Aspartate

The acidic amino acid L-asparlale (aspartie acid asparagic acid aminosuccinic acid 2-aminobutane-dioic acid one-letter code D: molecular weight 133) contains 10.5% nitrogen.

Nutritional summary

Function: The nonessential amino acid L-aspartatc (AspJ is used for the synthesis of L-asparagine. proteins, pyrimidine- and purine nucleotides, and the neurotransmitter N-methy I - D-aspartate. Its complete oxidation requires thiamin, riboflavin, niacin, vitamin B6, pantothenate, lipoate. ubiquinone, iron, and magnesium. Food sources: Dietary proteins from different sources all contain Asp. Requirements: Since it can be synthesized from oxaloacetate. dietary intake of Asp is not necessary as long as enough total protein as a source of the amino group is available. Deficiency Prolonged lack of total protein causes growth failure, loss of muscle mass and organ damage.

Excessive intake: Very high intake of protein and mixed amino acids (more than three times the RDA or 2.4 g. kg) is thought to increase the risk of renal glomerular sclerosis and accelerate osteoporosis. Information on specific risks from high intake of Asp alone is lacking.

Endogenous sources

The Krebs cycle intermediate oxaloacetate is the abundantly available precursor for Asp synthesis. Aspartate aminotransferase (EC2.6.1.1). which contains pyridoxal-5'-phosphate (PLP) like all known aminotransferases, uses the amino group from L-glutamatc for Asp synthesis. A few other enzymes, such as alaninc-oxomalonate

COOH I

COOH

Abbreviations

Asp L-aspartace

PLP pyridoxal-S'-phosphate aminotransferase (EC2.6.1.47), catalyze similar, but quantitatively minor reactions. Another minor source of Asp is the deamination of L-asparagine.

Dietary sources

Since ail food proteins contain a significant percentage of Asp, total protein intake is a major determinant of Asp intake. Relatively Asp-rich proteins are consumed with soybeans (124mgg total protein) and other legumes. Proteins with intermediate Asp content are consumed with fish (100mgg). eggs | lOOmg/g), ricc(94mg/g), and most meats (around 90 nig g). Wheat (50 mg g) is at the low end of this distribution.

Digestion and absorption

Hydrochloric acid and various proteases from stomach, pancreas, and small intestine break dow n food proteins. The resulting mixture of free amino acids and small peptides is absorbed nearly completely from the duodenum and jejunum.

The hydrogen ion peptide col ran sport ers PepTl (SLC15AI) and PepT2 (SLC15A2) take up Asp-containing di- and tripeptides. free Asp can enter intestinal cells via the Xag transport system (including EAAT3/SLCIA1). Three sodium ions are cot ran sported with each aspartate ion in exchange for one potassium ion. The molecular identity of the transporters) that mediate efflux mechanism is not yet established.

di/tri peptides r ^

fpepTl^l

di/tri peptides

ATPase

ATPase

Intestinal lumen

Capillary lumen

Brush border membrane

Basotateral membrane

Capillary endothelium

Figur* K.fiS tntrsunal absorption of L-a span,u p

NADH

L-Malate

Ox a to ace I ate

Aspartate o-Ketoglutarate

Glutamate

Cytosoi

Dicarboxylate transloca se o-Ketoglutarate

Glutamate-aspartate trans locase

Dicarboxylate transloca se

Glutamate-aspartate trans locase it

-Ketogi uta rate

Glutamate

Mitochondrial matrix

L-Ma late

Oxaloacetate

Aspartate

NADH

Figure a.tie The malate aspartate shuttle mowi reducing equivalents and the precursors for aspartate synthesis into mitochondria

Transport and cellular uptake

Blood circulation: Most Asp in blood is bound in proteins and only minimal amounts (2p.mol/l or less) circulate as free amino acid (Hammarqvist et at , 20011. Several high-affinity glutamatc transporters also accept Asp, including the excitatory amino acid transporters 1 (EAATl, GLASTI, SLCIA3), 3 (EAAT3, SLClAli. and 4 (EAAT4, SLCIA6).

Mitochondrial translocation: The malate aspartate shuttle moves the carbon skeleton and amino group for Asp synthesis from cytosoi into mitochondria, assembles Asp there and transports it back out into cytosoi. Malate from the cytosolie Krebs cycle crosses into mitochondria via dicarboxylate translocase (SLC25A11) and is oxidized to oxaloacetate by malate dehydrogenase I EC 1.1,1.37). The glutamatc for oxaloacetate transamination is brought into mitochondria by glutamatc aspartate translocase in exchange for Asp. This exchange is especially important in the liver to provide Asp for the cytoso-lic steps of the urea cycle. In both liver and all other tissues the shuttle moves reducing equivalents front cytosoi into mitochondria to fuel oxidative phosphorylation.

