The conditionally essential amino acid arginine (2-amino-5-guanidinovaleric acid, one-letter code R; molecular weight 174) contains two amino, one imido group and another nitrogen atom, and thus contains 32.1% nitrogen.


Arg L-arginine

BH., tetra hydro bio pterin

Glu L-glutamate

OAT ornirhine-oxo-acid aminotransferase (EC2.6.1.13) OCT ornithine carbamoyl transfera se (EC2.1.3.3)

Nutritional summary

Function: The conditionally essential amino acid L-arginine (Arg) is used for high-energy-phosphate storage in muscle (phosphoarginine and creatine), protein synthesis, and nitric oxide production, li is also used as an energy fuel: its complete oxidation requites thiamin, riboflavin, niacin, vitamin B6. pantothenate, iipoate, ubiquinone, iron, and magnesium.

Food sources: Adequate amounts are consumed with protein from most sources. Dietary supplements with manufactured Arg arc commercially a\ailable. Requirements: Due to the possibility of endogenous synthesis from L-glutamate (Ctlu). dietary intakes are not usually needed except in newborn infants. Increased dietary intakes may be beneficial for wound heating, tissue repair, and immune function when needs are increased due to severe illness, infection, or injury. Deficiency: Prolonged lack of protein causes growth failure, loss of muscle mass, and organ damage.

Excessive intake: Very higli 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. The risk from high intakes of manufactured supplements is not completely understood, but may include liver and kidney failure, mental disturbances, and other severe dysfunction.

Endogenous sources

Endogenous synthesis in the small intestine from I -glu tarn inc. L-glutamate (Glu) and L-proline contributes about one-fifth (Wu and Morris. I998) of the Arg utilized in the



HjN HN Hgur« 8-73 L-Arsininu body for protein synthesis, energy generation, and synthesis of functional compounds including nitric oxide, creatine i > I g/day), and phosphoarginine (Wu et at., 1997). Endogenous synthesis requires adequate intakes of niacin and vitamin B6. It takes place in two separate stages. The first stage takes place in the small and large intestine and converts the precursors, glutamine. Cilu. or proline, into ornithine and citruiline. Arg synthesis is completed mainly in the kidneys and, to a lesser extent, in the liver.

The lirst two steps of citrullme synthesis in the small intestine from Glu (and indirectly from glutamine) use the Afunctional pyrroline 5-carboxylate synthase (no EC number assigned), fins enzyme comprises phosphorylation (glniamate 5-kbiase. EC2.7.2.111 and reduction (glutamate 5-semialdehvde dehydrogenase. EC1.2.1.41) activities (Wu and Morris, 1998). Citruiline synthesis is completed by omithine-oxo-acid aminotransferase (ornithine transaminase or ornithine aminotransferase. OAT. EC2.6.1.13, PLP-dependent) and ornithine carbamoyl transferase (OCT, EC2.1.3.3). The ornithine citruiline carrier (SLC25AI5) can then shuttle citruiline into the cytosol in exchange Tor ornithine.

After transport via the bloodstream and uptake through the transport system y ' into proximal tubular epithelium of the kidney, citruiline is converted by another two enzymatic reactions into Arg. Argininosuccinate synthase (EC6J.4.5) adds aspartate in an ATP-energized reaction. Argininosuccinate lyase (EC4.3.2.1) finally releases Arg and fumarate.

Dietary sources

Proteins have a particularly high Arg content in rice |N3mg g), oats (71 mg g). and soy-beans (78 mg g). The protein in meals, fish. eggs, and most beans contains around 60 mg g. Protein from cow milk and wheat contains less than 40 mgg. The variation of the relative Arg content of food proteins notwithstanding, total protein intake remains the major determinant of Arg intake. Daily intake of Arg may be 56mg/kg(Beaumier etai, 1995) or higher (Wu and Morris. 1998).

Digestion and absorption

Arg-eonlaming proteins are digested, as all other proteins, by an array of secreted enzymes from stomach, pancreas, and small intestine, and by amtnopeptidases at the brush border membrane. The combined action of these enzymes releases small peptides and free amino acids. Di- and tripeptides are taken up through the hydrogen ion peptide cotransponcrs 1 (PepTI, SLCT5A1) and 2(PepT2, SLCt5A2).

