Leucine

The hydrophobic neutral branched-chain amino acid I.-leucine (2-am i no-4-methyl- cooh valeric acid, alpha-aminoisocaproic acid. 2-amino-4-mcthylpentanoic acid, one-letter code L; molecular weight 1311 contains I0,7"u nitrogen.

CM2 I

Abbreviations / \

BCAA branched-chain amino acids

CoA coenzyme A Flgur* 8.55 L-Leucmc

HMGCoA hydroxymethylglutaryl-CoA Leu L-leucine

LATI L-type amino acid transporter 1 (SLC7A5)

LAT2 L-type amino acid transporter 2 (SLC7A8)

Nutritional summary

Function: The essential amino acid L-leucine (Leu) is needed for the synthesis of proteins. It is also an important energy fuel, especially in muscles: its breakdown requires thiamin, riboflavin, pyridoxine. niacin, cobalamin. biotin. pantothenate, lipoatc. ubiquinone, magnesium, and iron.

Food sources; Adequate amounts are consumed w hen total protein intakes meet recommendations. since dietary proteins from different sources all contain Leu. Corn and dairy protein contains slightly more Leu than protein from most other foods Requirements: Adults arc thought to require more than 40mg/kg per day (Kuspad et al.. 2002).

Deficiency: Prolonged lack of Leu. as of all essential amino acids or a lack of protein, causes growth failure, loss of muscle mass, and organ damage. Additional Leu might increase lean body mass m people with muscle wasting, possibly also concurrent with exercise.

Excessive intake. Very high intake of protein and mixed amino acids (more than three times the recommended dietary allowance or 2.4 g leg) in thought to increase the risk of renal glomerular sclerosis and accelerate osteoporosis. The consequences of very high intakes of Leu have not been adequately evaluated.

Dietary sources

Leu is an essential amino acid that cannot be synthesized by humans from other amino acids or kcto acids and must be derived from foods, therefore. All food proteins contain Leu, usually between 7 and 9%. Slightly richer sources arc the proteins in milk and dairy products(9,8%), com (12.3%}. and sorghum (13,2%I, Mature human milk protein contains 10.4% Leu.

Digestion and absorption

Proteins are hydrolyzed bj various enzymes: most of them arc derived from the stomach wall and pancreas.

The hydrogen ion peptide cotransporters I (PepTl. SLC15A11 and to a lesser extent. 2 (Pep 12. SLC15A2) mediate uptake ofdi- and tripeptides. including those containing Leu. Free Leu can cross the small intestinal brush border membrane via the sodium-driven transporter ii (identical with system li NBB, Avissar et at., 2001

Like most neutral amino acids. Leu can be exchanged for other neutral amino acids across the brush border membrane in cither direction by the rRAT(SLC3Al (-anchored di'tr oeptid di'tr oeptid

Intestinal lumen

Capillary lumen

Brush border membrane

Ba so! a lera I membrane

Capillary end ol helium

Figur« 8.56 Internal absorprinn of L-leucine amino acid transporter BATl/b" ' (SIX 3, Chairoungdua <7 ul., 1999). The 4F2 (SLC3A2) glyeoprotein-anchored transporter LAT2 (SLC7A8)can exchange Leu across the basolateral membrane in both directions in exchange for other neutral amino acids.

Leu can also be absorbed from the colon lumen, but the extent of this is unknown (Utsunomiya-Tate et ul., 1996). Uptake proceeds via ASCT2 and possibly other transporters. Little is known about Leu transport across the basolateral membrane of colonic enteroeytcs.

The intestines sequester about 20% of ingested Leu after uptake. Only a small portion of this is oxidized: most is incorporated into newly synthesized proteins or converted to alpha-ketoisocaproate and released (Matthews et til, 1993).

Transport and cellular uptake

Blood emulation; Leu is a ubiquitous component of proteins in blood and can be taken up by cells via mechanisms specific to the respective proteins. Free Leu (plasma concentrations are around 120 jimol/l) enters cells mainly via system L, including the specifically identified hetcroexchanger LAT1 (SLC7A5). The branched-chain amino acid transaminase (LC2.6.1.42). which is located at the inner mitochondrial membrane, may function as an importer of branched-chain amino acids.

Materno-fetal transfer Leu uptake across the microvillous membrane of the syncytium) phoblast is mediated by LATl (Ritchie and Taylor. 2(H)!). transport across the basal membrane proceeds via LAT2 (SLC7A8). both in exchange for other neutral amino acids (Jansson, 2001). The driving force for LATl/LAT2-mcdiatcd transport is the concentration gradient of small neutral amino acids (glycine. L-alanine, L-cysteinc) established by the sodium-dependent transport systems A and ASC. Only some ofthe Leu taken up by the placenta from maternal circulation reaches the fetus, a significant proportion is metabolized (Scislowski et til, 1983).

Blood bram barrier: System L mediates Leu transpon across both sides ofthe neurocn-dolhelial cell layer. The molecular identity and location ofthe responsible transporters) remain unclear.

Metabolism

Most I cu is broken down via the main catabolic pathway intoacetoacetate and acetyl-CoA in a sequence of six cnzyme-catalyzed steps that are initiated by transfer ofthe amino group to alpha-kctoglutarate. Complete oxidation of Leu via this pathway is dependent on adequate availability of thiamin, riboflavin, pyridoxine, niacin, pantothenate. biolin, ubiquinone, and lipoic acid. A much smaller amount (5-10%) is oxidized via beta-hydroxy beta-methylbutvrate (HMB). Another alternative metabolic sequence, the beta-keto pathway, appears to be significant only in testes. This pathway-is remarkable because its initial reaction is catalyzed by one of only three enzymes that require cobalamin as a prosthetic group.

