevich B, Cherniavsky E, Tkachov S, Matuzani-Ruban A, Leon A, Shapira Y, Teichberg VIThe contribution of the blood glutamate scavenging activity of pyruvate to its neuroprotective properties in a rat model of closed head injuryNeurochem Res.(2008 Jun)
6.^Gottlieb M1, Wang Y, Teichberg VIBlood-mediated scavenging of cerebrospinal fluid glutamateJ Neurochem.(2003 Oct)
7.^Zlotnik A1, Sinelnikov I, Gruenbaum BF, Gruenbaum SE, Dubilet M, Dubilet E, Leibowitz A, Ohayon S, Regev A, Boyko M, Shapira Y, Teichberg VIEffect of glutamate and blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome and pathohistology of the hippocampus after traumatic brain injury in ratsAnesthesiology.(2012 Jan)
8.^Wilkins HM1, Harris JL2, Carl SM3, E L4, Lu J5, Eva Selfridge J6, Roy N6, Hutfles L3, Koppel S3, Morris J1, Burns JM7, Michaelis ML8, Michaelis EK8, Brooks WM9, Swerdlow RH10Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesisHum Mol Genet.(2014 Jul 15)
11.^Chen D1, Bruno J, Easlon E, Lin SJ, Cheng HL, Alt FW, Guarente LTissue-specific regulation of SIRT1 by calorie restrictionGenes Dev.(2008 Jul 1)
12.^Braeckman BP1, Houthoofd K, Vanfleteren JRIntermediary metabolismWormBook.(2009 Feb 16:1-24)
14.^Edwards CB1, Copes N, Brito AG, Canfield J, Bradshaw PCMalate and fumarate extend lifespan in Caenorhabditis elegansPLoS One.(2013)
15.^Rafaeloff-Phail R1, Ding L, Conner L, Yeh WK, McClure D, Guo H, Emerson K, Brooks HBiochemical regulation of mammalian AMP-activated protein kinase activity by NAD and NADHJ Biol Chem.(2004 Dec 17)