Asparagine

The neutral amino acid L-asparagine (L-beta-asparagine. alpha-aminosuccinamic acid, aspartic acid beta-amide, atheine. asparamide, agedoite, one-letter code N; molecular weight 132) contains 21.2% nitrogen.

Abbreviations

Asn L-asparagine

PepTl hydrogen ion/peptide cotransporter (SLC15A1) PepT2 hydrogen lon/peptide cotransporter (SLC15A2) PLP pyridoxal S'-phosphare

COOH I

O NHj

Figure 8.70

L-Asparagine

Nutritional summary

Function: The nonessential amino acid L-asparagine (Asm is used for the synthesis of L-aspanate and of proteins. Its complete oxidation requires thiamin, riboflavin, niacin, vitamin B6, pantothenate, lipoate, ubiquinone, iron, and magnesium. Food sources; Dietary proteins from different sources all contain Asn. Requirements; Since it can be synthesized from L-aspartate. and this from oxaloacetate, dietary intake of Asn 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. Asn depletion through the use of exogenous asparaginase is employed Ibr the antitumor treatment of some leukemias.

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

Endogenous sources

Asparagine synthase (ECfi.3.5,4) uses L-glutamine as the amino group donor to generate Asn from aspartate. An alternative pathway is catalyzed by aspartate-amnionia ligase (HC63.I.I). Ami nation of the Krcbs cycle intermediate oxaloacetate by aspanate aminotransferase (EC2.6.1.1) can always generate ample amounts of the precursor L-aspartate. as long as total protein and \ itamin B6 supplies are adequate.

Dietary sources

All foot! proteins contain Asn. but quantitativ e information is not readily available from publications or standard food composition tables. Grain proteins are relatively rich in Asn. Prolonged heating, particularly at alkaline plf, promotes the generation of protein-bound D-asparagine (de Vrese end., 200(1). Deamidation with the release of ammonia can also occur to some extent during heating or hydrolysis.

Digestion and absorption

Denaturjtion and hydrolysis of proteins begins with mastication of foods in the mouth and continues in the stomach under the influence of hydrochloric acid pepsin A (EC3.4.23.1), and gastriein (3.423.3). Several pancreatic and brush border enzymes continue protein hydrolysis, though none specifically cleaves peptide bonds adjacent to Asn.

Asn as pari of di- and tripeptides is taken up via the hydrogen ion peptide cotrans-portcrsPtpTI (SLCT5AI) and PepT2 (SLC15A2). The sodium-ammo acid cotransport system B" (ASCT2; Av issar a a!., 2001; Bode, 2001) at the small intestinal brush border membrane accepts Asn with high affinity. The sodium-independent transport system b° \ comprised ofa light subunit BATI (SLC7A9) and a heavy subunil rBAT (SLC3 AI). exchanges Asn for most other neutral amino acids.

membrane membrane endothelium

Figure 8.71 Intestinal absorption of L-asparaginr membrane membrane endothelium

Figure 8.71 Intestinal absorption of L-asparaginr

Anii can move across the basolateral membrane via the sodium-amino acid cotrans-port systems ATA2 (Sugawara ei al., 2000) and die sodium-independent transporter heterodimers LAT2 + 4F2 (SLC7A8 + SLC3A2), yl.ATI+4F2 (SLC7A7 + SLC3A2\ y' I AT2 +4F2 (SLC7A6 + SL.C3A2). Tiie directionality of the transport depends on the prevailing intracellular concentrations

Transport and cellular uptake

Blood circulation: Asn concentration in plasma tends to be arotind 30-60 pmol-'l {Hammarqvist et id.. 2001). Uptake from blood into tissues relies largely on the sodium-dependent transport systems N (SN1 and SN2, in liver, muscle, and brain). ASC7B0 (ASCT2: particularly in lung, muscle, pancreas, and neuronal glia). B"1' (cotransports with one chloride and two sodium ions, in lung, mammary gland, and other tissues), and A Expression patterns of the system A transporters vary in characteristic fashion between different cell types. ATA2 is present in most cells (Sugawara ft al., 2000) while ATA3 is restricted to liver (Hatanaka et al., 2001).

tiln- and L-asparagine-specilk uniporters. cittin (SLC25A13) and aralarl (SLC25AI2) mediate the transfer fromeytosol into mitochondria (Indiveri ft id., 199H). Citrin, expressed mainly in liver, kidneys, and other tissues, otherwise transports citrate.

Blood-brain barrier: Transfer of Asn into and out of brain is lightly controlled since L-glutanune, which is carried by the same transporters, generates the potent neurotransmitter L-glutamate. LATI (SLC7A5) and ATA I (Varoqui et id.. 2000) are expressed in brain capillary endothelial cells and contribute to Asn transport, but their locations, relative importance and the role of other transporters is not completely understood. A model for the transfer of Asn from circulating blood into brain (Bode, 2001) envisions uptake into astrocytes via system B" (ASCT2) and export into the intercellular space through SN1, Neurons take up Asn mii transporters ATA I and ATA2. Maternofeta! transfer: The sodium-amino acid cotransport system A (possibly also ASC and N), and the sodium-independent exchanger LATI mediate Asn uptake from maternal blood across the brush border membrane of the syncytiotrophoblast. Transfer across the basolateral membrane proceeds via the sodium-independent transporters LATI and LAT2 (SLC7AS) and the sod ium-amino acid cotransport system A. The system A transporter ATAl is expressed at a high level in placenta (Varoqui et al., 2000). but iis exact location is not yet known.

Metabolism

Removal of the y-amido group by asparaginase (EC?.5. I.I, requires pyridoxal-5'-phosphate like all transaminases) in liver and kidney cytosol is usually the first step of Asn breakdown. The pyridoxal-5'-phosphate-dependent aspartate aminotransferase (EC2.6.1.1 > removes the «-amino group can and produces the Krebs cycle intermediate oxaloacetic. The urea cycle in liver and kidney cytosol prov ides an alternative pathway for aspartate metabolism. Argininosuccinate synthase (EC6.3.4.5) condenses aspartate and citrulline. and the successive actions of argininosuccinate lyase (EC4.3.2.1) and arginase (EC'3.5.3.1) then release urea and ornithine.

Other transaminases, including asparagine-oxo-acid aminotransferase (EC2.6.1.14), are of lesser quantitative significance. The I -oxosuceanamatc resulting from the transfer of the «-amino group can be conv erted to oxaloacetatc by omega-amidase (EC3.5.1.I >.

Storage

Proteins in muscles and other organs contain some Asn that can be released in response to low protein intake.

Excretion

Losses into feces are negligible as long as gastrointestinal function is normal.

The kidneys filter a gram or more per day. most of which is reabsorbed in healthy people. flie proximal renal tubules take up free Asn mainly through the sodium-amino acid cotransport system B" (ASCT2){Avissare/ id.. 2001; Bode, 2001), di- and tripeptides via pepTl and pcpT2, Asn, if it is not metabolized in the renal epithelial cells, is then exported across the basolateral membrane via the sodium-dependent transporters ATA2 and ASCT1.

COOH I

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