Transport and cellular uptake

Blood circulation: While most Lys in blood is pan of proteins, the concentration of free Lys in plasma is around 195 p.mol/1. Uptake into tissues proceeds mainly via various members of system y'. The gly coprote in-anchore d heteroexchangers y LAT1 and y' LAT2 contribute to a smaller extent to Lys uptake in some tissues. At least one of these transporters is also active in red blood cells.

The mitochondrial ornithine transporter I {ORNTl. ornithine/citrulline carrier; SLC25AI5) can move Lys from cytosol into mitochondria (Indiveri et al.. 1999).

Materno fetal transfer Since Lys is an essential amino acid the fetus is fully dependent on transfer across the placenta. Several members of system y * (CAT-1. CAM, C AT-2 B) mediate uptake from maternal circulation into the syntrophohlast layer. Lxport towards fetal circulation uses mainly the membrane-anchored heterodimer composed of y LATI (SLC7A7) and glycoprotein 4F2 (SLC3A2). Lys is exchanged by the y ' LATI transporter for a neutral amino acid and a sodium ion.

Blood brain barrier: While there is no doubt that circulating blood has to supply the essential nutrient Lys to brain, knowledge about the mechanism for transfer across the blood-brain barrier is limited. The 4F2-anchored exchange complex y * LAT2 is known to contribute significantly (Broer er al, 2000). Adequacy of Lys intakes influences flux into brain (Tews el al., 1988).

Metabolism

Lys catabolism transfers the two amino groups to alpha-ketoglutarate and generates two molecules of acetyl-CoA. The main pathway proceeds via saceharopinc to alpha-ketoadipate in liver cytosol, and then continues in mitochondria to acetyl-CoA. An alternative peroxisomal pathway via L-pipecolate is most important in brain and also contributes to some extent to Lys breakdown in other extrahepatic tissues.

The first two steps of Lys breakdown via the main pathway use the bifunctional protein semiaklehyde synthase that combines the activities of lysine ketoglutaratc reductase (EC1.5.1.8) and saccharopine dehydrogenase (EC 1.5.1.9). In the end, these acliv ¡ties move the cpsilon amino group from Lys to alpha-ketoglutarate.

Oxidation by aminoadipate-semialdehyde dehydrogenase (EC 1.2.1.31. magnesium-dependent) and pyndoxa 1-5'phosphate-dependent transamination by 2-aminoadipate aminotransferase (EC2.6.1.39) generate alpha-ketoadipate. The mitochondrial oxodicarboxylate carrier (OI)C. no SLC number assigned) moves this intermediate from cytosol into mitochondria (Ftcrmonte et al., 2(H)]). where oxidative decarboxylation by oxoglutarate dehydrogenase (EC 1.2.4.2) continues iLs metabolism. This multi-subunit enzyme contains thiamin pyrophosphate and lipoamidc as covalently bound cofactors. Glutaryl-CoA dehydrogenase (ECL3.99.7) then catalyzes both FAD-dependent oxidation and decarboxylation loerotonyl-CoA. Beta-oxidation ofcrotonyl-CoA finally releases two acetyl-CoA molecules.

Alpha-deaminaiion by L-Iysine oxidase (EC 1.4.3.14) starts the pipecolate pathway of Lys breakdown. Two as yet unchaiacterized steps then generate pipecolate. This Lys intermediate is transported into brain neurons via the high-affinity proline transporter PROT and may influence excitation (Galli et al.. 1999). Oxidation by the FAD-containing L-pi peculate oxidase (EC1.5.3.7; [Jlst et al.. 2000) and non-enzymic hydration generate alpha-aminoadipate semialdehyde and thus rejoin the main pathway.

Storage

Body proteins contain about 82mg/g (Smith. 1980). Normal turnover of body proteins will release significant amounts of Lys. In the case of isolated Lys deficiency, protein mobilization may increase through incompletely understood mechanisms.

L-Lysirve

NH-j. HJOJ

Lvflmf]

6-catboxyl3ie

trf"

o n-Kotoadipaicp

OKixfuirbnxYJjilu

OKixfuirbnxYJjilu

«-KeToadpcitB

NAO f t HMOA

¡JFhyu ruoefuwu iTTf/twuilu'FADI

NADU

GlulafylCoA

CtotonyH CoA 0

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ACTtyl C<lA

AceM-CaA

L-3- Hydimytouty tyl -CoA

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Acetyl CnA

Figure (t.S4 Alierrtait pathways degrade L-lysitic via vacch.iropint; or pipecolatc

Excretion

Losses of intact Lys are minimal due to efficient recovery both from intestines and kidney. In contrast, the dead-end metabolite methyllysine is not well reabsorbed and most is excreted w ith urine.

