COOH Trans-3-Methyl glutaconyl-CoA


Methylglu la-cony I-CoA hydratase


CH2 1




HjC^ XCH, (i-Leucine


XCH3 fi-KetoisocaproiC acid succinyl-f CoA


|i- Keioisocap royi-CoA






Figure 8.57 Metabolism ofL-lcucme similar properties (Nissen and Abumrad, 1997). The subsequent steps are known to alternatively rejoin the main pathway at the level of 3-methylcrotonyl-CoA or HMGCoA. The enzymes necessary for these reactions are not yet well characterized. Beta-keto pathway: An alternative pathway of Leu degradation proceeds via L-beta-leucine aminomutase (EC5.4.3.7) and generates beta-hy droxy-beta-meihy lbutyrate; this enzyme requires adenosylcobalamtn. Significant L-beta-leucine aminomutase activity present in testes where about a third of Leu metabolism proceeds via the beta-keto pathway. In all other investigated tissues leucine 11 ux through the beta-keto pathway accounts for less than 5% of Leu metabolism (Poston, 1984). The enzymes responsible for this pathway arc not yet well characterized.


Body protein contains 5-Id"» Leu (Mero. 1999). Protein can be mobilized rapidly, especially from muscle, and used as an energy fuel. In the fasting state, most of the amino groups are transferred to pyruvate; the resulting L-alantne is exported to the liver for urea synthesis and gluconeogenesis. Glucose is returned to the muscle to complete this alanine glucose cycle. In the fed stale L-glutamine is the predominant transamination product.


The organization of Leu «absorption from the proximal tubule lumen closely resembles small intestinal absorption. The bulk action of the sodium-driven brush border transporter 13" (Avissar et al., 2001) is supplemented by the rBAT <5LC3Al »-anchored heteroexchanger BAT 1 b"'' (Chairoungdua et al., 1999), Transport across the basoiateral membrane depends mainly on the 4F2 (SLC3A2) glvcoprotein-anchorcd transporter LAT2 (SLC7A8).


Branched-chain alpha-keto acid dehydrogenase (EC2.6.1.42) is the key regulatory enzyme for Leu (and L-valinc L-isoleucine) metabolism, which helps preserve this essential ammo acid for protein synthesis during starvation The enzyme is inactivated by a specific, calmodulin-dcpendent kinase ([3-methy 1-2-oxobuianoate dehydrogenase (lipoamide)] kinase; EC2.7.1.I15) and activated by a specific phosphatase ([3-methyl-2-oxobutanoate dehydrogenase tlipoamidcij-phosphatase; EC3U.3.52). Branched-chain alpha-keto acid dehydrogenase is also inhibited by the products of the reaction it catalyzes. isovaleryl-CoA. isobutvryl-CoA, and 2-methy Ibutyry 1 -CoA.

An intake imbalance with inadequacy of one of the branched-chain amino acids (valine, leucine, or isoleucinci causes activation oforbi to frontal cortex, frontal gyrus, and thalamus and leads to the development of conditioned taste aversion (Gietzen and Magrum, 2001). Expression of several genes in response lo inadequacy changes, but the mechanisms responsible for learning to balance branched-chain amino acid intake remain elusive.


Energy fuel Eventually, most Leu is broken down providing about 6.0kcal/g. About 60% of ingested Leu is oxidized within □ few hours (Toth etat., 2001). The main site of Leu oxidation is skeletal muscle. Liver, intestines and other organs are responsible for much smaller percentages of Leu utilization as an energy fuel. Protein synthesis: Virtually all proteins contain Leu as pari of their specific sequence. A lack of Leu, as of all essential amino acids, limits protein synthesis. High concentration of free Leu in muscle, as after a protein-rich meal, stimulates protein synthesis (Mero. 1999). Leu and the other branched-chain amino acids have anabolic effects on skeletal muscle (Anthony et ul.. 2001), The protein kinase mTOR (mammalian target of rapamycin) is a key target: high Leu availability increases mTOR activity, which leads to the by per phosphorylation ofribosomal protein S(i kinase (SfiKl) and eukary-otic initiation factor4E binding protein I (4E-BP1). Signaling downstream of4E-BPI initiates the translation of capped mRNAs; events following SfiK I activation eventually increase the synthesis of proteins needed for translation. Both Leu and its minor (5-10"o) metabolite beia-hydroxy-beta-methylbutyrate (HMB) are sometimes used to boost muscle mass in people with muscle wasting due to AIDS or other diseases (Kreider. 1999; Mero, 1499; Nissen ft at.. 2000).

