Figure 3.6 l-Glutamate

The acidic amino acid I -glutamate (L-glutamic acid 2-aminopenianedioic acid, monosodium glutamate, one-letter code F; molecular weight 147) contains 9.5% nitrogen,


CABA y-amino-N-bucyrate

Clu L-glutamate

MSG monosodium glutamate

RDA recommended dietary allowance

Nutritional summary

Function: The nonessential amino acid L-glutamate (Glu) is used for the synthesis of L-glutaminc. I.-proline, 1,-arginmc, proteins, and functional folate. Glu is essential for brain function. It also contributes, through L-glutaminc, to the synthesis of purines, NAD. FAD. and many other essential compounds, Glu plays an important role in the regulation of energy and nitrogen metabolism and is a major energy fuel; its complete oxidation requires thiamin, riboflavin, niacin, vitamin B6. pantothenate, lipoate. ubiquinone, iron, and magnesium. Glu in foods is specifically recognized by taste receptors that convey a meaty flavor referred to as umami.

Food sources: Dietary proteins from different sources all contain Glu. Dietary supplements containing crystalline Glu. monosodium glutamatc (MSG ), or other salts are commercially available.

Requirements: Since it can be synthesized from alpha-ketoglutarate, dietary intake of Glu is not necessary as long as enough total protein 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 limes the RDA or 2.4 g kg) is thought to increase the risk of renal glomerular sclerosis and accelerate osteoporosis. Controlled studies have not detected any specific health risks or discomfort in conjunction with the consumption of I Og of MSG,

Endogenous sources

Most Glu in blood comes from muscle (50%), kidney (15%). and liver (5-10%), largely synthesized tie novo by transamination or animation of alpha-kctoglutarate (Gcrich et al., 2000).

Glutamate dehydrogenase (EC 1.4,1.3) catalyzes the NADPH-dependent amidation of alpha-kctoglutarate. This reaction binds potentially toxic free ammonia as amino acid.

Almost any amino acid can donate its ammo group to the abundant Krebs cycle intermediate alpha-ketoglutarate for the synthesis of Glu. Numerous Pl.P-dependent enzymes catalyze these transfers, usually with some specificity. Examples include aspartate aminotransferase( land alanine aminotransferase(Kt A somewhat unique case is the synthesis from the urea cycle intermediate L-ornithine by ornithine-oxo-acid aminotransferase (EC'2.6.1,13). because this reaction releases both Glu and I,-glutamate 5-sem¡aldehyde; the latter can then be converted into a second Glu molecule by glutamate-5-semialdehyde dehydrogenase (EC Small amounts of Glu are generated from the breakdown of L-histidine and L-proline and by deamida-tion of L-glutaminc by glutaminase (EC3.5.1.2) at the cytosolic face of the inner mitochondrial membrane.

Dietary sources

Particularly Glu-nch proteins are consumed with wheat (324mg g protein) and rye (279 mgg). The proportions are intermediate in oats (220 mg g). rice (195 mg g). dairy products (200 nig g), and soy products (200mg/g). Lower relative contents are found in beef, pork, chicken, fish, eggs, and beans (all around I50mg/g). Daily dietary Glu intake has been estimated to be about 28g in a man weighing 70 kg (Garattini. 2000). Poods that naturally contain a relatively large concentration of free glutamate include some forms of culinary seaweed and blue cheeses (Daniels et ut.. 1995). The rapid consumption of as much as lOgofmonosodium glutamate. commonly used as a flavor enhancer, is not likely to pose any health risks or causc discomfort i 'Chinese Restaurant Syndrome') as previously suspected (Walker and Lupien, 2000),

Prolonged heating, particularly at alkaline pH. promotes the generation of protein-bound D-glutamate (de Vrese et al., 2000). Some D-glutamate may be ingested w ith marine bivalves and plants (Man and Bada. 1987).

Taste perception: In addition to the four basic flavors recognized by (European) tradition, a fifth has been characterized that is specilically linked to the detection ofGIu by a metabotrophic glutamate receptor on taste buds of the tongue (Kurihara and Kashiwayanagi, 2000). The technical term for the Glu flavor is 'umami* (savory).

