The AtlasAmino acidsNegatively charged
AspartateAsp · D
The shortest acidic amino acid: a carrier of electrons into mitochondria, of nitrogen into urea, and the metabolite growing cells breathe to make.
Molecule · Asp · 9 heavy atoms
Aspartate
C4H7NO4133.10 g/mol
The shortest acidic amino acid: a carrier of electrons into mitochondria, of nitrogen into urea, and the metabolite growing cells breathe to make.
Built fromthe charted ones open their own entry
- Codes
- Asp · D
- Formula
- C4H7NO4
- Molar mass
- 133.10 g/mol
- Systematic name
- (2S)-2-aminobutanedioic acid
- Side chain
- Carboxymethyl: one carbon and a carboxylic acid; negatively charged at the pH of blood.
- Class
- Negatively charged
- In the diet
- Dispensable
- Carbon skeleton
- Glucogenic
- pKa
- α-COOH 1.88 · α-NH3+ 9.60 · side chain 3.65
- Isoelectric point
- pH 2.77
- Hydropathy
- -3.5 (Kyte–Doolittle)
- Codons
GAUGAC- Main transporters
- SLC25A13 (citrin (AGC2)), SLC25A12 (aralar (AGC1)), SLC1A3 (EAAT1)
pKa and isoelectric point: Nelson and Cox, Lehninger Principles of Biochemistry, table of amino acid properties (free amino acid, 25 °C). Hydropathy: Kyte and Doolittle, J Mol Biol 1982. Essentiality: Reeds, J Nutr 2000. Formula and mass computed from the structure.
In brief
What it is
An amino acid whose side chain is a single carbon ending in a carboxylic acid, so it is negatively charged at the pH of blood. The body makes it from oxaloacetate, a Krebs cycle intermediate, by transamination 1,2.
Why it matters
It shuttles electrons from the cytoplasm into mitochondria in the malate–aspartate shuttle 1, and proliferating cells depend on making it: a main reason they need mitochondrial respiration at all is to supply aspartate 2,3. The enzyme that makes it, aspartate aminotransferase, is AST, one of the two liver enzymes on every routine blood test 4.
Where it runs short
Cells that cannot make aspartate stop dividing; supplying it, or a transporter to import it, lets cells with no working respiratory chain proliferate again 2,3. Some tumours in low oxygen are limited by aspartate 5.
Where it turns
Defects in the carriers that move aspartate out of mitochondria cause disease: citrin deficiency in the liver and AGC1 deficiency in the brain 6,7.
In the diet it does not matter. In a dividing cell it is one of the things oxygen is for.
The molecule
Aspartate is the shorter of the two acidic amino acids: a single carbon between the backbone and a carboxylic acid. Its side chain pKa is about 3.7, so at the pH of blood it is negatively charged.
In proteins, aspartate and asparagine residues slowly rearrange of their own accord into isoaspartate and D-aspartate, kinks that damage the protein. A dedicated enzyme repairs them; mice without it accumulated damaged proteins in brain, heart, liver and red cells, grew poorly and died of seizures at about six weeks 8.
Move across the chart to read the charge at any pH.
Computed from its pKa values (α-carboxyl 1.88, α-amino 9.60, side chain 3.65) by the Henderson–Hasselbalch equation, for the free amino acid in water at 25 °C. Inside a folded protein the same groups can shift by a unit or more. The faint lines are the other amino acids.
Kyte–Doolittle hydropathy index: positive values avoid water and tend to be buried inside a folded protein, negative values sit on its surface. Each letter is an amino acid; choose one to open it.
| 1st ↓ 2nd → | U | C | A | G | 3rd |
|---|---|---|---|---|---|
| U | UUUPhe | UCUSer | UAUTyr | UGUCys | U |
| UUCPhe | UCCSer | UACTyr | UGCCys | C | |
| UUALeu | UCASer | UAAStop | UGAStop | A | |
| UUGLeu | UCGSer | UAGStop | UGGTrp | G | |
| C | CUULeu | CCUPro | CAUHis | CGUArg | U |
| CUCLeu | CCCPro | CACHis | CGCArg | C | |
| CUALeu | CCAPro | CAAGln | CGAArg | A | |
| CUGLeu | CCGPro | CAGGln | CGGArg | G | |
| A | AUUIle | ACUThr | AAUAsn | AGUSer | U |
| AUCIle | ACCThr | AACAsn | AGCSer | C | |
| AUAIle | ACAThr | AAALys | AGAArg | A | |
| AUGMet | ACGThr | AAGLys | AGGArg | G | |
| G | GUUVal | GCUAla | GAUAsp | GGUGly | U |
| GUCVal | GCCAla | GACAsp | GGCGly | C | |
| GUAVal | GCAAla | GAAGlu | GGAGly | A | |
| GUGVal | GCGAla | GAGGlu | GGGGly | G |
Where it comes from
Every cell makes aspartate by transamination of oxaloacetate, in the mitochondria by GOT2 and in the cytoplasm by GOT1 2,9. Making oxaloacetate needs the electron acceptor NAD⁺, and regenerating NAD⁺ is what the respiratory chain does; that is the link that makes aspartate synthesis depend on oxygen 3.