Mam catabolic pathway: Breakdown of Leu in mitochondria can begin with the transfer of its amino group to alplia-ketoglutarate by branchcd-chain amino acid transaminase (EC2.6.1.42). The activity of an alternative enzyme, L-leucine-aminotransferase (I AT,

EC2.6.1.6) is significant only in a few specialized tissues, such as testes (Sertoli cells) and pancreas. The resulting alpha-ketoisocaproic acid then undergoes oxidative decarboxylation; this reaction is irreversible. The enzyme responsible For this activity, branched-chain alpha-keto acid dehydrogenase (HC1.2.4.4), is a large complex in Hie mitochondrial matrix consisting of multiple copies of three distinct subunits. The subunit El catalyzes the decarboxylation reaction with reduced coenzyme A as a cosub-strate. El itself is a heterodimer of an alpha chain with thiamin pyrophosphate 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-Co A, and reduces lipoamide to dihydrolipoamidc in the process. The lipoamide dehydrogenase component, subunit E3 (EC1.8.1.4), transfers the hydrogen from dihydrolipoamidc via its FAD group to NAD. The glycine cleavage system (EC1.4.4.2) and the dehydrogenases for pyruvate (FC1.2.4.1) and alpha-ketoglutarate (EC2.3.1 .(>1) use the same enzyme subunit. The enzyme complex is inactivated bv phosphorylation (13-mcthyl-2-oxobutanoate dehydrogenase (lipoamide)] kinase; EC2.7.1.I 15). and reactivated by dephosphorylation ([3-methyl-2-oxobutanoate dehydrogenase (lipoamide)]- phosphatase; EC'3.1.3.52). Branched-chain alpha-keto acid dehydrogenase is defective in maple syrup disease which affects the breakdown of Leu as well as the other branched-chain amino acids. L-isoleucine and I,-valine.

The next step, conversion of isovaleryl-CoA into 3-methylcrotonyl-CoA. is catalyzed bv isovaleryl-CoA dehydrogenase (EC1.3.99.10). This enzyme is not identical with the analogous enzyme (2-methylacyl-CoA dehydrogenase. EC 1.3.99.12) for the acyl-CoA products of L-valine and L-tsoleucine metabolism. Isovaleryl-CoA dehydrogenase is a flavoprotein closely associated with electron-transferring fiavoprotein (ETF) and another flavoprotein, ETF dehydrogenase(ECl.5.5.1). FAD is used in each of these three components of the mitochondrial electron transfer system to form a cascade that eventually reduces ubiquinone to ubiquinol; this can then be utilized directly for ATP synthesis through oxidative phosphorylation. Excessive amounts of isovaleryl-CoA, which accumulate to neurotoxic levels in patients with deficiency of isovalcryl-C'oA dehydrogenase, can be conjugated by glycine-N-acylase (EC2.3.1.13) and excreted as with urine as isovalerylglycine.

A biotin-containing enzyme, methylcrotonyl-CoA carboxylase (EC6.4.I.4), catalyzes the next, irreversible conversion to tnms-3-melhyI glutaconyl-CoA, followed by hydration (methylglutaconyl-CoA hydratasc, EC4.2.1.18) to hydroxy methylglutaryl-CoA(HMGCoA).

HMGCoA reductase (ECL1,1.34) catalyzes the reaction that commits HMGCoA to the cholesterol synthesis pathway. Indeed, l.eu has been found to provide a significant proportion of the carbon in de novo synthesized cholesterol (Bloch el a!.. 1954). Alternatively. HMGCoA can be cleaved into acetyl-CoA and acetoacetate by HMGCoA lyase (EC4.U.4).

Beta-hydroxy beta-methylbutyrate: Conversion to beta-hydroxy beta-methylbutyrate (H\IB) accounts for 5 10% of Leu catabolism (Nissen and Abumrad, 1997). Alpha-keto isocaproate dioxygenase. the cytosolic iron-containing enzyme responsible for oxidative decarboxylation, may actually be 4-hydroxypheny¡pyruvate dioxygenase (ECT.13.11.27, catalyzes second step of tyrosine catabolism) judging from its very

COOH I

»-Ketoiso-caproic acid

Branched-chain amino acid transaminase )PLP)

L-glutamaie n-keto-glutarale

COOH I

(J-Leuorte aminormjlase (AooCbii

HjC^ SCH, L-Leucine

CoA-SH NAD "^S Branched-chain

«■kelo acid dehydrogenase (TPP. Iipoamide)

u-Ketoisocaproale dioxygenase (Fe)

CO. NADH

S-CoA

COOH

Isovaleryl-CoA

Isovaleryl-CoA dehydrogenase (FAD)

^|rTFdA0DVUb'qUirWe tiydrogenase Y

WFAD.Fe ¡A etffadh, ublqulnd

S-CoA I

COOH

H ;C CHa fi-hydroxy (i-methyl butyrate-CoA

Methyl-crotonyl-CoA carboxylase (biotin, Mg' )

S-CoA 1

CH II

My Life My Diet

My Life My Diet

I lost over 60 pounds and 4+ inches off my waist without pills, strenuous exercise, or any of the things that the diet experts tell you to do...and I did it in less than 4 months! If you have the desire, and can read through my e-book , then this is for you! I could have easily made it a lot more difficult, with stacks of information that people will never read, but why?

Get My Free Ebook


Post a comment