Digestion and absorption

Healthy individuals absorb amino acids and proteins in the proximal small intestine nearly completely. Food proteins are hydrolv/cd by an array of gastric, pancreatic, and enteral enzymes, which generate Glu as part of oligopeptides, and in free form. The former can he taken up through the hydrogen ton. peptide cotransponers I (SLC15AI. PepTlJand 2 (SLC15A2, PcpT2).

Enterocytcs take up free Glu from the intestinal lumen via the high-affinity sodium cotransporter EAAT3 (SLC'lAl). corresponding to system XÁíi. Each glutamate anion is transported with three sodium ions in exchange for one potassium ion. The sodium-dependent system ASC provides an additional minor route < Mordrelle et al, 1997). as may various other transporters w ith low efficiency.

Very little of the ingested Glu reaches portal blood or systemic circulation unchanged (Voting and Ajami. 2(KX>). About a third is oxidized completely in enterocytcs. and nearly as much is exported after partial oxidation to L-alanine or lactate (Reeds et al,. 2000); smaller amounts are incorporated into mucosal proteins or converted to L-prolinc (6%), glutathione (6%), I -arginme (4%). and citrulline.

The molecular identity of the transporters) that mediate efflux mechanism is not yet established.

Transport and cellular uptake

Blood circulation: Normal plasma concentrations of free Glu are around 14 p. mo I I (Hatnmarq vist etai, 2001), Glu is largely taken up by tissues via several members of the sodium-dependent system XÁÍ, including EAAT1 (GLAST1, SLCTA3), EAAT2 (GLTI, SLCIA2). EAAT3 (EAAt'l, SLCIAI), EAAT4 (SLCIA6). and EAAT5 (SLC1A7).

Glu can be transported into mitochondria by glutamate-aspartate trans locase in exchange for L-aspartate and by the ¡>1 uta mate-hydroxide translocase in exchange for a hydroxy! ion. The former exchange is especially important in the liver to provide mitochondrial I -aspartate for the cytosolic steps of the urea cycle.

Intracellular Glu can be taken out of some cells, particularly macrophages and other immune cells, in exchange for cystine via the glycoprotein 4F2-!inked transporter xCT (Verrey et a/.. 1999). which is expressed in liver and a few other tissues. Blood-brain barrier: Transport into brain uses mainly a sodium-independent transporter. which is not the sodium-independent x-G system (Benrabh and Lefauconnier. 1996).

The system x-C together with 4F2, which exchanges L-cystine for Glu. provides cystine to neurons for glutathione (Kim et al., 2001 ).

Materno-fetal transfer: Glu passes both apical and basal membranes via the sodium-dependent system XÁT; transporters EAAt'l, GLTL and GLASTl (Novak et til.. 2001): the exact location of each of these transporters remains unclear. The relative contribution of individual transporters appears to vary with developmental stages, but has not been assessed in humans, yet. It should also be pointed out that relatively large amounts of Glu are produced by the fetal liver from maternal L-glutamine and taken dl/tri pe pi »des

3 Na

aigtriine. dtrutline, glutathione 3Nn"'

aigtriine. dtrutline, glutathione 3Nn"'

3 Na parhal oxidation {alanine, lactate i

Intestinal lumen


Brush border membrane

Baaolatera) membrane

Capillary lumen

Capillary endothelium

Ftgur* 8.7 Inteittnal absorption of L-glutamatc up by the placenta as an important energy fuel. There is thus little Glu transfer from maternal to fetal circulation (Garattini. 2iKH>). the net flux of Glu is rather from the fetus to the placenta.


