Info

cooh I

cooh

cooh

CHa t cooh

cooh

L-Tryptophan (Trp, W)

cooh 1

L-Phenylalanine (Phe, F) - Aromatic amino acids ■

cooh I

COOH I

CH2 I

COOH

L-Aspartate (Asp. D)

COOH I

CHa CH,

COOH

L-Glutamaie (Glu. E)

L-Histidine

COOH I

CH2 I

cooh I

ch2 ch2

- Basic amino acids -

rigurr H.3 The most common ammo acids in proteins

TabJ* 8.1 Common ammo acids

Protein amino acids Metabolic Tate Chemical structure

Glycine

Gly

G

L-Alnnme

Ah

A

L-Proline

Pro

P

I-Valine

Val

V

L- Leucine

Leu

L

L-lsoleucme

lit

I

L- Phenyl alanine

Phe

F

L-Tyrosine

V

V

L-Tryptophan

Trp

W

L-Methionine

Met

M

L-Cystsine

Cys

C

L-Sermc

Ser

S

L-Thrconine

Thr

T

L-Aspartate

Asp

0

L-Glutamale

Glu

E

L-Asparagme

Asn

N

L-Gtucamine

Gtn

Q

L-Histidtne

H il

H

L-Lysine

Lys

K

L-Argininc

Arg

R

L Hydrcwyprotinc

Hyp

L-Hydroxyzine

L-ycarboxy glutamate

Gta

3-Methyl-histidine

Selenocystemc

Sec

Nan-pfOUm ammo audi

D-Serine

D- Aspartate

L-Camitine

Taurine

L-Ornithine

L-Cilrulline

BeLa-alanine

Beta-leucine

One-Mrbon

Aliphatic

Glucogenic

Aliphatic

Glucogenic

Aliphatic imino

Glucogenic

Branched chain

Kctogenic

Branch ed-cham

Glucogenic +

ketogeme

Branched-chain

Glucogenic +

kernten it

Aromatic

Glucogenic +

ketogenic

Aromatic

Glucogenic +

ketogenic

Aromatic

Glucogenic

Sulfurous

Glucogenic

Sulfurous

Glucogenic

Alcoholic

One-carbon or glucogenic

Alcoholic

Glucogenic

Acidic

Glucogenic

Acidic

Glucogenic

Neutral amide

Glucogenic

Neutral amide

Glucogenic

Basic

Ketogenic

Basic

Glucogenic

Basic

Glucogenic

Modified Pro

Modified l.ys

Modified Glu

Modified Hit

Selenous

Alcoholic

Acidic

Glucogenic Glucogenic Glucogenic isolcucinc arc another abundant source of amino groups for transamination in muscle, especially in the postprandial phase. All of these aminotransferases require pyridoxal 5-phosphate as a c ova lenity bound eofacior.

Ammonium ions can also contribute directly to amino acid synthesis, but the ex ten I is limited. Glutamate dehydrogenase (FCI.4.1,3) catalyzes the NADPH-dcpcndenl amidation of alpha-ketoglutarate in mitochondria. Alternatively, ammonia can also be linked there to glutamate by glutamate dehydrogenase (EC1.4,1.3) in a distinct. NADPI Independent reaction. Ammonia in eytosol. on the other hand is used by glu-tamaie-ammonia ligase (EC6.3.I.2) for glutamate amidation in an ATP-eneigized reaction.

Ammo acids as precursors: Tyrosine, cysteine, glutamine, asparagine, arginine. ornithine, eitrullinc. proline, taurine, and carnitine are derived from other amino acids, some of

Tabla 8.2 Amino acid prttmwrs

Protein amino acids

Precursors

Glycine

C)y

C

Ser, Thr » Choline, Became, Glyoxylate

¡.-Alanine

Ala

A

Pyruvate Trp, Asp, Taurine, Thymine,

L-Proline

Pro

P

Glu

L-Valine

Val

V

None

L Leucine

Leu

L

None

L-tsoleucme

lié

1

None

L-Phenylalanine

Phe

F

None

L-Tyrostne

Tyr

Y

Phe

L-Tryptopfran

Trp

W

None

(.-Methionine

Met

M

None (extensive regeneration from

homocysteine)

L-Cysteine

Cys

C

Met

L-Senne

Ser

S

Gty, 3-Phospboglyceraie

L-Threonine

Tlir

T

None

L- Aspartate

Asp

D

Oraluacetate

L-GI uta mate

Glu

E

Atp ha ■ lict aglu ta rat e

L-Asparagine

Asn

N

Asp

L-GI uta mine

Gin

Q

Clu

L'Histidine

His

H

None

L-Lysine

Lys

K

None

L-Argminc

Arg

R

Gin, Glu. Pro. L-Ornithine. L-Cirrulline

L-Hydrtwtyproline

Hyp

Pro

L- Hyd rojrytys in e

Lys

l.-y-carboxy glutamate

Cía

Glu

.VM ethyl- h i stid i ne

His

Self oocyst une

Sec

Ser

Non-proUin ¡imino Oitdi

D-Senne

L-Ser

D-Aspartate

L-Asp

L-Camnine

Lys

Taurine

Cys

L-Ornithtne

Arg Clfi, Glu, Pro

L-Citrullme

Ornithine

Bi-ta-alanine

Uracil

Reta-leucine

Leu

which arc essential and have to come from food. Tyrosine can be derived from the essential amino acid phenylalanine by hydroxylation. Cysteine is synthesized via the trans-sulftiration pathway from methionine. Glutamine and asparagine are the amidation products of their respective dicarboxylate amino acid precursors. Arginine. ornithine, citrulline, and proline start out from glutamate; net synthesis occurs only in the intestinal wall. The precursor lor taurine synthesis is cysteine.