Sod i uní-dependent transport systems arc known to facilitate Arg uptake into ente-rocytes of the distal small intestine, including at least one high-capacity, low-affinity system and a low-capacity, high-affinity system (lannoli et at.. 1998). One of these is the sodium-dependent transport system B°' + , Even more important is the sodium-independent uptake via system y' and BATl-b1, (linked to rBAT) in exchange for a neutral amino acid plus a sodium ion.

The transporters y" LATI (SLC7A7) and y' LAT2 (SLC7A6) have characteristics of amino acid system y and work only in conjunction with the same membrane


COOH L-Glu! amale



-y-Glui amaie kinase



Argmino-succinate lyase




V Glutamyl phosphate


— H \ Glutamate r CH3 v-semi aldehyde dehydrogenase ^

Glutamate y-semiaidehyde

Ornithine-oxo-acid a mino trans terase (PLP

amino acid , n-kelo acid


COOH Fuma rate



Ornithine carbamoyl-transí erase carbamoyl phosphate

ATPiMg t PP,




ATP/Mg 4 aspartate


Arginino-succinate synthase citrulline carrier


NH3 Cilrulline

Figure 8,74 Glutamate is an important precursor for intestinal arginme synthesis glycoprotein anchor 412 (SLC3A2). Both mediate Arg export across the basolateral membrane in etjuimolar exchange for glutamine or another neutral amino acid (Broer el at., 2000; Bode, 20011 While these systems arc not driven by the sodium gradient, they transport a sodium ion together with glutamine in compensation for the charge in Arg.

Enterocytes use about 40% of the dietary Arg for their own energy needs and protein synthesis. Only about 60°'» of the absorbed Arg reach the portal bloodstream. On ihe other hand, the enterocytcs are a major site of de novo Ant synthesis from glutamine. glutamate, and proline (Wu and Morris. 1998),

membrane membrane endothelium

Figure 8,75 Intestinal absorption of argirune membrane membrane endothelium

Figure 8,75 Intestinal absorption of argirune

Transport and cellular uptake

Blood circulation I'lasma concentration of Arg, typically around 94 pimol I (Teerlink et at., 2002), is lowest during the early morning hours and increases significantly alter meals (Tsai and Huang. 1999). Uptake from blood into tissues occurs mainly via sodiurn-independent transporters that have the characteristics of system y" (Wu and Morris. 1998). CAT-t. CAT-2A. and CAT-2B are representatives of that family of transporters. The CAT-2 isolbrms A and H are especially expressed in muscle and macrophages (Kakuda ct at., 1998).

The Arg-derived amine agmatine enters cells via the polyanune transporter (Satriano etal., 200H.

Ma temo-fetal transfer; Several members ofthey"* amino acid transporter family (CAT-l, CAT-4. and CAT-2B) are present at the maternal side of the syntrophoblast. but Arg uptake from maternal circulation appears to be made up of only a small proportion of total amino acid transfer (Cctin, 2001). Transfer across the basal membrane into fetal blood uses the heterodimcnc complex consisting of y ' LAT1 and 4F2 (SLC7A7 + SLC3A2). Blood brain barrier: System y * is the main conduit of transport for Arg into brain. CAT-3 is a brain-specific form in rats. Additional transporters may contribute to transport in either direction.


Arg breakdown in the liver proceeds mainly via ornithine and glutamate to alpha-ketoglutarate and releases four nitrogens (two with urea and another two in transamination reactions). Several of the necessary steps arc the same used for Arg cooh h,n-ch ch2

L-Arginine cooh i c=o ch,

CHa cooh n-Ketoglutarale

Various aminotransferases (PLP)


a-keto acid amino acid

Omithine-oxo-acid aminotransferase (PLP)


Ornithine carrier citai I Ii ne Ornithine

Ornithine-oxo-aad aminotrans (erase (PLP

amino acid k n-keto acid


Glutamate 7-semialdehyde amino r acid

Glutamate y-semi aldehyde dehydrogenase

cooh L-Glulamate

-,-Glutamate kinase oh cooh


OH * -y-Glutamyl phosphate

Figurr 8,76 Argininc Lüta bol ism in the trver dependí, on the transport of ornithine from cytosol into mitochondria synthesis operating in the reverse direction. Complete oxidation requires adequate supplies of thiamin, riboflavin, vitamin Bb. niacin, pantothenate, lipoate, ubiquinone, iron, and magnesium.