The metabolism ofGlu (Yang and Brunengraber. 20(H)) starts either with the transfer of its amino group to an a-keto acid by one of the many aminotransferases or the oxidative elimination of ammonia by glutamate dehydrogenase (EC The resulting a-ketoglutaratc can then be utilized via the Krebs cycle. The successive steps are catalyzed by the a-ketoglutaratc dehydrogenase complex (EC contains thiamin pyrophosphate and lipoate), succinate-CoA ligase. GDP-forming (suecinyl-CoA synthase: EC6.2.1.4) or ADP-forming (EC6.2.1.5), the ubiquinone-linked succinate dehydrogenase complex (ECT.3.5.1. contains FAD and iron), fumarate hydratasc (fumarase; EC4.2.1.2). malate dehydrogenase (EC" citrate (si)-synthase (EC4,1.3.7), aconitate hvdratase (aconitase: EC4.2.1.3, contains iron), and isocitrate dehydrogenase. NAD-using (F.CI.1.1.41), and NA DP-using (ECU.1.42).

D-glutamate can be metabolized in peroxisomes by D-aspartale oxidase (EC and other D-amino oxidases in liver and kidney. The metabolite D-5-oxoproline is excreted with urine (Sekura el al., I l)7(i)



COOH L-Glutamate n-heloacid

An amino-V transferase \ (PLP)

amino acid \


COOH n-Ketoglutarate

Glutamate dehydrogenase

n-Ketoglutarate dehydrogenase (TPP)

Lipoamide s-s n-Ketoglutarate dehydrogenase (TPP)



Lipoamide s-s








Dihydrotipoamide dehydrogenase (FAD)

□ihydrolipoamide S-succinyl-transf erase



□ihydrolipoamide S-succinyl-transf erase


figure: 8.8 The oxidation ofthr glutamate metabolite n-kelogiutaratt requires thiamin pyrophosphate, lipoamide, FAD, and NAD


Glu content in muscle in women (17.2%) is higher than in men (13,1%; Kuhn ct a!.. 1999). While turnover of protein in skeletal muscles and other tissues constantly releases some free Glu. starvation, trauma, and infection accelerate this protein catabolism.


Very little Glu is lost with feces or urine, because reahsorption is highly effective in healthy people.

i'epTI and pepT2 recover di- and tripeptides. Uptake from the tubular lumen proceeds via the sodium-linked Xag transport system (EAAC1, SLC1A1) and the sodium-independent rBAT (SLC3AI )-linked transporter BAIT (SLC7A9). The sodium-independent aspartate glutamate transponer 1 (AGTI. SLC7A?), associated with an as yet unidentified membrane-anchoring glycoprotein, moves Glu across the basolateral membrane (Matsuo el at., 2(102). Sodium- and potassium-dependent transpon has also been reported (Sacktor et at,, 14X1). but the identity of the responsible transponens) remains unknown.

Most nitrogen from metabolized Glu is excreted into urine as urea, a much smaller amount as free ammonium ions (from deamination by glutamate dehydrogenase and from oxidative deamination).


Accelerated protein catabolism and the ensuing rise in free amino acid concentration increases Glu concentration. Through mass action more Glu is converted by ami no-acid N-acety I transferase (EC2.3.I.I ) to N-acetylglutamate. Because (his is a strong activator of carbamoyl phosphate synthase I (EC6.3.4.I6), the use of Glu-dcrived ammonia for urea increases.

Glu and L-glutamine compete for glutaminase (EC3.5.1.2): the rate of Glu production from L-glutamine thus increases with decreasing intracellular Glu concentration ( Welbourne and Nissim, 2001 ),

During the first few minutes of intense exercise Glu is the most important source of anapleurotic Krebs cycle intermediates (Gibala et al.. 1997), Endurance exercise promotes glutamate dehydrogenase and glutamine formation (Graham et al., 1997).


Energy fuel: Complete oxidation ofGIu yields 3.09 kcalg (May and Hill, 1990) and is dependent on adequate supplies of thiamin, riboflavin, niacin, vitamin B6, pantothenate. lipoate. ubiquinone, iron, and magnesium. Since glucose can be synthesized from the Glu metabolite a-kctogluiarate, Glu is a glucogenic amino acid. Protein synthesis: Glulamatc-tRNA ligase (EC6.I.L17) links Glu with its correspondent t-RNA in an ATP magnesium-dependeul reaction. Post-lranslational gamma-carboxylation of specific gluiamyt-residucs in a few coagulation factors and othei proteins is vitamin-dependent and usually confers calcium and phospho lip id-binding ability. Another specific post-tninslatjonal modification is the formation of intermolecular epsi!on(gamma-glutamyl Hysine cross-links by various isoforms of protein-glutamine gamma-gtutamyl transferase (transglutaminase; EC2.3.2J3, cakiu in-dependent).