Post-translational modification; The precursors of a few amino acids are incorporated into specific proteins and modifications take place only during or after protein synthesis. Many amino acid residues in proteins are modified, and often acquire full functionality only after such changes. Common modifications include phosphorylation, acylation. and gly cosy lat ion I lowev er. after breakdown of a protein the modified amino acids can still he reutilized for protein synthesis. This is not true for a small group of amino acids that are permanently altered by modification of the protein. This group includes hydroxyproline. hydroxylysine. meihylhtstidme. gamma-carboxyglutamatc. gamma-carboxyaspartate. and carnitine. The post-translational hydroxylation of several procollagens and elastins generates hydroxyproline and hydroxylysine. Mcthylhistidine arises from the posl-translational mcthylation ofactir and myosin in muscle and the synthesis of anserine and a few other specific peptides. A \ itamin K-dependent reaction carboxylates the y-carbon of specific glutamate residues in some coagulation factors and a few other proteins. Analogous reactions with aspartate residues may also occur. The selenoeysieine residues, which are constituents of the reactive centers in a few enzymes, are produced by a complex series of reactions from the serine precursor. Serine-tRNA ligase (EC6.I.1.11) charges tttNA(Scr)Sc,; with serine. The pyridoxal phosphate-dependent L-seryl-tRNA5™ selenium transferase (EC2.9.1.1 l then substi-tuies the hydroxy! group of the serine with selenophosphate. The tRNA is now ready to add its load of selenoeysieine to an emerging peptide strand in an unusually complex process. Carnitine synthesis is similarly involved. In this ease, the lysine residues of myosin, actio, hi stones or other proteins are methylated three times by histone-lysine N - met hyf transferase tEC'2.1.1.43). After the proteins have been broken down in the course of their normal turnover carnitine synthesis proceeds with another four steps.

Dietary sources

Most amino acids are consumed with a wide variety of proteins and peptides in foods of animal and plant origin. These foods provide all the twenty amino acids used for making the body's own proteins, peptides, and other compounds requiring amino acids as precursors. Phenylalanine, tryptophan, methionine, histidine, lysine, valine, leucine, i so leucine, and threonine are called essential, because they have to be provided w ith food. Current recommendations are to consume daily ai least 0.8 g protein per kilogram body weight, more during pregnancy (Food and Nutrition Board, Institute of Medicine, 2002),

Several other amino acids, which are not incorporated into human proteins, have nutritional value nonetheless, as nonessential precursors for the endogenous synthesis of important compounds, or just as a source of energy; examples include carnitine, taurine, and ornithine. Finally, there are amino acids, which cannot be utilized well, such as some D-amino acids, or even are harmful. Particular peptides, of course, may have their own specific effects. Some are potent hormones (though most will not be taken up intact and active): others may be potent toxins (e.g., amanitin from death cap mushrooms 1.

C ooking of foods tends to improve overall bioavailability of protein and confers desirable flavors and aromas. I lowever. heating can modify amino acids in numerous ways and may lead to significant losses of cysteine, methionine, threonine, serine, and tryptophan (Dworsehak. 1980). Heating also can promote the cross-linking of L-alanine with other amino acids in food proteins (generating lysinoalanine, ornithi-noalanine. histidinoalatune. phenylethylaminoalanine), the formation of dehydroalamne.

methyldehydroalanine. beta-aminoalanine, and racemizarion to D-amino acids (Friedman. Another typical effect of heating is the cross-linking of amino acids and sugars. The attractive browning that develops during the cooking, frying or baking of foods reflects these reactions. Initially. SchifT bases form between lysines, arguhnes, and sugars, which rearrange to more stable Amadori products (Biemel ei til.. 2001). With continued heating these intermediates react further and form insoluble protein complexes with extensive lysine-arginme cross-links. These complexes are commonly referred to as Maillard products or advanced glycation end products. Presumably due to their low solubility and the extensive chemical modifications of their amino acid constituents such Maillard products have extremely low bioavailability and food value (Hrbersdoblerand Faist, 2001).

Another problem related to heating foods to high temperatures, such as with broiling, is the formation of cancer-inducing compounds. Condensation and pyrolysis of creatine with aromatic amino acids (2-amino-1 -mcthyl-<vphenylimida2o[4.5-b] pyridine. Phil'), glycine (2-amino-3,fi-dimeihylimida/o[4.5-l")quinoxaline. MelQx). or other amino acids generates very potent carcinogens (Oguri et a!., 1998; Schut and Snyderwine. 1999). These compounds readily attach to DNA (adduct formation) and cause mutations.

Digestion

Chewing and mixing with saliva (mastication) breaks solid foods into small particles and initiates digestion. The importance of oral protein-cleaving enzymes appears to be minimal, however. Predigestion becomes much more important in the stomach, The acidity of the added hydrogen chloride denatures ingested proteins. Pepsin (EC3.4.23.1) and gastriesin (pepsinogen C; EC3.4.23.3) hydrolyze proteins with broad specificity.

A second tier of protein-digesting enzymes comes from the pancreas. These include sev eral forms of trypsin, alpha-chymotrypsin, ehymotrypsin C. earbo.xypeptidase 13, and two forms each ofelastase II, endopeptidase I (EC3.4.2I.70). and carboxypeptidase A (EC3.4.2.11. Like most pancreas enzymes these proteases are not active when they reach the small intestine. Duodenal glands secrete duodenase (no EC number assigned. Zamolodchikova etui., 2000). This serine protease activates the brush border protease enteropepudasetenterokinase; EC3.4.21.9) by cleaving it. Entcrokina.se, in turn, cleaves and activates trypsin (EC3.4.21.4). and trypsin finally activates the other pancreas proteases. The activity of the protease ai the top of this activating cascade is inhibited by alphal-proteinase inhibitor (Gladysheva ei til., 2001). Additional proteases may have more narrow specificity. One such enzyme is tissue kallikrein (I C'3.4.21.35). a kinin activator, which is expressed in acinar cells together w ith its inhibitor kallistatin (Wolfet ui. 1998).

The third tier of enzymes works near or directly at the brush border membrane on a mixture that by now contains relatively small peptides. This means that individual amino acids, di- or tnpeptides are released predominantly near the surface of the brush border membrane from where they can be taken up into the epithelial cell layer. A few ami no peptidases, particularly membrane alanine aminopeptidase (aminopepndase N; EC3.-4.11.2), are relatively abundant. This enzyme releases N-terminal alanine and a broad spectrum of other amino acids from peptides, amides or arylamidcs. There is a considerable diversity of enzymes commensurate with the different substrates An example of an enzyme with a relatively narrow mission is folyfpoly-y-glutamatc carboxypeptidase, which converts food folate into the absorbable free form. The many people who ha\e a slightly less active form absorb food folate less well and are more like!} to suffer detrimental consequences of low intakes (Devlin et a!.. 2000).