Metabolism

The two major catabolic fates of Asp are transamination and utilization of the resulting oxaloacetate. and utilization in the urea cycle. A small amount of Asp is directly converted to alanine by aspartate 4-decarboxylase (EC4.1.1.I2, PLP-dependent) in liver and kidneys (Rathod and Fellman, 1985).

COON I

COOH Oxaloacetate

Aspartate aminotransferase tPLP)

cooh

h2n-ch ch2 cooh L-Aspartaie

Aspartate 4-decartioxyiase (PLP>

COOH

L-Alanme

Urea cycle

Figure L-Aspartate c,1tat>ol'irn by transamination. decarboxylation, or via urea synthesis

Transamination: The pyridoxal-5'-phosphate-dependent aspartate aminotransferase (EC2.6.1.1) moves the amino group from Asp to a-kctoglutarate. Both cytosoiie and mitochondrial Isofonms are abundant. Quantitatively minor transamination reactions are also catalyzed by a few other enzymes. Oxaloacetate can then be metabolized further through the standard Krebs cycle reactions.

Urea cycle: Asp functions as a critical substrate for urea synthesis in the mitochondria of liver and kidneys. Aigininosuccinate synthase (EC6.3.4.5) catalyzes the initial synthesis ofargininosuccinate from Asp and citrulline. Aigininosuccinate lyase (EC4.3.2.1) releases L-arginine and fumarate, and arginase (EC'3.5.3.11 finally releases urea and ornithine.

Protein modification; Amino-acid N-acetyltransferase (EC2.3.I.I) and aspartate N-acetvltransferase (EC2.3.1.17) catalyze ihe aeylation of aspartyl residues in some proteins, especially in brain. Aspartoacylase (EC3.5.1.15) deacetylates these aspartyl residues again,

Specific aspartyl residues in some vitamin K-dependent coagulation factors are hydroxylated by the iron-containing peptide-aspartate beta-dioxygenase(EC1.14.1 Lib). Aspartyl residues in myelin basic protein (MBP), a long-lived brain protein, gradually racemize to their D-form (Shapira et at.. B>KK),

Protein-L-isoaspartate (D-aspartate) O-methyltransferase (EC2.1.1.77) facilitates the S-adenosylmethionine-dependent methylation of chemically altered aspartyl residues in proteins. This modification is a critical step in the removal of damaged proteins.

Storage

Proteins in muscles and other organs contain large amounts of Asp thai can be released in response to tow protein intake.

Excretion

Asp losses with urine and feces are minimal in healthy people. Due to the low concentration in plasma very little is filtered in the kidneys. Uptake from the tubular lumen

COOH I

COOH Aspartate

Arginino-succinate synthase

Arginino-succinate synthase

COOH

COOH

Citrultine

COOH I

Ornithine

Ornithine delia-amino-

transterase

NH; Urea

COOH

II H NH

Argminosuccinate

Arginino-succinate lyase

COOH

H2N -CH

Arginino-succinate lyase

COOH

H2N -CH

X

— CH?

\

CH, 1 1

COOH ]

COOH

CH, | 1

CH, |

Ii

NH |

CH

CH

COOH

COOH

Arginine

Figure ti.68 L<Aipaitatt is an important precursor lor urea synthesis

Fumarate

Arginine

Figure ti.68 L<Aipaitatt is an important precursor lor urea synthesis proceeds via the sodium-linked X M, transport system and the sodium-independent rBAT (SLC3A1 (-linked transporter BATI (SLC7A9). The sodium-independent aspartate, glutamate transporter I (ACT 1, SLC7A7). associated with an as yet unidentified membrane-anchoring glycoprotein, moves Asp across the basolateral membrane (Matsuo et aI., 2002}. Sodium- and potassium-dependent transport has also been reported (Saektor et a I., 1981). but the identity of the responsible transporters) remains unknown.

Regulation

Urea cycle: If Asp is abundantly available, the amino group is used to a significant extent for carbamoyl phosphate synthesis (via ghitamate and ammonia). If Asp supplies are on the low side, on the other hand additional amounts are generated by iransaminating oxaloacetic. Balancing Asp synthesis and breakdown thus maintains a steady stream of both carbamoyl phosphate and Asp for urea synthesis.