Cell proliferation: It has been suggested thai the Leu metabolite a I pha-ketoi socaproate stimulates the phosphory lation of PH AS-I (phosphorylatcd heat- and acid-stable protein regulated by insulin), a recently discovered regulator of translation initiation during cell mitogenesis (Xu et at., 1998), This effect appears to be particularly important for the promotion of beta-cell proliferation and augments the growth-stimulating effects of insulin and insulin-like growth factor 1 (IGF-I).

Ketogenesis: A significant proportion (40% of an ingested dose) is converted into acetyl-CoA and thereby contributes to the synthesis of ketones, steroids, fatty acids, and other compounds (Toth et at. 2001). Adipocytes in particular have a high capacity to generate ketone bodies from Leu.

Neurotransmitter metabolism: It has been suggested that Leu and the other branched-chain amino acids promote nitrogen transfer between astrocytes and neurons in the brain. This BCAA shuttle might be critical for the synthesis of the neurotransmitter L-glutamate (Hutson et a!., 2001).

Toxicity: High Leu concentrations in blood are potentially harmful. The mechanisms responsible for such toxicity arc not yet well understood.


Anthony JC. Anthony TO, Kimball SR. Jefferson I S. Signaling pathways involved in translational control of protein synthesis in skeletal muscle by leucine. ./ Nutr 2001:13 l:856S-860S

Avissar NL. Ryan CK. Ganapathy V, Sax ML. N;i -dependent neutral amino acid transporter ATBo is a rabbit epithelial cell brush border protein. Am J Physio! Cell Physiol 200t;281:C963 71

Bloch K. Clark LC. Haray 1. Utilization of branched chain acids in cholesterol synthesis. JSiotChem 1954:211:687 99

Chairoungdua A. Segawa H. Kim JY. Miyamoto K, Haga H, Fukui Y, Mizoguchi k. !to H, Takeda E, Endou H, Kanai Y, Identification of an amino acid transporter associated with the cystinuria-related type II membrane glycoprotein. J Biol Chem IW; 274:28845 8

Gietzen DW, Magnim I J. Molecular mechanisms in the brain involved in the anorexia of branehed-chain amino acid deficiency../ Nutr 200 I ;K51S-855S Hutson SM. Lieth E. LaNoue Kl Function of leucine in excitatory neurotransmitter metabolism in the central nervous system. J Nutr 2001;131:8465 850S .lansson T. Amino acid transporters in the human placenta. Pediatr Rex 2001: 49:141 7

Kreider RB. Dietary supplements and the promotion of muscle growth with resistance exercise. Sports Med 1999:27:97 110 Kurpad AVI Regas MM. Raj T, Masuthy k. Gnanou J. Young VR. Intravenously infused

HC-leucinc is retained in lasting healthy adult men. J Nutr 2002; 132:1906-8. Matthews DE, Marano MA. Campbell RG. Splanchnic bed utilization of leucine and phenylalanine in humans. Am J Physiol 1993:264: El 09--18 Mero A. Leucine supplementation and intensive training. Sports Med 1999;27:347-58 Nissen SL. Abumrad NN. Nutritional role of the leucine metabolite jB-hydroxy 0-methvl-

butyrate t HMB). J Nutr Biochem 1997:8:300 11 Nissen S, Sharp RL. Panlon L. Vukovich M, Trappe S, Fuller JC jr. /3-hydroxy-/i-methy]-butyrate(HMB) supplementation in humans is safe and may decrease cardiovascular factors../ Nutr2000; 130:1937 45 Poston JM. The relative carbon llux through the alpha- and the beta-keto pathways of leucine metabolism, J Biol Chem 1984:259:2059 61 Ritchic JW. Taylor PM. Role of the System I permease LAT1 in amino acid and iodothy-

ronine transport in placenta, Biochem./2001;356:719-25 Scislowski PW, Zolnierowiez S. Swicrczynski J, Elewski L. Leucine catabolism tn human term placenta. Biochem Med 1983;30:141-5 Toth M.I. MacCoss MJ, Poehlman ET. Matthews DE. Recovery of( l3)CO(2| from infused [l-( l3|C)leucinc and [1,2-(13 )G(2 J] leucine in healthy humans. Am J Physiol Endocrinol Metuh 2001:281 :F233 41 Utsunomiya-Tate N, Endou H. Kanai Y. Cloning and functional characterization of a system ASC-tike Na+-dependent neutral amino acid transporter. J Biol Chem 1946: 271:14883-90