The first step ofArg catabolism (in cytosol) uses the final en/yme of urea synthesis, the manganese-dependent arginase (LC3.5.3.1 ). Transport of the resulting ornithine into mitochondria by the ornithine citrulline carrier (SLC25A15 ) is the rate-limiting step ofArg catabolism. This transporter usually exchanges an inwardly carried ornithine molecule Tor an outwardly transported citrulline molecule. Since a proton instead of citrulline can also serve as the counter ion I Indiveri etui., 1000). removal of ornithine from the urea cycle sequence docs not impede the functioning of the ornithine citrulline carrier. The della-amino group of ornithine can then he moved by mitochondrial omithine-oxo-acid aminotransferase (ornithine transaminase: EC2.6.1.I3, PLP-dependent) to alpha-ketoglutarate. pyruvate, or glyoxylatc. Glutamale-5-semialdehyde dehydrogenase (EC1.2.1.41) produces glutamate. which can then be transaminatcd by more than a dozen PLP-dependent aminotransferases, including aspartate aminotransferase (EC2.6.1.1) and alanine aminotransferase (EC2.6.1.2). to the Krebs cycle intermediate alpha-ketoglutarate.

Protein argmine N-methy(transferases use S-adenosy [methionine (SAM I to methylate a small portion of arginyl residues in specific proteins. This activity is important for mRNA splicing. RNA transport, transcription control, signal transduction, and maturation of protein such as the myelin basic protein. Type I enzymes dime thy I ate asymmetrically, type II enzymes methylate proteins such as the myelin basic protein symmetrically. Protcin-arginine N-meihy ¡transferases 1,3.4. and 6 arc type I enzymes whereas isoform 5 is a type II enzyme (Frankel et ul. 2002). Breakdown of symmetrically methylated proteins release symmetric N((i),N'(G)-dimethylarginine. and breakdown of asymmetrically dimethylated proteins generates asymmetric N(G).N(G)-diiueihylargtnitic (ADMA). Dimeihylargininasc (dimethylarginine dimethylaminohydroluse: EC3.5J.I8, contains zinc), which is present in two isoforms in most tissues, converts these metabolites to L-cltrulline by cleaving ofTmethylamine ordimethylamine. respectively.


The Arg content of skeletal muscles at rest is about 0.35mmol/kg(Hammarqvist etai. 2001). Increased metabolic demand, through the action of adrenaline. Cortisol, glucagon, and other mediators, can trigger the release of 40% of these reserves within hours. Significant mobilizable Arg stores are also present in liver, kidneys, and other organs, but their quantitative contribution is less well understood.


At its typical plasma concentration, more than fig of Arg are filtered daily in a 70kg man. Most of this is recovered from the proximal tubular lumen through the sodium-dependent system B . and the sodium-independent systems y' and BAT 1 <b0'J (linked to rBAT). The mechanisms are the same as those mediating small intestinal Arg uptake.

On the basolateral side, again the transporters y'LATl (SLC7A7) and y'L.AT2 (SLC7A6) mediate export towards the capillaries (Broer et ul., 2000; Bode. 2001). The inner medullary collecting ducts in the kidney take up Arg via CAT I (system y '), but do not express CAT2A. CAT2B. or CAT3 (Wu et at.. 2000).


Information on regulatory events in Arg homeostasis is still very incomplete. The control of dietary intake as well as differential distribution to liver and other tissues contributes to a steady supply for vital functions and the avoidance of excess.

Selection of foods may be milueneed by their Arg content as suggested by observations in rats (Yamamoto and Muramatsu. I9fi7). Subjects with citrullinemia. an inborn error of argmine synthesis, have been reported to crave beans, peas, and peanuts, which are high in argmine (Walser, 1983); this observation could lie another indication of some kind of feedback control of Arg intake.

Arg potentiates glucose-induced insulin secretion (Thams and Capito, 1999), which in turn shifts Arg away from use for glueoncogenesis and towards use for protein synthesis. The rate of endogenous Arg synthesis appears to be little affccted by intake levels (Castillo et til.. 1994). Inflammatory cytokines and endotoxin acting on system y* transporters enhance uptake of Arg into particular tissues. This system is expressed only at a low level in hepatocytes, but strongly induced by cytokines (Kakuda etat., 1998). The control ofCAT-2 expression indicates the level of complexity at work. Not only does this gene encode for two distinct tsoforms (CAT-2 and CAT-2A) with ten-fold difference in substrate-binding affinity, but it also has four separate fully functional promoters that allow differential response to a particular stimulant (Kakuda etui, 1998).