Glulamylation: The attachment of multiple glutamyl residues is essential for the function and metabolism of specific proteins, such as the tubulin of the cytoskeleton. The bulk of folate in foods also contains five or more glutamyl residues, which must be removed by digestion before the vitamin can he absorbed. Glutamyl residues are attached again in target tissues as required for full folate function. Ammo acid synthesis: Glu is the donor or recipient of amino groups in numerous transamination reactions and is thus the major currency for amino acid metabolism. It is a direct precursor of L-glutamine, and thus relevant for the synthesis of purine nucleotides including NAD and FAD. Proline synthesis from Glu proceeds in four steps, which are catalyzed by glutamate 5-kinase (HC2.7.2.11). glutamate gamma-semialdehyde dehydrogenase (ECI.2.41). and delta l-pvrroline 5-carboxylate reductase (EC1.5.1.1). Glu in small intestine, but not in other tissues, is the precursor of cit-rulline, which is used in liver and kidneys for the synthesis of both urea and arginine. Metabolic effects: Due to its central metabolic position Glu affects regulation of macronutrient disposition in numerous ways. It is a regulator of glycogen synthesis, gluconcogcncsis, and lipolysis (Stumvoll et al., 1999).

Krebs cycle anapleurosis: Another important function is to replenish the supply of Krebs cycle intermediates. Some leakage and breakdown of these intermediates occurs inevitably, and without constant addition of new intermediates the Krebs cycle would slow down and even cease to work. Dietary Glu glutamine provides the bulk of intermediates (as (f-ketoglutaiate); smaller amounts come from glucose (via biotin-dependent pyruvate carboxylation), aspartate asparaginc breakdown, the biotin-and vitamin B12-dependent metabolism ofpropionyl-CoA (from odd-chain fatty acids, valine, threonine, and methionine), Fumaratc from phenylalanine tyrosine catahoiism. and dietary intake of Krebs cycle intermediates.

Glutathione: Glu is a constituent of the tripeptide y-glutamylcvsteiny¡glycine (glutathione). which is an important intra- and extracellular antioxidant. The exoenzyme ■y-glutamy (transferase (EC2.3.2.2) initiates glutathione degradation by transferring the glutamyl residue to other peptides.

Neurotransmission: Glu is the main excitatory neurotransmitter in brain and appears to be especially important for memory and learning. Glu acts by binding to ligand-gated ion channels and to G-protein linked (metabotropic) receptors. Overall, there are three families ofGlu receptors with numerous subtypes, which serve a broad range of signaling functions in addition to neurotransmission.

Another Glu-derived neurotransmitter in brain is y-amino-N-butyrate (GABA). It is synthesized by two genetically distinct isoforms of the PLP-depcndent glutamate decarboxylase (EC', DECl, and DEC2. GABA metabolism depends on 4-aminobutvrate aminotransferase (GABA-transaminase; EC2.6.I.19) and succinate semialdehyde dehydrogenase (ALDH5A1: EC'l.2,1.24), GABA and histidine are the constituents of the dipeptide homocarnosin. which is likely to be important for GABA storage in brain.