Xu G. Kwon G. Marshall CA. Lin TA. Lawrence JC Jr. McDaniel ML, Branched-chain amino acids are essential in the regulation of PHAS-I and p70 S6 kinase by pancreatic beta-cells, A possible role in protein translation and mitogcnic signaling. J Biol Chem 1998;273:28178-84

cooh h2n-ch Valine i ch

/ \ The hydrophobic neutral amino acid L-valine (2-ami no isovaleric acid, 2-amino-3-

methylbutylbutyric acid, alpha-aminoisovaleric acid, 2-amino-3-mcthylhutanoic acid. Figure a.sa L-v.ihnt! one-letter code V: molecular weight 117) contains 12.0% nitrogen.


Co A coenzyme A

FTF electron-transferring flavoprotein

LATI L-type amino acid transporter 1 (SLC7A5)

LAT2 L-type amino acid transponer 2 (SLC7A8)

RDA recommended dietary allowance

Val L-valine

Nutritional summary

Function: The essential amino acid L-valine ( Vail is needed for the synthesis of proteins. It is also used as an energy fuel: its complete oxidation requires thiamin, riboflavin, niacin, vitamin B6. vitamin 1312. pantothenate, biotin. lipoate. ubiquinone, magnesium, and iron.

Food sources: The proteins in foods from animal and plant-sources typically contain about 40 60 mg/g Val. Dietary supplements with crystalline Val. often in combination with other amino acids, are commercially availablc.

Reifuirements: Adults are thought to require at least 20 mg kg per day (Young and Borgortha, 2000).

Deficiency: Prolonged lack of Val as of all essential amino acids or a lack of protein causes grow th failure, loss of muscle mass and organ damage. Excessive intake: Very high intake of protein and mixed amino acids (more than three times the RDA or 2.4 g, kg) is thought to increase the nsk of renal glomerular sclerosis and accelerate osteoporosis.

Dietary sources

Dietary proteins from different sources all contain Val. Protein from milk, eggs, and rice has a slightly higher content (mom than 60 mgg of total protein) than protein from meats, legumes or corn (about 50mg/g), or wheat (44 mg/g).

Digestion and absorption

Proteins are hydrolyzed by various enzymes from gastric, pancreatic, and intestinal secretions.

The hydrogen ion peptide cotransporters (SLC15A1. PepTI). and to a lesser degree. PepT2 (SLC15A2) mediate uptake of di- and tripeptides. including those containing Val. Free Val crosses the small intestinal brush border membrane via the sodium-driven transporter B° (Avissar et ai, 20(11 ), I ike many other neutral amino acids. Val can be exchanged for other neutral amino acids across the brush border membrane in either direction by the rBAT (SLC3AI ^anchored amino acid transporter BAT l b11, (SLC7A0) (Chairoungdua ei ui. 1099).

The 4F2 (SLC3A2) glycoprotein-anchored transporter LAT2 (SLC7A8) can move V'al across the basoiateral membrane in both directions in exchange for other neutral amino acids.

(WW peptides

(WW peptides

Intestinal lumen

Capillary lumen

Brush border membrane

Basóla le ral membrane

Capillary endothelium

Intestinal lumen

Capillary lumen

Brush border membrane

Basóla le ral membrane

Capillary endothelium

Figur» 8.S9 tntMiinal abiorprion of L-valirte

The intestines sequester about 20% of ingested branched-chain amino acids after uptake. Only a small portion of this is oxidized, most is incorporated into newly synthesized proteins or converted into alpha-keto acids and released (Matthews et ai, 1993).

Transport and cellular uptake

Blood circulation: Cells can take up Val bound in the various blood proteins via mechanisms specific to the respective proteins. Free Val enters cells mainly via the sodium-driven transporter B and transporters of the sodium-independent system L. including the glycoprotein 4F2 (SLOA2M inked LAN (SLC7A5) (Verrey ei ai, 1999).

The branched-chain amino acid transaminase (FC2.6.1.42) which is located at the inner mitochondrial membrane may function as a transporter of branched-chain ammo acids.

Blood brain barrier One or more members of the L-type amino acid transporter family mediate the exchange of Val for other neutral ammo acids across both sides of the brain microvessel endothelial cells. Their molecular identity is not yet established, Materno fetal transfer: The sodium-driven transporter B" in the brush border membrane mediates Val uptake into the syncytiotrophoblast: its transport capacity is expanded by the heteroexchanger LAT1 4F2 (Jansson, 2001).