Absorption

The digested protein products are absorbed with relatively high efficiency (more than 80%) from the proximal small intestine. Some further absorption continues as necessary throughout the small and large intestine. A minute portion of larger peptides and proteins can migrate rapidly through enteroevtes (Ziv and Uendayan, 2000).Transcytosis of relatively intact proteins can explain some phenomena relating to intestinal hormone function as well as food allergies, but has no relevance for absorption efficiency. Enterohepatic circulation of amino acids is significant (Chang and Lister. 1980), Two proton-driven cotransporters are available for the uptake of di- and tripeptides from the intestinal lumen. The hydrogen ion peptide cotransporter 1 (SLC15AI, PcpTl i is most abundant and has broad specificity. The hydrogen ion/peptide cotransporter 2 (SLCI5A2. PfepT2) is much less abundant and has higher affinity.

Amino acids are taken up through mechanisms that are much more specific. This helps to reduce the uptake of some D-amino acids and other potentially toxic compounds. Absorption is mainly driven by the sodium gradient that is established by the sodium/potassium-exchangingATPase (EC3.6.3.9) at the basolateral membrane. This process also generates a proton gradient and a negative membrane potential that favors the inllux of cations. The most immediate use of the sodium gradient for amino acid absorption is the sodium-driven transport of amino acids from the intestinal lumen into the enlerocyte. Transport system FT is especially important for bulk uptake (Avissar eta!,. 2001); Other sodium cotransport systems are B ' (Nakanishi. Hatanaka et til,, 2001), ASC, beta. 1MINO. a little characterized leucine transporter, and the anionic transporter EAACI X.v, for glulamate and aspartate. Uptake of cationic amino acids farginine. lysine, and ornithine) through y* 'CAT-1 (SLC7A11 and of carnitine through OCTN2 (SLC22A5) is driven by the voltage differential. The high intracellular concentration of imported amino acids then drives, through a neutral exchange mechanism, the uptake of other amino acids from the intestinal lumen The same concentration difference can drive the export of amino acids across the basolateral membrane, if the gradient during the absorptive phase is strong enough to overcome the steep sodium gradient. The direction of the substrate flux across the basolateral membrane reverses in the postabsorptivc phase, especially during lasting, and the enterocytes receive amino acids for their own nutriturc from the capillary bloodstream. Sodium-coupled transporters at the basolateral membrane include systems A (ATA2. Sugawara t'l at.. 2000), and N (SN2, Nakanishi. Sugawara el al„ 2001). The taurine transporter (SLC6A6) is present only in the distal small intestine where large amounts of taurine have to be

Tabic 8.3 A muitiluite of protein-hydrotynng enjtynws act on

i food through out th

ie gastrointestinal tract

EC code

Activation

Preferential activity

Sahnr

N - acetyl muramoyl-L-a la nine amidase

3.51 28

Kalhkrein 1

3.J.21.35

Stomach

Pepsin A

3.4.23.1

Phc- j -Xaa, Leu-1 -Xaa, broad specificity

Gastncsin (pepsinogen C)

3.4.23 3

Tyr-1 -Xaa

Pancreas

Trypsin I (catiomc)

3.4.21,4

Entero kinase

Arg-1 -Xaa or lys-1 -Xaa

Trypsin 11 (anionic)

3.4.21.4

Entefo kinase

Arg-1 -Xaa or t.ys-1 -Xaa

Trypsin III

3.4 21,4

Entero kinase

Arg-1-Xaa or Lys-1-Xaa

Alpha -chymorrypsi n

3.4.21.1

Entero kinase

Tyr-].Xaa, orTrp-|.Xaa. or Phv-j-Xaa,

Or Leu-1 -Xaa

Chymotrypsm C

3.4.21.2

Leu-1 Xaa, or Tyr-1-Xaa, Or Phe- |-Xia. or

Mei-j Xaa, or Trp (-Xaa. or Gin-1 -Xaa, or

Asn-|-Xaa

Pancreatic elastasc HA

3.4.21.71

Trypsin

Leu-1-Xaa, Met-|-Xaa, Phe |-Xaa

Pancreatic elastase IIB

3.4.21,71

Trypsin

Leu-1 -Xaa. Met-1 -Xaa, Phe-1 -Xaa

Pancreatic endopeptidase E (EL3A)

3.4.21.70

Ala -1 -Xaa (not elastin)

Pancreatic endopeptidase E (EL3B)

3.4.21.70

Ala-1-Xaa (not elastin)

Carboxypepttdase Al

3.4.2.1

Trypsin

Terminal Xaa except Asp, Glu, Arg, Lys Or Pro

Carboxypepttdase A3

3.4.2.1

Trypsin

Terminal Xaa incept Asp, Glu, Arg, Lys or Pro

Carboxypeptidase B

3.4.17.2

Trypsin

Terminal Lys or Arg

Tissue kallifcrem

3.4,21.35

Trypsin

Arg-[-Xaa

Small-intestinal brush bonier

Duodena«.-

None

Activates entero peptidase

Ertteropeptidase (Enterokinase)

3.4.21.9

trypsmogen ITPK | IVGG

Gamma-glutamyt transpeptidase (gamma-CT)

2.3.2.2

5-L-glutamyl-1 -Xaa

Leucine ammopepttdase (LAP)

3.4.11.1

Zinc

N-terminal Leu

Membrane alanine ammopeptidase

(Ammopeptidase N}

3 4.11.2

Zinc

Ala-1 -Xaa, others more sltnvly

X-Pro aminopeptidase

3.4.11.9

Manganese

Pro-J-Xaa

Membrane dipeptidase

3.4.13.19

Zinc

Hydrophobic di peptides

Dipe pi idyl-peptidase IV

3.4,14.5

Xaa-PrO' | -Xcc

Angiotensin 1'Convening enzyme

3.4.15.1

Zmc

Carboxy terminal Pro | Xaa

Nepri lysin

3.4.24.11

Zinc

Hydrophobic aa in some proteins

Meprin A (PARA-peptide hydrolase)

3.4.24.18

Zinc

Carboxyl side chains of hydrophobic residues

GtycyMeucyl dtpeptidase

3.4 13 Tfi

Zinc

Hydrophobic di peptides

Fofyl poly-y-gl uta mate carboxypeptidase

3 4,17.21

Zinc

Gamma-peptide bonds in Ac-Asp-Glu,

Asp-Gtu. and Glu-Glu

N-acetyl a ted acid d'peptidase-like protein

3,4 1 7 21

Zinc

C-terminal glutamyl from Ac-Asp-Glu or

pccroyl-gamma pccroyl-gamma recovered after the bacterial hydrolysis of bile acid conjugates. The equiltbrative transporter TATt carries the aromatic amino acids tryptophan, tyrosine, and phenylalanine (Kim el«//,. 20(11).