Benrabh H, Lefauconnier JM. Glutamate is transported across the ral blood-brain harrier by a sodium-in dependent system. Neurvsci Lett 1996:210:9-12 Daniels DH. Joe FL Jr. Diachenko GW. Determination ttf free glutamic acid in a variety of foods by high-performance liquid chromatography. Foot} Add Cont 1995;12:21-9 Garanini S. Glutamic acid, twenty years later. JNutr 2000:130:901 S- 909S Gerich JF.. Meyer t . Stumvoll MVV Hormonal control of renal and systemic glutamine metabolism. JNutr 2000:130:995S-1001S Gibala MJ. Mac Lean DA, Graham TF. Saltin B. Anapleroiic processes in human skeletal muscle during brief dynamic exercise.J Physiol 1997;502:703-13 Graham TF, Turcot te I P. Kiens B. Ktchter FA. Effect of endurance training on ammonia and amino acid metabolism in humans. MedSci Sports Exercise I997;29:646 63 1 iammarcp ist F. Fjesson B, Wernerman J. Stress hormones initiate prolonged changes in the muscle amino acid pattern. Clin Physio! 2001:21:44 50 Kim .IV. Kanai Y, (.hairoungdua Cha SH. Matsuo H. Kim Dk. Inatomi J. Sawa H. Ida Y, Endou ¡1. Human cystine glutamate transporter cDNA cloning and uprcgulaticm by oxidativ e stress in glioma cells. Biocftim Biophys tela 2001:1512:335 44 kuhn KS. Schuhmann k, Stchle I'. Darmaun D. Furst I* Determination of glutamine in muscle protein facilitates accurate assessment of proteolysis and tie novo synthesis-derived endogenous glutamine production. Am J Clin Nutr 1999; 70:484 l) kurthara k, kashiwayanagi M. Physiological studies on umami taste. ./ Nutr 2000; I30:931S- 934S *

Man EH. Bada JL, Dietary D-amino acids. Annu Rev Nutr 1987;7:209-25 Matsuo H, Kanai Y, kim A'. Chairoungdua A. Kim do K. Inatomi J. Shigeta Y, Ishimme 11, Chaekuntode S. Tachainpa k. Choi HW. Bahu E. Fukuda J. Endou M. Identification of a novel Na' -independent acidic amino acid transporter with structural similarity to the member of a heterodimerie amino acid transporter family associated w ith unknown heavy chains. JBiolChem 2002;277:21017-26 May ME. Hill JO. Energy content of diets of variable amino acid composition. Am J ( 7in Nutr 1990;52:770-6

Mordrelle A. I luncau JK Tome D. Sodium-dependent and-independent transport of 1.-glutamate in die rai intestinal crypt-like cell line li t. -17. Biochem Biophys Res Comm 1997:233:244-7

\uvak D, Quiggle j-. ArtimeC, Beveridge M. Regulation of glutamate transport and transport proteins ina placental cell line. Un JPfoshl Cell Physiol 2001:281:CI0I4-CI022 Reeds PJ, Burrin DG. Stoll B, Jahoor F. Intestinal glutamate metabolism. ./ Nutr 2000; 130:978S-982S

Sacktor B, Rosenbloom II . Liang CT, Cheng I Sodium gradient- and sodium plus potassium gradient-dependent I -glutamate uptake in renal basolateral membrane vesicles. J MemhBiol 1981:60:63 71 Sckura R, vander Werf P. Meister A. Mechanism and significance of the mammalian pathway for elimination of D-glutamate. inhibition of glutathione synthesis bv D-gtutamate. Biochem Biophys Re* Comm t976;7l:l I 18 Stumvoll M. Perriello G. Meyer C. Gerich J. Role of glutamine in human carbohydrate metabolism in kidney and other tissues. Kidney hit 1999;55:778 92

Verrey I. Jack DL, Paulsen IT. Saier MM Jr. Pfeiffcr !i New glycoprotein-assoeiated amino acid transporters../ Membrane Rod 1999; 172: l SI 92 de Vrcse M. Frik R. iîoos N, Hagemeister H. Protein-bound D-ammo acids, and to a lesser extent lysinoulaninc. decrease true ileal protein digestibility in minipigs as determined with 115 JN-labeling../ Nurr 2000; 130:2026-31 Walker R. Lupien JR. The safety evaluation of monosodium glutamate. J Sutr 2000; I30M 049S-1052S