DispensableMade from oxaloacetate in mitochondria and in the cytoplasm by the two aspartate aminotransferases, GOT2 and GOT1, so it is not needed in the diet 2,9.
How much
None; every cell makes it 2.
Where it is in food
- All protein. Aspartame contributes a small amount as it is digested 10.
In the bottle · enzymaticIndustrial L-aspartic acid was one of the first products of immobilised whole cells: Escherichia coli held in a gel, whose aspartase joins ammonia to fumarate, in columns that kept working with a half-life of about 120 days 11,12.
What the body does with it
The malate–aspartate shuttle, proposed in 1962 and later named for Piet Borst, is the main route by which liver and heart oxidise the NADH made in glycolysis. Its driving step is the export of aspartate from mitochondria in exchange for glutamate and a proton, powered by the respiratory chain 1.
Aspartate is a building block of nucleotides, and growing cells need it in quantity. When respiration fails, GOT1 reverses to make aspartate in the cytoplasm, and losing GOT1 kills cells whose respiration is blocked 2. In tumours, low oxygen lowers aspartate, and raising it, with an aspartate transporter, made tumours grow faster in mice 5.
In the urea cycle aspartate contributes the second nitrogen of urea, condensing with citrulline at argininosuccinate synthetase, the enzyme defective in citrullinaemia type 1 13.
In three sentences each
Why proliferating cells breathe
Two 2015 studies found that a main job of the respiratory chain in dividing cells is to provide electron acceptors for making aspartate; giving aspartate, or pyruvate to regenerate those acceptors, rescued proliferation when respiration was blocked 2,3.
The malate–aspartate shuttle
NADH made in the cytoplasm cannot cross into mitochondria, so its electrons ride across on malate and come back out as aspartate; the export of aspartate, in exchange for glutamate and a proton, is what drives the cycle 1.
How it is made, moved and broken down
Aspartate and oxaloacetate interconvert in one step, so aspartate’s carbons are as available for making glucose as oxaloacetate’s 1. Its free D form, D-aspartate, is found in neuroendocrine tissue, where in rats it stimulates the release of LH and testosterone 14.
Carbon skeleton · glucogenicTransamination turns it straight back into oxaloacetate, the starting point of gluconeogenesis 1.
- Oxaloacetate + glutamate
- Aspartate aminotransferase (AST)GOT2 (mitochondria), GOT1 (cytoplasm) · vitamin B6
- Aspartate + 2-oxoglutarate
- Cytosolic NADH + oxaloacetate
- Malate dehydrogenase 1MDH1 · NADH
- Malate
- Malate dehydrogenase 2MDH2 · NAD⁺
- Oxaloacetate + NADH
- GOT2, then aspartate–glutamate carrierGOT2, SLC25A12/13 · vitamin B6
- Aspartate, exported
- Citrulline + aspartate
- Argininosuccinate synthetaseASS1 · ATP
- Argininosuccinate
How it crosses membranes
- SLC25A13 · citrin (AGC2)liver mitochondria — exports aspartate in exchange for glutamate; its loss causes citrin deficiency 6
- SLC25A12 · aralar (AGC1)neuron and muscle mitochondria — its loss causes a hypomyelinating encephalopathy 7
- SLC1A3 · EAAT1cell membranes — imports aspartate; in some cancer cells, the reason they tolerate blocked respiration 5
Where it matters most
- Brain
- Neuronal AGC1 supplies aspartate to the cytoplasm; without it myelin fails to form 7.
When it goes wrong
Inherited
Citrin deficiency
SLC25A13 · autosomal recessive
Three forms: neonatal intrahepatic cholestasis, which usually resolves with a lactose-free, medium-chain triglyceride formula by age one; a childhood phase of failure to thrive and abnormal lipids; and adult-onset type II citrullinaemia, which in Japan affects about one person in 100,000 and can cause coma and fatal brain swelling 6,15,16. A diet low in carbohydrate and high in fat is expected to prevent progression 16.
How it is foundCitrulline on newborn screening, which misses some cases, then SLC25A13 sequencing 15,17.
Inherited
AGC1 deficiency
SLC25A12 · autosomal recessive
Arrested psychomotor development, low tone and seizures with global failure of myelination, from loss of the neuronal aspartate–glutamate carrier 7.
How it is foundBrain MRI and SLC25A12 sequencing 7.