Iloth sides of the enterocytes have transporters that operate m exchange mode. 1 hesc transporters are anchored to the plasma membrane by two distinct glycoprotein components, rBAT (SLC3AI) at the luminal side and 4F2 (SL.( 3A2) at the basolateral

Table 8.4 Small intestinal amino acid transporter»

Brush border membrane

Ba/fl/N8S/ASCT2 (SLC1A5) Na*

ASC Na*

beta/TAUT/ GAT- CI"

IM1NO Na*

leucine transporter Na"

ËAAT3 SLC1A1 ) 3 Na * f3AT1(b& ~ ) -!- r8AT [SLC7A9 +SLC3A1)

y"/CAT-l 0CTN2

Basoiatcnil membruiie

Taurine transporter (5LCiiA6) NaCI

y'LATI + 4F2 (SLC7A7 + 5LC3A2) y ' LAT2 + 4F2 (SLC7A6 + SLC3A2) LAT2 + 4F2 (SLC7AS + SLC3A2) Asc-1 + unidentified heavy chain naa - neutral ammo acid

DCys > M,G,L > V H, C. R. taurine, beta leucine, carnitine C, A. S, C, T, D-Ser, D-Thr, D-Cys Beta-leucine. taurine, CABA. aminobutyrate P.OH-P, taurine, beta-leucine L

H, A, N,Q> D-Arg. D-Lyi R, K, ornithine Carnitine

A, S. M, C, P, N, Q > H, G Q.N.G.A.S, H Tatinne, beta-leucine

naa R,K, ornithine naa y.F.W,T.N,I.C,S,L,V.Q > H.A.M.G

side. The heteroex changer BAT I . b°-' (SLC7A9) at ihe luminal side transports a very broad range of amino acids, including branched-cham amino acids, cystine (CssC). and aromatic amino acids. Several hctcrocxchangers operate at the basolaterat side, including y{+)LATl, y( + )LAT2. LAT2. and Asc-i (Verrey el til.. 1999; Fukasawa el «/., 2000; Wagner el a/., 2001). Ail of these are functional only as a complex with the much larger membrane-anchored 4F2 universal transporter component

While amino acid absorption is most active in the proximal small imestine, uptake also occurs from the ileum (predominantly for taurine) and colon. It should be pointed out that the gut is a tissue with particularly rapid turnover and therefore in constant need of amino acids for protein synthesis, as an energy fuel, and for functionally important metabolites. These are supplied across the hasolatcral membrane.

Transport and cellular uptake

Blood circulation: The bulk of amino acids circulates with blood as a component of proteins, which are taken up by tissues according to their specilic properties, flic concentration of total free amino acids in plasma tends to be around 2.3mmol !. The concentrations of individual amino acids range from around [Qfimol/l (homocysteine. cysteine, hydroxy proline) to over KM) p. mol I (glutamme, alanine, glycine, valine.

lysine, leucine, threonine, and serine). Plasma concentrations ofgJutamine, glutamate, alanine and other major amino acids increase significantly after meals (Tsai and I luang. 1999). An exception is proline, whose plasma concentration rises in response to a meal with considerable delay.

The transporters mediating uptake of amino acids from circulation arc of the same type described for the intestinal tract. Expression of specific forms in a particular tissue reflects the adaptation to the needs of these cells. Differential expression of the three known members of the transport system A for small neutral ammo acids may serve as an illustration. Liver expresses all three known forms. Stimulation with glucagon increases expression of ATA2 and ATAI. but suppresses expression of liver-specific ATA3 (Matanaka, I luang. Murtindale el al., 2001). ATA3 transports the cationic amino acids arginine and lysine with high efficiency, whereas ATA2 and ATAI do not (Haianaka. Huang, Ling etai., 2001). Fasting increases the flow of alanine from muscles into circulation. Glucagon induces al the same time this shift in expression pattern, which increases the uptake ofATA2/ATA 1 -favored amino acids such as alanine without increasing uptake of arginine or lysine. Thus, selective uptake into the liver allows the utilization of muscle-derived alanine for glue oncogenes is while sparing other amino acids for use by extra-hepatic tissues. The glucagon effect on liver cells subsides after a meal and the increasingly active ATA 3 promptly expands the spectrum of amino acids utilized in liver. Blood brain barrier: The endothelial cells of brain capillaries form a highly effective seat that separates the luminal space from the brain (Pardridge, 1998), Passage of amino acids from circulation into brain has to be mediated by specific transporters on both sides of the endothelial cell. Amino acids that are not accepted by one of the available transporters cannot cross, Amino acids are also transported out of the brain into the capillary lumen, which is essential to remove excess excitatory amino acids (Hosoya el al.. 1999). A few specific proteins can cross the blood brain barrier to a limited extent by endocytosis (Tamai et at., 1997).

The hetcroexhanger LATI. which is expressed at both sides of the brain capillary cell epithelial cell (Duclli etai, 2000). provides the main route for large neutral amino acids across the blood-brain barrier (Kiltian and Chikhale, 2001). LAT2 is also expressed in brain (Wagner et al.. 20011. Sodium-dependent system A also appears to mediate transfer of neutral amino acids from blood into brain (Kitazawa et til, 20011. Arginine and other cationic amino acids can cross via the 41;2-anchored exchange complex y+LAT2 (Broer et al., 2000). A high-aflinity transporter with system N properties mediates uptake of glutamate from the brain capillaries I Emus etai, 1998). However, a sodium-dependent glutamate transporter at the abluminal side of" the blood brain barrier facilitates efflux under most conditions and maintains a low brain concentration of this excitatory amino acid compared to circulation (Smith. 2000). Ii is presumably these mechanisms that mediate the ready elllux of excess L-aspartate, but not D-asparatate, from brain into circulation (Hosoya et al.. 1999). Materno-fetal transfer; All essential amino acids as well as large amounts of nonessential amino acids pass from maternal circulation via the placenta to the fetus. The rate at which tndiv idual amino acids are transferred from the mother to the fetus are coordinated with the rate at which they arc used for fetal growth (Paolini el al.. 20011. Leucine, isoleucine. valine, serine, and glutamine constitute the bulk of net amino

Tabic Ä.S typii»! ton ten [rat ion s at btr amino acids in plasma

Amino acids Plasma concentration (fimol/l)