Function

Protein synthesis: Asp is u constituent of most proteins and peptides synthesized in the body. Aspartate-tRNA ligase (EC6,1,1.12) links Asp with its correspondent t-RN Ain an ATP magnesium-dependent reaction. Asp residues in proteins can be post-translationally earboxylated paralleling the vitamin ((.-dependent gamma-earboxvlalion of L-giu-tamatc residues. Information on this type of protein modification is still very sparse. Energy fuel: Ev entually, most ingested Asp is used as an energy fuel (2.3kcal g>. Asp transamination and subsequent oxidation requires adequate supplies of thiamin, riboflavin, niacin, vitamin Bft. pantothenate, lipoate. ubiquinone, iron, and magnesium Asp is a gluconeogenic amino acid since its metabolite oxaloacctate can be converted to glucose.

Asparagme synthesis Cilutamiiie-hydrolyzing asparaginc synthase (EC6.3.5.4) and aspartate-ammonia ligasc (EC6.3.I.1) catalyze the ATP-driven transamination of Asp to L-asparagine

Argmmeynthesis: Mitochondrial argminosuccinate synthase (EC6.3.4.5) condenses Asp and citrulline to argininosuccinate. The cleavage of this intermediate by argininosuc-cinate lyase (EC4.3.2.I) releases L-argjnine and fumaratc. While urea is the main product of this pathway, some arginine is not immediately hydrolyzed and becomes available to cover about one-fifth of the body's arginine needs (Wu and Morris, 1998), Nucleotide synthesis: Asp provides two of the live nitrogen atoms in adenosine nucleotides, one of the lour nitrogens in guanosine nucleotides, and one of the nitrogens m pyrimidme nucleotides (uridine, thymine, and cytosine).

Vitamin metabolism. Asp can donate an amino group donor in the conversion ofpyri-doxal to pyridoxamine by pyridoxin™ nc-oxaloacetatc aminotransferase (EC2.6.1.31). D aspartote: Incompletely characterized enzymes (probably pyrido.xal-5'-phosphate-dependent) in cerebral cortex and other brain structures, adrenals, testis, and possibly other tissues racemize L-aspanatc to D-aspartate (Wolosker et id., 2000). Since concentrations are highest during embryonic development and infancy, some of the specilk functions may relate specifically to that period in life, A subtype of glutamate receptors in the brain responds to N-methyl-D-aspartate, which is presumably produced by local methylation of D-aspartate. Peroxisomal D-aspartate oxidase (EC1.4.3.1). which can

Purine nucleotides

Pyrimidme nucleotides

Purine nucleotides

Pyrimidme nucleotides f igurr H.6*) Nucleotide iyntht'vs depend;. on L-aspartate contain cither FAD or 6-hydroxyflavin adenine dinucleotide, catabolizes both N-mcthyl-D-aspartate and D-aspartate.

N-acetylaspartate The amount of N-acetyl aspartate in brain is regulated and the genetic impairment of its deacetylation (Canavan disease) causes severe spongy degeneration of cortical white matter. Low N-acety! aspartate concentration in brain, on the other hand, may be associated with certain chronic pam syndromes (Grachev elal.. 2002). Nonetheless, the function of N-acetyl aspartate remains unclear.

References

Oraches ID, Thomas PS, Ramachandran TS. Decreased levels of N-acety (aspartate in dorsolateral prefrontal cortex in a case of intractable severe sympathetically mediated chronic pain (complex regional pain syndrome, type It. Brain Cognition 2002:49:102 13 Hammarqvist F, Fjesson B. Wernerman J. Stress hormones initiate prolonged changes in the muscle amino acid pattern. Clin Physio! 2001:21:44-50 Matsuo H. Kanai Y. Kim JY, Chairoungdua A. Kim do K. Inatomi J. Shigeta Y. Ishimine II, Chaekuntodc S. Tachampa K. Choi IIW. Babu E. Fukuda J. Flndou H. Identification of a novel Na' -independent acidic amino acid transporter with structural similarity to the member of a treterodimeric amino acid transporter family associated with unknown heavy chains. JBiolChem 2002:277:21017-26 Rathod PK. Fellman JII. Identification of mammalian aspartate-4-decarboxylase. Anh

Biochem Biophys 1'>85:238:435-46 Sacktor B, Rosenbloom 1L. Liang CT, Cheng L. Sodium gradient- anil sodium plus potassium gradient-dependent L-gluiamatc uptake in renal basolaferal membrane vesicles, J MembrBiol 198l;60:63 71 Shapira R, Wilkinson KD, Shapira Ci. Racemization of individual aspartate residues in human myelin basic protein. J Neurochem 1988:50:649 54 Wolosker H. D'Aniello A. Snyder SH. D-aspartate disposition in neuronal and endocrine tissues; ontogeny, biosynthesis and release. Seumsdence 2000;100:183-9 Wu Ci. Morris SM, Arginine metabolism: nitric oxide and beyond, Biochem J 1998; 336:1 17

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