Energy fuel: Most catabolic pathways of Arg lead to complete oxidation with an energy yield of 3.3kcal/g (May and Hill. 1990). The necessary reactions arc dependent on thiamin, riboflavin, niacin, vitamin lift, pantothenate, lipoate, ubiquinone, iron, and magnesium.

Protein synthesis: Signilicant amounts of Arg are needed for protein synthesis. Argininc-tRNA ligase (EC6.1 .1,19) loads Arg onto its specific tRNA. I lair protein has a relatively high Arg content and is adversely affected by Arg deficiency. Nitric oxide synthesis: All isoforms (NOS1, NOS2, NOS3) of nitric oxide synthase (ECI. 14.13.39) require one mole BHj and one mole heme per dimer as cofactors (Raflerty et at., 1999). Diminished BH4 synthesis and the resulting decrease in nitric oxide production has been suggested to contribute importantly to impaired angiogen-esis (Marinos et ui. 2001). and epithelial dysfunction and insufficient vasodilation (iiruhn et at., 20011. Nitric oxide synthesis is inhibited by asymmetric N(G).N(G)-dimethylarginine {ADMA) at moderately elevated concentrations, but not by

CH? Arginine CHj decarboxylase (PLP) 1



L- Argmine Agmatine

FigU'F 8,77 Decarboxylation nf Argmme genefjirs a pttrenr amine cooh I



Nitric oxide synthase (heme)

cooh i


Figur» 8.78 NiLnt omde synrhesi* from argifiwe depends on BH4 and heme as cofactors symmetric N{G),N'(G)-dimethylarginine (Masuda el at.. 2002). Plasma concentrations of both compounds iire below 0.5 p.mol/1 in normal subjects (Teerlink et al.. 2002), but distinctly elevated in people with diabetes, renal failure, and other diseases. High-energy phosphates: Daily production of the high-energy storage compound creatine is about 15 mg/kg using Arg and glycine as precursors. The synthesis takes place in two stages, starting in the kidneys, and coming to completion in the liver. Another, functionally related energy-storage compound for muscle ts phosphoarginine. Ag/natin: The amine produced through the mitochondrial decarboxylation of Arg (argi-nine decarboxylase. EC4.1.1.19, PLP-dependent) interacts w ith neurotransmitter receptors in brain, is an acceptor of ADP-ribose (immunemodulator), tempers the proliferative effects of potyamines (through its effects on ornithine decarboxylase and the putrescine transporter), causes vasodilatation and increases renal GFR. and slows nitric oxide production (Blantz et at.. 2000).

Hormone stimulation: Increased Arg intake elicits the release of prolaetine, insulin, glucagon, growth hormone, and enhances the number and responsiveness of circulating lymphocytes to mitogens.

Arginine deiminase may inhibit proliferation of human leukemia cells (by inducing cell growth arrest in the Gl-and/or S-phascand apoptosis) more potently than analogous asparaginase treatment ((Jong et at.. 2000),


Beaumier L, Castillo l„ Ajami AM. Young VR, Urea cycle intermediate kinetics and nitrate excretion at normal and "therapeutic" intakes of arginine in humans. Am J Physiol 1995:269:E884 E896 Blantz RC, Satnano J. Gabbai F. Kelly C, Biological effects of arginine metabolites, tela

Physiol Scand 2000; 168:21 5 Bode BP. Recent molecular advances in mammalian glutamine transport. ./ Ntitr 200I;131:2475S 2485S

Brocr A. Wagner CA. Lang F, Broer S. Tlie heterodimeric amino acid transporter 4F2hc/y+ LAT2 mediates arginine efflux in exchange with gltitamine, BUtchem ,/ 2000;349i787 95