Glycine

248

L-Ala nine

316

L- Proline

170

L-Valine

220

L- Leucine

120

L'lsoleucine

63

L-Phenylalanine

S3

L-Tyrosme

60

L-Tryptophan

46

L-Methionine

25

L-Cysteme

9

L- Cystine

60

Homocysteine

9

L-Serine

114

L-Threonine

128

L-Aspartate

2

L-Glutamate

32

L-Asparagme

47

L'Glutamine

655

L-Histidine

87

L- Lysine

195

L-Arginine

86

S- Hyd roity- L-prol i ne

It

L-Ornithine

66

L-Citrullinr

34

Taurine

49

Soune Data from Oiumo-Filho etal., 1997, Hungrtdi, 2002 (cystine, homocysteine, and hydroxyproline); Katrusiak ei al, 2001 (cysteine)

Soune Data from Oiumo-Filho etal., 1997, Hungrtdi, 2002 (cystine, homocysteine, and hydroxyproline); Katrusiak ei al, 2001 (cysteine)

acid transfer from maternal circulation into the placenta (Cetin, 2001). Methionine and phenylalanine are also among the amino acids ¡hat arc transferred with particular efficiency. Glycine, of which relatively little is taken up from maternal blood, is a major product of placental amino acid metabolism and milch of it is transferred to the fetus. The major transporters at the maternal side of the syntrophoblast in the placenta are tJansson. 2001; Ritchie and Taylor, 20OI > the sodium-dependent transporters A (probably AIA2; Cramer el aL, 2002), B°. XA(l (including E A AT 1-4; Cramer etal., 2002), and beta (Norberg ft al„ 1998). I.ATI can lake up most neutral and some cat ionic amino acids in exchange for other neutral amino acids. Several other transporters also contribute to amino acid uptake or release at the maternal side of the placental interface.

System ASG is the main sodium cotransportcr on the fetal side, ATA2 and or ATA I plays a quantitatively smaller role (Jansson, 2001), The sodium-independent systems LAT2 (Wagner et al.. 200I). y L AT I I Kudo and Boyd, 2001). Asc-1 (Fukasawa et al., 2000), Asc-2 (Chairoungdua etai, 2001), TAT1 (Kim et aL 2001 ),and others all contribute to transport from placenta to the fetus.

Tabu R.6 Ammo acid Cram porter» in human placenta

In

Out

In

Maternal Side

A(ATA2)

Na1

A,S, M, P, N is> G, Q. H

ASC

Na*

G. A, S, C.T

RVB/NBB

Na"

V, l,L,T, F, W»>A,5,C

beta-TAUT/GAT-

CI"

beta, taur, GABA, ammcibuiyrate

Xj., (EAAT1, SLC1A3)

3 Na4

K*

D, E

X^. (EAAT2,SLCIA2)

3 Na'

K'

D. E

X«; (EAAT3.SLC1A1)

3 Na 1

K*

D. E

Xju, (EAAT4, SLC1A6)

3 Na'

KH

O. E

IAT1 + 4F2 (SLC7A5 + SLC3A2)

naa

Y, F, W, T, N, 1, C, S, L. V.

Q H, A, M, G

y" (CAT-1, CAT-4, CAT-2B)

R, K, tim, choline, polyammes

Fetal side

A(ATA2)

Na"

A, S, M.P.N :^>G,Q, H

ASC

Na"

G.A.S, C.T

System T (TAT1)

F, Y, W

LAT2 + 4F2 (SLC7AS 4 SLC3A2)

naa

Y,F,W,T, N.I.C, S, L,V,

Q3> H.A.M,G

y'LATI + 4F2

naa

K. R. H, Q, N

(SLC7A7 i- SLC3A2)

Asc-1 + heavy chain

naa

A, S, C, G, T, D-Ala, -Ala V,

M, H, 1, L,F

A*c-2 + heavy chain

naa

S, A. G, T C, V. 1. L. F. T,

D-Ala, D-Ser naa = neutral amino add

D-Ala, D-Ser naa = neutral amino add

Metabolism

One of the first steps in the breakdown of amino acids is the removal of the amino group. Typically this involves a transamination reaction, often with alpha-kctoglutarate as the acceptor. All transaminases require pyridoxal S-phosphate as a covalently bound cofactor. Ammonia may also be released directly, such as in the deamination reaction catalyzed by D-amino acid oxidase (ECl.4,3.3), which occurs especially in the kidneys (D'Aniello ct ai, IW3). The breakdown of a few amino acids invokes nothing more than the reversal of the reactions responsible for their synthesis. Cilutamate, for example, may shed its amino group in any of numerous possible transamination reactions and the resulting alpha-ketoglutarate can be utilized through the Krebs cycle. Some other amino acids require a much larger number of reactions and may depend on several vitamin cofaetors. The complete oxidation of tryptophan, for example, takes more than twenty steps and requires adequate supplies of thiamin. nbotla\ in, vitamin B6, niacin, pantothenate, lipoate. ubiquinone, iron, and magnesium.

Most of the amino acids in proteins (alanine, valine, isoleucinc. proline, phenylalanine, tyrosine, methionine, cysteine, serine, threonine, aspartate, glutamate, glutamme. aspartate, asparagine. hist ¡dine, and arginine) can be converted into glucose and arc referred to as glucogenic, therefore. Isoleucine. lysine, phenylalanine, tyrosine, and tryptophan are considered ketogenic, because their eatabolism generates ketone bodies or their precursors (acetoacetate, acetate or acetyl-CoA), Glycine: Most glycine is convened into serine (using 5,10-m ethy 1 enc leirahydro folate) or undergoes deamination. decarboxylation and one-carbon transfer to folate (generating 5.10-methylenetetrahvdrofolate). Much smaller amounts arc converted into glv-oxylate. Glycine is used for purine nucleotide synthesis. Glycine breakdown requires riboflavin, vitamin Bfi. niacin, folate, lipoate. ubiquinone, iron, and magnesium L-Alanine: Transamination generates pyruvate, which can be metabolized to acetyl-CoA (which would make alanine kelogenic). orused for glucose synthesis. D-alanine can also be utilized after conversion to pyruvate (Ogawa and Fujioka, I0K1) by glycine hydroxymethyltranslera.se (EC2.1.2.1). Complete alanine breakdown requires thiamin, riboflavin, v ilamin Bf>, niacin, lipoate. ubiquinone, iron, and magnesium. L Proline: The hulk of proline is broken down via glutamate to alpha-ketoglutarate. which can then be used for glucose synthesis or further metabolism through the Krebs cycle. A very significant amount is used in the intestines as a precursor for the synthesis of citrulline, ornithine, and arginine. The oxidation of proline is remarkable for its generation of oxygen free radicals I Donald et al.. 2001), Complete oxidation of proline depends on thiamin, riboflav in, vitamin B6, niacin, lipoate. ubiquinone, iron, and magnesium. Only the kidneys metabolize significant amounts ofhydroxyproline. The intermediary products are pyruvate and glyo.xylate. The latter can be transaminated to glycine.