Welbourne T, Nissîm 1, Regulation of mitochondrial glutamine glutamate metabolism by glutamate transport; studies with 15N, Am J Physiol Cell Physiol 200I;2XO:C 1151-9 Vang D, Bnmengraber II. Glutamate. a window on liver intermediary metabolism. J Nutr 2000; 130:991 S 994S

Young VR, Ajami AM, Glutamate: an amino acid of particular distinction. J Nutr 2000; 130:892S~900S



ch2 I


O NH, ligurr 6.9 L-Glutamine

The neutral, aliphatic amino acid L-glutamine (glutamic acid 5-amide. 2-aminoglu-taramic acid one-letter code Q: molecular weight 146) contains 15.7% nitrogen, Glutamine is unstable in aqueous solutions, particularly upon heating (sterilization), because it forms a cyclical deamtnaiion product.


Gin L-glutamine

PepTI hydrogen lon/peptide cotransporter (SLC15A1)

PLP pyridoxal S'-pbosphate

RDA recommended dietary allowance

Nutritional summary

Function. The nonessential amino acid L-glutamine (Gin) is needed for the synthesis of proteins, neurotransmitters, nucleotides, glycoproteins, and glycans. It is also a valuable precursor for glucose and other important metabolites. Because of the easy interchangeability with L-glutamate, it essentially serves all the functions of this amino acid, too. Complete oxidation of Gin as an energy fuel requires niacin, thiamin, riboflavin, pyridoxine, pantothenate, lipoate, ubiquinone, iron, and magnesium. Food sources: Proteins from plant and animal sources contain Gin and provide precursors for additional endogenous synthesis.

Requirements Adequate amounts are consumed when total protein intakes meet recommendations, since dietary proteins from all typical food sources contain a significant percentage of Gin. and the body can use other amino acids for additional synthesis.

Deficien<y; Prolonged lack oftotal protein intake as a direct source of Gin or for Gin synthesis causes grow ill 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 2.4g kg) is thought to increase the risk of renal glomerular sclerosis and accelerate osteoporosis. The consequences of very high intakes of Gin have not been adequately evaluated.

Endogenous sources

Muscles, liver, small intestine, and other tissues produce significant amounts of Gin Irom glutamate (Labow et a!., 2(H) 1 ). The only enzyme capable of catalyzing the ATP-driven single-step reaction is glutamate ammonia ligase (glutamine synthase; EC6.3.1.2),


Glutamate ammonia ligase


L-Glutamate L-Glutamine

Figure «.10 Endogenous synthesis of I. £'ut .irrnnr

Dietary sources

All food proteins contain Gin. Therefore, Gin intakes depend more on the amount than on the type of protein consumed.

Synthetic peptides, such as l.-alanyl-L-glulamine and glycy 1-1.-glutamine, are commercially available for clinical nutritional support

Digestion and absorption

Denaturation and hydrolysis of Gin-containing proteins begins w ith mastication of foods in the mouth and continues in the stomach under the influence of hydrochloric acid, pepsin A (EC3.4.23.1), and gastricin (3.4.23,3). Several pancreatic and brush border enzymes continue protein hydrolysis, though none specifically cleaves peptide bonds adjacent to Gin.

Gin is taken up from the small intestinal lumen mainly \ la the sodium-amino acid «»transport system H° (ASCT2; Avissar el al.. 2001; Bode, 2001). The sodium-independent transport system b° \ comprised of a light subunit BAT1 (SLC7A0) and a heavy subunit rBAT (SLC3A1). exchanges Gin for another neutral amino acid. Gin

Brush border membrane

Basolateral membrane

Capillary lumen

Brush border membrane

Basolateral membrane

Capillary endothelium

Figure B.11 Intestinal absorption of Lglutamme as a component ot'di- or tripeptidcs can also be taken up via the hydrogen ion peptide cotransporters I (SLt'l 5AI. PepTl)and 2 (SLC15A2, PepT2).

Export across the basolateral membrane uses the sodium-amino acid cotransport systems ATA2 (Sugawara et a/., 2000) and the sodium-independent transporter heterodimers LAT2 + 4F2 (SLC7A8 + SLC3A2). y L.AT1 + 4F2 (SLC7A7+ SLC3A2), y LAT2 + 41 2 (SLC7A6 + SLC3A2).