A significant percentage of the Vat taken up from maternal circulation is metabolized in the placenta (Cetin. 2001). The remainder is taken across the basolateral membrane by LAT2 4F2 in exchange for another neutral amino acid.


The main pathway of Val breakdown to propionyl-CoA is initiated by transamination followed by another six reactions. Propionyl-CoA can then be converted to the Krehs cycle intermediate suceinyl-CoA via three additional steps. The entire metabolic sequence requires vitamin 116. thiamin, riboflavin, niacin, pantothenic acid lipoatc, biotin. and v itamin 1112. Val is glucogenic since it is broken dow n to suecmyl-CoA.

Branched-chain amino acid aminotransferase 2 {EC2.6.1.42) moves the amino group of Val to alpha-ketoglutarate- Alternatively, valine-3-methyl-2-oxovaIerate aminotransferase (EC2.6.1.32) can use the amino group of Val to reconstitute the L-isolcucine metabolite (S)-3-methyl-2-oxopomanoaie (Dancis et ai. 1%7). While the relative importance of this pathway remains to be elucidated it has been found that Val concentrations in blood are elevated in people with half the normal activity of this particular aminotransferase.

The next step is catalyzed by branched-chain atpha-keto acid dehydrogenase (EC which is a large complex in the mitochondrial matrix consisting of multiple copies of three distinct subunits. The subunit El catalyzes the decarboxylation reaction with reduced coenzyme A as a cosubstrate. El itself is a heterodimer of an alpha chain with thiamin pyrophosphate (TPP) as a prosthetic group, and a beta chain. Subunit E2 anchors the lipoic acid residue, which serves as an acceptor for the decarboxylated substrate. transfers it to acetyl-CoA. and reduces lipoamide to dihydrolipoamide in the process. The lipoamide dehydrogenase component, subunit E3 (ECl.8.1.4). transfers the hydrogen from dihydrolipoamide via its FAD group to NAD. The glycine cleavage system (ECl.4,4,2) and the dehydrogenases for pyruvate (ECl.2.4.1) and alpha-ketoglutarate (EC2.3.1.61) use the same enzyme suhunit. The enzyme complex is inactivated by phosphorylation ([3-mcthyl-2-Oxobutanoatc dehydrogenase (lipoamide)] kinase. EC2.7.1.115). and reactivated by dephosphorylation ([3-methyl-2-oxobuiauoate dehydrogenase (lipoamide)|-phosphatase. EC3.1J.52). Branched-chain alpha-keto acid dehydrogenase is defective in maple syrup disease, which affects the breakdown of all three branched-chain amino acids, including L-lcucine and L-isoleucine.

A small amount of Val appears to be decarboxylated directly to S-beta-aminoisobu-tyrate (BAIH) by branched-chain alpha-keto acid dehydrogenase (ECl ,2.4.4), Most of the BAIB in blood is the S-stcreoisomer and thus derived from Val. R-BAIB. in contrast. which is the dominant stereoisomer excreted with urine, is derived from thymine breakdown Methylmalonic setnialdehyde dehydrogenase (EC can metabolize both forms to propionyl-CoA.

Acyl-CoA dehydrogenase-8 (no EC number assigned) oxidizes isobutyryl-CoA to methylacrylyl-CoA (Telford et ul., |W); Andresen elul.. 2000), and reduces FAD in the closely associated mitochondrial electron-transferring flavoprotein (ETF). Its deficiency causes the accumulation and urinary excretion of isobutyrate derivatives (Roe et ul., 1998), The extent to which other acyl-C'oA dehydrogenases, particularly short-chain acyl-CoA dehydrogenase (ECl.3.99.2), also contribute to isobutyryl-CoA metabolism in various tissues remains to be seen.

A separate iron-sulfur llavoenzyme associated with the acyl-CoA dehydrogenases, I'TF dehydrogenase (ECl .5.5.1). uses the FA DM 2 to generate the oxidative phosphorylation fuel ubiquinol.


CH Branchad-cliain amino acid CH transaminase 2 (PLP)

H jC CH3

n-keto- L-tsoleueine vale rate -¿ii-— L-Valine ^^^ «-Keloisovaterate Valine 3-methyl 2-oxovaleraie aminotransferase (PLP)

cooh I


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