L-Valine: Ten reactions arc required to metabolize valine tosuccinyl-CoA, which can then be utilized further through the Krebs cycle and oxidative phosphorylation. Complete oxidation requires thiamin, riboflav in. niacin, vitamin B6, vitamin B12, pantothenate, biotin, lipoate. ubiquinone, iron, and magnesium.

L-Leuane: Most leucine is metabolized to acetoacetate and acetyl-CoA, This makes leucine the main ketogenic amino acid. About 5 10% is oxidized via /3-hydroxy beta-mcthylbutyrate(HMB) to acetyl-CoA. Even smaller amounts (mainly in testis) arc convened in an adenosylcobalamin-dependent reaction to bcta-leucinc. Normal leucine metabolism uses thiamin, riboflavin, vitamin B6. niacin, v itamin BI2. biotin, pantothenate, lipoate, ubiquinone, iron, and magnesium.

L-lsoleuane: This brancbed-chain amino acid is broken down to succinyl-CoA and acetyl-CoA in six steps. Utilization depends on adequate availability of thiamin, ribollav in, niacin, vitamin B6, vitamin H12. pantothenate, biotin. lipoate. ubiquinone, iron, and magnesium.

¡.-Phenylalanine ¿.-tyrosine: The tetra hyd rob io pterin -dependent hydroxylation of phenylalanine generates tyrosine. Catabolism of tyrosine generates the glucogenic Krebs cycle intermediate fumarate and the ketogenic metabolite acetoacetate in five reaction steps. Complete oxidation of phenylalanine requires biopterin. ascorbate, thiamin, riboflavin, niacin, \ itamin B6. pantothenate, lipoate. ubiquinone, iron, and magnesium. Tyrosine is also precursor of catecholamines and melanin.

L-T/yptophan Almost alt tryptophan is eventually metabolized through a long sequence of" reactions to alanine and two acetyl-CoA molecules. Alternative tryptophan derivatives of' biological importance include serotonin, melatonin. NAD. and NADP. Adequate supplies of thiamin, riboflavin, vitamin B6, niacin, pantothenate, lipoate, ubiquinone, iron, and magnesium are necessary for normal utilization.

L-Methionme'L-cysteine: Methionine is converted into cysteine via homocysteine. The intermediate homocysteine is extensively remelhylated to methionine in a folate- and vitamin BI2-requiring reaction. Most cysteine is metabolized to pyruvate through several alternative pathways. Smaller amounts are converted into alanine and taurine. These metabolic pathways require thiamin, riboflavin, niacin, vitamin B6, pantothenate. lipoate, ubiquinone, iron, and magnesium. Disposal of the toxic sulfite requires molybdenum.

L-Serine Breakdown of serine can proceed with pyruvate as an intermediate, but most is used for the synthesis of glycine, cysteine, alanine, selcnocysteine. and choline (v ia phosphatidylscrine). These arc then eventually cataboli/ed. Complete oxidation requires thiamin, ribollavin, vitamin B6. niacin, lipoate. ubiquinone, iron, and magnesium. L-Threonine: The mitochondria cataboiize threonine to acetate and glycine. An alternative mitochondrial pathway can generate a spectrum of metabolites including aee-tol. lactaldehyde or D-lactate. Cytosolic metabolism leads to the glucogenic Krebs cycle intermediate succinyl-CoA. Threonine breakdown uses thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12. pantothenate, biotin, lipoate, ubiquinone, ¿inc. iron, and magnesium.

L-Asparagme L-aspartate: Asparagine can be deaminated to aspartate, and this to the glucogenic Krebs cycle intermediate oxaloacctate. Aspartate is a precursor of purine and pvrimidine nucleotide synthesis. Complete oxidation of either one depends on thiamin, riboflavin, niacin, vitamin B6, lipoate, ubiquinone, iron, and magnesium. L Glutamine L-glutamate: Glutamine can be deaminated to glutamate. and this to the glucogenic Krebs cycle intermediate alpha-kctoglutarate. Glutamine is a precursor of purine and pyrimidinc nucleotide synthesis. Complete oxidation of either glutamine or glutamate depends on thiamin, riboflavin, niacin, vitamin B6, ubiquinone, iron, and magnesium,

L-Histidine: Most histidine is metabolized to glutamate. A minor alternative pathway generates imidazole pyruvate, imidazole acetate, and imidazole lactate, which are excreted.

The methyl histidine from modified proteins and anserine cannot be utilized as an energy fuel. Histidine breakdown requires thiamin, riboflavin, vitamin B6, niacin, pantothenate, lipoate, ubiquinone, iron, and magnesium.

L-Lysine: This canonic amino acid is broken down into two molecules ofacetyl-CoA in ten to thirteen stops, depending on the pathway. Complete oxidation depends on thiamin, ribollax in. vitamin Bft. niacin, pantothenate, lipoate, ubiquinone, iron, and magnesium. L Argmine: Breakdow n of arginine proceeds via glutamate to alpha-kctoglutarate, which is metabolized further through the Krebs cycle or used for glucose synthesis. Arginine is also a direct precursor of creatine and nitric oxide. Thiamin, riboflavin, vitamin B6, niacin, pantothenate, lipoate, ubiquinone, and magnesium are needed for the utilization of arginine.

Urea synthesis: Most of the nitrogen ingested with protein eventually ends up as urea in urine. Urea synthesis occurs mainly in the liver. Carbamoyl phosphate synthase I

(EC6.3.4.16) in the mitochondrial matrix condenses ammonia and bicarbonate in an ATP-driven reaction. Mitochondrial ornithine carbamoyltrans(erase (EC2.I.3.3) can then join L-ornithine and carbamoyl phosphate to form eitrulline. The ornithine lor this reaction comes from the cytosol, from where the mitochondrial ornithine transporter 1 (SLC25AI5) shuttles it in exchange for eitrulline across the inner mitochondrial membrane (Camacho cl til., 1999), In the cytosol. eitrulline is condensed with E-aspartate in an ATP-driven reaction (aigitnnosuccinalc synthase: EC'6.3.4.5). Argininosuccinatc lyase (EC4.3.2.1) then cleaves this intermediate into fwnarale and L-aigmine. The cycle is finally completed when the manganese-requiring enzyme arginase(EC3.5.3.1) cleaves L-arginine into urea and L-ornithine. While ornithine is mostly recycled during urea synthesis, it comes ultimately from de now synthesis in the small intestine. Smaller amounts may he taken up from food sources.