Inherited
GOT2 deficiency
GOT2 · autosomal recessive
An early-infantile epileptic encephalopathy with low serine, high citrulline, lactate and ammonia; the seizures responded to serine and pyridoxine 9.
How it is foundMetabolic studies and exome sequencing 9.
Inherited
Citrullinaemia type 1
ASS1 · autosomal recessive
The enzyme that joins aspartate to citrulline fails; presentations range from life-threatening neonatal hyperammonaemia to mild late onset and purely biochemical cases 13.
How it is foundPlasma citrulline and ASS1 sequencing 13.
Biomarker
Macro-AST
A benign cause of a persistently raised AST, from the enzyme bound into a large complex that is cleared slowly; recognising it spares patients repeated investigation 18,19.
How it is foundPolyethylene glycol precipitation 18.
How it is measured
Aspartate itself is part of the plasma amino acid panel, but the measurement that matters clinically is its enzyme, AST. The ACG guideline treats AST and ALT together as markers of liver cell injury 4, and their ratio carries information about the time course and stage of disease 20. Before acting on a high AST alone, haemolysis, muscle injury and macro-AST should be excluded 18,21.
- AST (aspartate aminotransferase)Measured with ALT as a liver test; raised in liver cell injury, and also released from muscle and red cells 4,21.The AST-to-ALT ratio, the De Ritis ratio, reflects the time course of injury, because AST has a shorter half-life than ALT, 18 against 36 hours; a high ratio predicts fibrosis and cirrhosis in chronic liver disease 20.Haemolysis in the tube raises AST strongly 21,22. Macro-AST, the enzyme bound to an antibody, keeps AST high for years without disease and is confirmed by polyethylene glycol precipitation 18,19. Assays without vitamin B6 added read low in deficient patients 20.
Food, supplements and the evidence
Establishedreplicated in people, for a named outcome
Uncertainsmall, short, mixed, surrogate or preclinical
What is strange about it
Children with citrin deficiency, a defect of the liver’s aspartate carrier, choose for themselves a diet high in protein and fat and avoid carbohydrate from early infancy; in a Japanese survey, carbohydrate content was the strongest predictor of what they disliked 27. The treatment that guidelines recommend is much the same diet 16.
Aspartame, the sweetener, is a methyl ester of aspartyl-phenylalanine 10. In 2023 the WHO’s cancer agency classed it as possibly carcinogenic to humans, group 2B, while the WHO’s food additives committee kept the acceptable daily intake at 40 mg/kg, calling the epidemiology not convincing 23,24.
D-aspartate is sold to raise testosterone on the strength of a 12-day study in 23 untrained men 14; in trained men, 3 g a day did nothing over 28 days, and 6 g a day lowered testosterone 25,26.
Where it connects
In the Atlas
Topics on the map
On the map
A star in The rest of the amino acids, one of 6. Half of aspartame, and the nitrogen donor the urea cycle and every purine depend on. The sweetener argument and the biochemistry are not the same argument.
Sources
27 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.
- 1Borst P. The malate-aspartate shuttle (Borst cycle): how it started and developed into a major metabolic pathway.doi:10.1002/iub.2367 · PMID 32916028
A personal history; aspartate efflux drives the shuttle.
- 2Birsoy K, Wang T, Chen WW, et al. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis.doi:10.1016/j.cell.2015.07.016 · PMID 26232224
GOT1 reverses when respiration fails; aspartate rescues growth. Cell studies.
- 3Sullivan LB, Gui DY, Hosios AM, et al. Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells.doi:10.1016/j.cell.2015.07.017 · PMID 26232225
Electron acceptors limit aspartate synthesis. Cell studies.
- 4Kwo PY, Cohen SM, Lim JK. ACG clinical guideline: evaluation of abnormal liver chemistries.doi:10.1038/ajg.2016.517 · PMID 27995906
How to interpret AST and ALT.
- 5Garcia-Bermudez J, Baudrier L, La K, et al. Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours.doi:10.1038/s41556-018-0118-z · PMID 29941933
SLC1A3 import; cell and mouse studies.
- 6Kobayashi K, Sinasac DS, Iijima M, et al. The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein.doi:10.1038/9667 · PMID 10369257
SLC25A13; about 1 in 100,000 in Japan.
- 7Wibom R, Lasorsa FM, Töhönen V, et al. AGC1 deficiency associated with global cerebral hypomyelination.doi:10.1056/NEJMoa0900591 · PMID 19641205
One child; abolished carrier activity.
- 8Kim E, Lowenson JD, MacLaren DC, et al. Deficiency of a protein-repair enzyme results in the accumulation of altered proteins, retardation of growth, and fatal seizures in mice.doi:10.1073/pnas.94.12.6132 · PMID 9177182
Mice without the isoaspartate repair enzyme died at about 42 days.