Castillo L. Sanchez M, Chapman TE, Ajami A, Burke JE Young VR. The plasma flux and oxidation rate of ornithine adapt ively decline with restricted arginine intake. Pro( Natl Acad Set USA 1994:91:6393 7 Cetin I. Amino acid intercomersions in the fctal-placental unit: the animal model and human studies in vivo. Pediatr Res 2001;49:148 -53 !-rankel A.Yadav N, Lee J. Branseombe TL, Clarke S, Bedford M l. The novel human protein arginine N-methyltransferase PRM1'6 is a nuclear enzyme displaying unique substrate specificity../ Biol Chan 2002:277:3537 43 Gong II. Zolzer F. von Recklinghausen (i. Havers W. Schweigerer L. Arginine deiminase inhihits proliferation of human leukemia cells more potently than asparaginase by inducing cell cycle arrest and apoptosis. Leukemia 2000;14:826-9 Crohn N. Aldershvite J. Boesgaard S. Tetrahydrobioplcrin improves endothelium-depeudent vasodilation in nitrnglyeerin-toleram rats. Eur J Pharmacol 2001:416:245 9 Ilammarqv ist F. Ejesson B. Wernernian .1, Stress hormones initiate prolonged changes in the muscle amino acid pattern. Clin Physiol 2001;21:44-50 lannoii P. Miller J) I. Sax MC. Epidermal growth factor and human growth hormone induce two sodium-dependent arginine transport systems after massive enterectomy. J Parent Ent Nutr 1998;22:326-30 Indivcri C. Tonazzi A. Snpani 1. Palmieri F. The purified and reconstituted ornithine/ citrulline carrier from rat liver mitochondria catalyses a second transport mode: ornithine* H' exchange. BiochemJ 1999:341:705-11 Kakuda DK, Finley KD. Maruyama M. MacLeod C'L. Stress differentially induces anionic amino acid transporter gene expression. Biochim Biophys Acta 1998:1414:75 S4 Marinos RS. Zhang W. Wu G. Kelly K.A. MeiningerCJ. Tetrahydrobiopterin levels regulate endothelial cell proliferation. Am J Physiol Heart t in Physiol 2001 ;2X1:1I482 114X4 Masuda II. Tsujii T. Okuno T. Kihara K. Goto M. Azunia If. Accumulated endogenous NOS inhibitors, decreased NOS activity, and impaired eavernosal relaxation with ischemia. Am J Physiol Reg Integ Comp Physiol 2002:282:R1730 -R1738 Ma; ME, Hill JO. Energy content of diets of variable amino acid composition. Am J Clin Nutr 1990:52:770 6

Rafferty SP. Buyington JC, Kulansky R. Sun PD. Malech HL. Stoichiometric arginine binding in the oxygenase domain of inducible nitric oxide synthase requires a single molecule of tetrahydrobiopterin perdimer, Biochem Biophy Res Comm 1999;257:344-7 Satriano J. Isoine M. C'asero RA Jr. Thomson SC. Blantz Rt, Poly amine transport system mediates agmatine transport in mammalian celts. Am J Physiol - Cell Physiol 200!;2NI :C329-C334

TeeriinkT, Nij veldt RJ. de Jong S, van Leeuwen PA. Determination of arginine. asymmetric dimethvlarginine. and symmetric dimethylarginine in human plasma and other biological samples by high-performance liquid chromatography. Anal Biochem 2002: 303:131-7

Thams P. C'apito K. L-arginine stimulation of glucose-induced insulin secretion through membrane depolarization and independent of nitric oxide, Eur J Endocrinol 1999; 140:87 93

Isai PJ. Huang i'C. Orcadian variations in plasma and erythrocyte concentrations of glutamate, glutamine. and alanine in men on a diet without and with added monosodium glutamate. Metah Clin Exp 1999;48:1455-60 Walser VI. Urea cycle disorders and other hereditary hyperammonemic syndromes. In Stanbury JB. Wyngaarden JH, Fredrickson DS, Goldstein JL. Brown MS. The Metabolic Basis of Inherited Disease. 5th cdn. New York. McGraw Hill 1983, pp.402-38 Wu F, Cholewa Ii. Mattson DL. Characterization of L-arginine transporters in rat renal inner medullary collecting duct. Am J Physiol Reg httegr Comp Physiol 2l)00:27S:R 1506 12 Wu Ci. Davis PK. Flynn NE, Knabe DA, Davidson JT. Endogenous synthesis of arginine plays an important role in maintaining arginine homeostasis in post weaning a row nig pigs .JNutr 1997;127:2342-9 Wu ( r. Morris SM. Arginine metabolism: nitric oxide and beyond. Biochem J 1998;336:117 YamamotoY, Muramatsu K. Self-selection ofhistidine and arginine intake and the requirements for these amino acids in growing rats. J NutrSci Vitaminol 19X7:33:245 53

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