Ornithine synthesis from L-gluiamate occurs in kidney, intestine, brain and other tissues. Glycine amidinotransferasc IEC2.1.4.11 in the kidney, which is the rate-limiting enzyme for creatine synthesis, produces L-ornithine and guanidinium acetate from L-argtnine and glycine. An alternative synthesis pathway, mainly in the small intestine. starts with the phosphorylation by mitochondrial gamma-glutamatc 5-kinase (EC2.7.2.11). In humans the same protein also catalyzes the subsequent reduction to glutamate gamma-semi aldehyde (glutamate gamma-semialdehvde dehydrogenase: EC1.2.1.41). Ornithine-delta-aminotransferase (EC2.G.1.13) can then complete ornithine synthesis by transferring the amino group from L-glutamate or a number of other amino acids to glutamate gamma-semialdehyde.

A constant proportion of L-glutamatc in liver mitochondria is acetylated by ammo-acid N-acetyltransferase (EC2.3.1.1). Since N-acctyl glutamate activates carbamoyl phosphate synthase, the concentration of L-glutamate sets the pace of urea synthesis.

Storage

A healthy young adult male contains about 14% protein, much of this in muscle tissue. Due to the constant rapid turnover ol proteins in musclcs and some other tissues about 3-5g/kg in healthy adults {Raguso et al-. 2000) arc bmken down daily. Inadequate intake ofa particular amino acid can be covered temporarily, though al the expense of muscle mass. Insufficient or imbalanced protein intake, immobilization, hormonal dysfunction, excessive cytokine action and other factors are most commonly the underlying cause of low muscle mass (sarcopenia). especially in older people (Bales and Ritchie. 2002).

Excretion

Renal salvage; Only minimal amounts of amino acids are lost with urine intact. While several grams are filtered per day almost all of this is recovered by a highly effective combination of sodium-driven and exchange transport systems. Proteins and peptides are cleaved by various brush border exoenzvmes. including membrane Pro-X car-boxypeptidase(EC3.4.17.16) and angiotensin l-eonvening enzyme (ACE: EC3.4.I5.1). Di- and tripeptides can be taken up via sodium peptide cotransporter I (PepTl, nh,

2 ATP

2 ADP

Carbamoyl phosphate H^COa synthase t

Carbamoyl phosphate 0

«^nrnifhinti^

Glutamate cooh hjn-ch

Ornithine carbamoyl-transf erase

Ornithine

Glutamate cooh hjn-ch ch2 ch2 cooh

-Aspartate cooh h2n-ch ch2

cooh

Arginino-s ne c ma te synthase

PPi cooh h2n-ch ch2 ch2

Ornithine cooh h2n-ch ch, ch, CHj

cooh hjn-ch CH;

ch, cooh

hn cha nh cooh Argirtinosuccinate

Ornithine delta-amino-transie rase

Argimno-succinate lyase cooh ch

ch cooh Fumarate cooh han-ch ch, ch2 ch., NH

han nh Arginine

Cytosol

Glutamate

Ornithine

Glutamate

-Aspartate

Ornithine

Mitochondria

Urea

Figure 8.4 Urea synthesis combines two ammo moieties for excretion

SLCI5A1) in the SI segment oi'the proximal tubule and sodium peptide cotrans-porter 2 (PepT2. SLCI5A2) in the S3 segment (Shen et al„ 19991.

Neutral amino acids enter epithelial cells mainly via the sodium-dependent neutral amino acid transporters B' (Avissar ei ul„ 2001). ASC. and B1Cilutamate and aspartate use the \ transport system The sodium-dependent transporters GAT-l and GAT-3, which are better known from brain for their role in neurotransmitter recovery, ferry gamma-amino butyric acid iGAUAl, hypotaurine. and beta-alanine across the proximal tubular brush border membrane (Muth et al„ 1998). Proline, hydroxyproline. taurine, and beta-alanine arc taken up by the sodium-dependent imino transporter (Urdaneta et at., 199K), and bctaine enters via the sodium- and chloride-dependent betaine transporter (SLC6A 12)- Taurine uptake via the taurine transporter (TAUT, SLC6A6) is sodium- and chloride-dependent (Chesney et at., 1990), High concentrations of osmolytes, such as taurine and betaine, protect epithelial cells against the high osmotic pressure in the medulla.

Specificity and capacity of the sodium-dependent transporters is expanded considerably by the rBAT (SLC3AI Minked transporter BAIT (SLC7A9). This transporter, which accounts for most, if not all, activity of system b°- . shuttles small and large neutral amino acids across the brush border membrane in exchange for other neutral amino acids. Carnitine enters the cell via the organic cation transporter OCTN2 in exchange for I et racthy I am moni um or other organic cations (Ohashi et at.. 2001).

Amino acids are utilized to some extent in tubular epithelial cells for protein synthesis. energy production, and other metabolic pathways. The case of hydroxyproline is somewhat special, because the kidneys are the main sites of its metabolism, mainly to serine and glycine I Lowry et ul., 19S5). I lydroxvproline is derived from dietary collagen and from endogenous muscle, connective tissue, and bone turnover. It reaches the mitochondria of the tubular epithelial cells through a translocator that is distinct from that for proline (Atlante et at. 1994). Hydroxyproline is then oxidized by 4-oxoproline reductase (hydroxyproline oxidase; HOl.t.l. 104) to 4-oxoproline (Kim et til., 19l>7). 4-1 lydroxy-2-oxoglutarate aldolase (EC4.1.3.I6) generates pyruvate and glvoxylate. Glycine is produced when the pyndoxal-phosphate-dependent alanine-glyoxvlate aminotransferase (EC2.6.I.44) uses alanine for the animation ofglyoxyJate.