Starvation increases expression of"the transport systems A and L, whereas ASC and non-mediated uptake arc not affected (Muni/ et <//.. 1993).

Transport and cellular uptake

Blood circulation: (jln has a higher plasma concentration (typically 300-600 jjl mo 1/1) than any other amino acid (Hammarqviste/o/.. 2001 >. Uptake From blood into tissues relics largely on the sodium-dependent transport systems N (SN1 and S Ni 2. in liver.

Hgurr 8,12 The glutamine-gluramate shuttle moves surplus placental nitrogen to the fetus

muscie, and brain). A SOU" (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 el al.. 20(10) while ATA3 is restricted to li\er (Hatanaka el al., 2001).

Gin- and L-asparagine-specitic uniporters, citrin (SLC25A13) and aralarl (SUC25A12) mediate the transfer from cytosol into mitochondria (Indiveri ei al., IW8). Citrin. expressed mainly in liver, kidneys and other tissues, otherwise transports citrate.

Ciln constitutes about 60% of the free amino acids in muscle cells (I lammarijvist iv<//,, 2001).

Blood brain barrier: Transfer of Gin into and out of brain is tightly controlled since its immediate metabolite, L-glutamatc. is a potent neurotransmitter that is toxic in excess. LATI (SLC7A5) and ATA I (Varoqui eta!.. 2000) are expressed in brain capillary endothelial cells and contribute to Gin transport, but their locations, relative importance, and the role of other transporters is not completely understood. A model for the transfer of Gin from circulating blood into brain (Bode, 2001) envisions uptake into astrocytes via system B" (ASCT2) and export into the intercellular space through SN I. Neurons take up Gin via transporters ATA 1 and ATA2.

Materno-fetal transfer: The sodium-amino acid cotransport system A (possibly also ASC and N), and the sodium-independent exchanger LATI mediate Gin uptake from maternal blood across the brush border membrane of the syncytiotrophoblast. Transfer across the basolateral membrane proceeds via the sodium-independent transporters L.AT I and LAT2 (5LC7A8) and the sodium-amino acid cotransport system A. The system A transporter ATA) is expressed at a high level in placenta (Varoqui el al.. 2000). but its exact location is not yet known. The placenta takes up significant amounts of L-glutamatc from the fetus, ami dates some of it, and returns the resulting tiln back to the fetal liver. This placental gIutarninc-gtutamate shuttle captures amino groups that arc released during ammo acid cataholism in the placenta and conserves them for use by the fetus.


Fhe y-amido group of Gin can be released directly as ammonia or used for the synthesis of urea, amino acids, nucleotides, amino sugars, and glycoproteins. Ihese reactions generate L-glutamate that can be deammated to «-ketoglularale and then metabolized through the Krebs cycle.

Giutaminasc (EC3.5.I.2) in mitochondria is not only the key enzyme for Gin breakdown. but ts also important because it generates glulamaie (needed especially in brain as a neurotransmitter) and releases ammonia (contributes in kidneys to pll regulation). Two distinct genes encode prolcins with giutaminasc activity. Alternative splicing of one. the K•giutaminasc gene, gives rise to at least three isoforms with tissue-specific expression patterns. The ammonia can lie bound in carbamoyl phosphate (for urea synthesis in liver and kidneys) if it is not excreted directly or reincorporated into glutamatc.

Enzymes that transfer the y-amido group of Gin to ketoacids include glutamine pyruvate aminotransferase (EC2.6.1.15). Additional aminotransferases act on Gin with low activity. All aminotransferases require pyridoxal 5'-phosphate (PLPi as a prosthetic group. Carbamoyl synthetase II (ECf>.3.5.5) is a multifunctional cytosolic liver enzyme that uses the y-amido group of Gin for the synthesis of carbamoyl phosphate in an ATP-dependent reaction.




Am motrans (erase (PLP)

L-Glulamate i

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