- 9van Karnebeek CDM, Ramos RJ, Wen XY, et al. Bi-allelic GOT2 mutations cause a treatable malate-aspartate shuttle-related encephalopathy.doi:10.1016/j.ajhg.2019.07.015 · PMID 31422819
Four children; serine- and pyridoxine-responsive.
- 10Magnuson BA, Burdock GA, Doull J, et al. Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies.doi:10.1080/10408440701516184 · PMID 17828671
Structure and use levels against ADIs. Industry-funded review.
- 11Tosa T, Sato T, Mori T, et al. Basic studies for continuous production of L-aspartic acid by immobilized Escherichia coli cells.doi:10.1128/am.27.5.886-889.1974 · PMID 4598223
The immobilised-cell process.
- 12Sato T, Mori T, Tosa T, et al. Engineering analysis of continuous production of L-aspartic acid by immobilized Escherichia coli cells in fixed beds.doi:10.1002/bit.260171209 · PMID 1106792
Column half-life about 120 days.
- 13Diez-Fernandez C, Rüfenacht V, Häberle J. Mutations in the human argininosuccinate synthetase (ASS1) gene, impact on patients, common changes, and structural considerations.doi:10.1002/humu.23184 · PMID 28111830
137 mutations; spectrum of citrullinaemia type 1.
- 14Topo E, Soricelli A, D’Aniello A, et al. The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats.doi:10.1186/1477-7827-7-120 · PMID 19860889
23 men, 12 days; and rats.
- 15Inui A, Ko JS, Chongsrisawat V, et al. Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition.doi:10.1002/jpn3.12042 · PMID 38374571
Lactose-free MCT formula; most recover by age one.
- 16Kido J, Makris G, Santra S, et al. Clinical landscape of citrin deficiency: a global perspective on a multifaceted condition.doi:10.1002/jimd.12722 · PMID 38503330
Three forms; low-carbohydrate, high-fat diet with MCT.
- 17Wang P, Hu L, Chen Y, et al. Enhancing newborn screening sensitivity and specificity for missed NICCD using selected amino acids and acylcarnitines.doi:10.1186/s13023-025-03532-7 · PMID 39799340
Screening misses some cases.
- 18Reddy N, Odish FS, Agrawal S. Macro-aspartate aminotransferase: a benign cause of abnormal laboratory findings.doi:10.7759/cureus.23841 · PMID 35530879
Case report.
- 19Arshad I, Zouridis S, Syn W. Macro-aspartate aminotransferase mimicking hepatic injury: a diagnostic dilemma for clinicians.doi:10.1136/bcr-2025-269789 · PMID 41839520
Case report.
- 20Botros M, Sikaris KA. The De Ritis ratio: the test of time.PMID 24353357
AST half-life 18 h, ALT 36 h; the ratio’s meanings; pyridoxal phosphate in assays.
- 21Dobrijević D, Pastor K. When hemolysis misleads: implications for the clinical interpretation of enzyme activities in pediatric samples.doi:10.3390/medicina62091724 · PMID 42796331
Haemolysis raised LDH and AST most.
- 22Hung YE, Chiu YI, Shiesh SC, et al. The influence of haemolysis in patient samples on biochemical tests analysed using Roche Cobas8000 analyzer.doi:10.1177/00045632251356827 · PMID 40551378
Haemolysis bias exceeded reference change values for AST.
- 23Riboli E, Beland FA, Lachenmeier DW, et al. Carcinogenicity of aspartame, methyleugenol, and isoeugenol.doi:10.1016/S1470-2045(23)00341-8 · PMID 37454664
The IARC Monographs summary: aspartame group 2B.
- 24Goodman JE, Boon DN, Jack MM. Perspectives on recent reviews of aspartame cancer epidemiology.doi:10.1016/j.gloepi.2023.100117 · PMID 37637718
JECFA kept the ADI; epidemiology not convincing.
- 25Willoughby DS, Leutholtz B. D-aspartic acid supplementation combined with 28 days of heavy resistance training has no effect on body composition, muscle strength, and serum hormones associated with the hypothalamo-pituitary-gonadal axis in resistance-trained men.doi:10.1016/j.nutres.2013.07.010 · PMID 24074738
3 g/day, 28 days: no effect.
- 26Melville GW, Siegler JC, Marshall PW. Three and six grams supplementation of D-aspartic acid in resistance trained men.doi:10.1186/s12970-015-0078-7 · PMID 25844073
24 men; 6 g/day lowered total testosterone.
- 27Okamoto M, Okano Y, Okano M, et al. Food preferences of patients with citrin deficiency.doi:10.3390/nu13093123 · PMID 34579000
Carbohydrate the strongest predictor of aversion.
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