The main sodium-dependent amino acid transporters of the basolateral membrane arc system A (preferentially transports alanine, serine, glutamine) and ASCTI (alanine, serine, cysteine, threonine, glycine). Net transferof individual amino acids importantly depends on their ow n concentration gradient. As on the luminal side, some transporters operate in exchange mode. Small neutral amino acids are the main counter molecules, because their concentration is the highest, functional studies have characterized transport system Asc for smali neutral amino acids, but no corresponding gene or protein lias been identified yet. Glycoprotein 4F2 anchors the amino acid exchangers typical for this side to the basolateral membrane (Verrey etal., 1999). The L-type transporter I AT2 (SLC7AX) accepts most neutral amino acids for transport in either direction. Arginine and other cationic amino acids can pass through related hetcrodimers; one of these is 41-2 in combination with y ' LAI 1 (SLCA7). another consists of 4F2 and v I AT2 (SLC7A6). These transporters can exchange a cationic amino acid for a neutral amino acid plus a sodium ion. GAT-2 mediates betaine, beta-alanine. and some taurine transport. The same compounds may also leave via the sodium chloride-dependent taurine transporter (SLC6A6).

Excretion with urine: Most nitrogen is excreted with urine as urea (O.lftg nitrogen per gram ingested protein), creatinine (0.5g d). uric acid (0,2g d). and a few minor nitrogen-containing compounds. Elimination of these metabolic end products is important, because they are toxic at higher than normal concentrations. Urea freely passes through the renal glomeruli, which means thai a healthy adult male produces ultrafiltrate with more than 2(>g urea nitrogen. Since some reabsorption occurs, only about half of this amount is excreted with urine. A much smaller amount of protein-derived nitrogen is excreted as ammonia.

Fecal losses: Much smaller amounts of protein-derived nitrogen are lost from the intestinal tract. Losses are due to the shedding of intestinal epithelia (desquamation) and incomplete absorption ofdictary proteins. More than one-tenth of ingested protein is not absorbed in healthy people, and the unabsorbed percentage may be much higher for some proteins with low digestibility or in people with digestive or absorptive disorders* I leymsfield et at, 1994).

Regulation

Nitrogen balance; Healthy adults usually maintain constant lean body mass and neither accumulate protein nor lose protein mass. Since their combined nitrogen intakes (mainly as protein) more or less equal their nitrogen losses, they are said to be in nitrogen balance. Growing children and adolescents accumulate nitrogen and arc therefore said to be in positive nitrogen balance. Starv ing. immobilized, and severely ill people, in contrast, break down tissue protein and lose more nitrogen than ihey take in: they are said to be in negative nitrogen balance.

Glucagon, catecholamines. Cortisol, thyroid hormones, and cytokines promote the breakdown of tissue protein and its use for gluconeogensis. Excessive release of cytokines, such as tumor necrosis factor, jnterleukin 1 11L-I). and mtcrlcukin 6 (1L-6), may be responsible for the accelerated protein catabolism in conditions such as tumor cachexia, but the details are not well understood (Tisdalc. 1998). Several hormones promote protein synthesis (anabolic hormones), including insulin, insulin-like growth factor I (IGF-1). growth hormone, and testosterone. Muscle use and the abundance of free amino acids, especially branched-chain amino acids, arc potent determinants of the rate of protein synthesis in muscles (Tipton et al., 20011. Leucine and Us metabolites increase protein synthesis (Anthony et al., 2001: Liu et al.. 2001) by activating a distinct signaling cascade that includes ribosomal protein Sf> kinase (SbK1) and eukary-otic initiation factor 4E binding protein 1 (4E-BP1),

Function

Protein synthesis. Daily protein turnover may be as much as 300 g, which means that the same amount has to be resynthesi/ed. The 20 basic amino acids are required lor the synthesis of most of the more than 30000 different proteins that constitute the human body. Deficiency of any single one affects all body functions and is ultimately not compatible with life.

Gluconeogenesis: Brain needs glucose as its main energy fuel. When carbohydrate sources and intermediary metabolites are depleted, amino acids are used for the synthesis of glucose (gluconeogenesis). Skeletal muscle is the major source due to its large mass, but proteins from all other tissues are also utilized. The alanine cycle mediates the transfer from muscle to the liv er. The amino groups from muscle amino acids are preferentially transferred lirst to alpha-ketogtutarate and then from glutamate to pyruvate. Various minor pathways accomplish the same. The carbon skeletons of glucogenic amino acids are mostly oxidized locally. Alanine, on the other hand, is exported into blood. The liver extracts alanine from blood incorporates the amino group into urea for excretion and uses the pyruvate for glucose synthesis. Energy fiw!. Eventually nearly all amino acids are fully oxidized to carbon dioxide, water and urea. Only very minor amounts of a few amino acids are converted into compounds that are excreted in a more complex form. On av erage, the oxidation of the amino acids in proteins provides 4 kcal/g.

Non-protein mediator synthesis: Several hormones are derived from amino acids, but are not peptides. This category includes catecholamines, serotonin, and melatonin.

Virtually all organic compounds involved in neurotransmission or modulation of neuron excitation are either amino acids or amino acid metabolites. Amino acids w ith

Glucose

COOH I

COOH I

COOH I

1 OH

Orij Glucose

COOH I

Alanine amino iransletase (PLP)

COOH I

Protein

Ammo acids r.-Keto-g kit a raie

Drverse amino V transferases I

COOH I

Alanine amino iransletase (PLP)

COOH I

n-Kelo-glutarate

Liver

Muscle

Fi^urr H.S The alanine cycle allows the utilization of muscle proteins lor glue oncogenesis in the liver such functions include g I uta mate, glycine, and proline. Amino-acid metabolites, which participate in neurotransmission, include gumma-amino hutyrate (GARA), N-methyl D-aspartate (NMDA), nitric oxide, serotonin, melatonin, histamine, and agmatine. Nucleotide synthesis: Two of the four carbons and one of the nitrogen atoms in purines come from glycine. Aspartate provides two of the five nitrogen atoms in adenosine nucleotides, one of the four nitrogens in guanosine nucleotides, and one of the nitrogens in pyrrolidine nucleotides (uridine, thymine, and cytosine).

References

Anthony JC. Anthony TO. Kimball SR. Jefferson LS. Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine. J Star 2001; 131:856S-S60S

Atlante A, I'assarella S, Quagliariello E. Spectroscopic study of hydroxy proline transport in rat kidney mitochondria. Biochem Biophvs Res Comm 1994;202:58 64 Avissar

Understanding And Treating Autism

Understanding And Treating Autism

Whenever a doctor informs the parents that their child is suffering with Autism, the first & foremost question that is thrown over him is - How did it happen? How did my child get this disease? Well, there is no definite answer to what are the exact causes of Autism.

Get My Free Ebook


Post a comment