Close to 5 g of Lys passes across the renal glomeruli, and most of this is reabsorbed from the proximal tubular lumen. Uptake proceeds via the sodium-dependent system the sodium-independent system yJ (CAT-1. SLC7A1 )and 2 (CAT-2. SLC7A2). and the transporter heterodimer consisting of BATl/b' (SLC7A9) and rBAI (SL( '3A1). The glycoprotein 4 f 2-1 inked transporters y LATI (SLC7A7) and y+ LAT2 (SLC7A6) on the basolateral side mediate export towards the capillaries {Broer et ul.. 2000; Bode. 2(1(11).

Regulation

Lys homeostasis is maintained in pan bv changes in the rate of protein cataholism. Lys metabolic utilization as well as oxidation as an energy fuel, but details of the responsible mechanisms remain to be elucidated. Lys catabolism increases greatly in response to intake (El-Khoury et ul., 1998).

Function

Energy fuel: Eventually, most ofthe ingested Lys is completely metabolized. The daily rate of Lys oxidation in healthy adults w ith low to moderate intakes is about 27 mg/kg body weiglu (Fl-Khoury el ul.. 2000). I ys is a particularly important energy fuel for muscles. Complete oxidation provides 4.92 kcal.g (May and Hill. 1990) and depends on adequate supplies of thiamin, riboflavin, niacin, vitamin B6. pantothenate, lipoate, ubiquinone, iron, and magnesium.

Protein and peptide synthesis: Lys is a regular component of most proteins and many peptides. Post-translational reactions can modify the amino group that is not engaged by the peptide bond in proteins. An important example is the conjugation of specific Lys residues in a few proteins to biotin by b i oti n-[p ro piony l-Co A -Cu rboxy lase (AT P-hydrotysing)] ligase (EC6.3.4.I0). Another type oT post-translational modification involving Lys residues is hvdroxyiation and subsequent formation of cross-links in eollagens. First, procollagen-lysine 5-d i oxygenase (ECl.14.11.4) attached to the rough endoplasmic reticulum uses alpha-keloglutarate and oxygen to hydroxy laic Lys residues adjacent to glycines in procollagen. Ascorbate keeps iron in this fcrroen/yme in the reduced state. Several genetically distinct isoforms exist. As procollagen extrudes into the extracellular space and forms the typical triple helix arrangements, the copper-enzyme lysyl oxidase (protein-lysine 6-oxidase; EC 1.4.3.13) links strands through the formation of bonds between Lys and hydroxylysine residues. Another example is the methylation of specific Lys residues in ¡listones, which is critical to maintain certain chromatin segments in the inactive slate (Peters etui, 2002). Carnitine synthesis: Lys is the critical precursor for endogenous carnitine synthesis in liver, kidney, and some other tissues. Daily production is about 0.2 mg kg and depends on the adequate availability of niacin, vitamin B6, folate, ascorbatc, S-adcnosy I methionine (SAM), and iron. Specilic lysine residues of myosin, act in. histones and a few-other proteins are trimethylated. Hydrolysis of these proteins during normal tissue turnover releases trimethyllysine and this is hydroxylated and modified further to finally yield carnitine.

Polyamine synthesis: The PLP-containing ornithine decarboxylase (EC4.I.I.17) converts Lys into cadaverine, which plays an important role in intra- and intercellular signaling, One example of its functions is the ability of cadaverine to prevent the escape of Shigella jiexneri from phagolysosomes by blocking transepithelial signaling to polymorphonuclear cells (Fernandez el a/., 2(101).

References

Bode BR Recent molecular advances in mammalian glutamine transport. J Nutr 2001; !3I:2475S-248SS

Broer A. Wagner CA, Lang F, Hroer S. The heterodimerie amino acid transporter 4F"2he y*LAT2 mediates argimne elllux in exchange with glutamine. Bioehem .1 2000: 349:787-95

Chairoungdua A, Segawa H, kim JY. Miyamoto K, Haga II, Fukut Y, Mizoguchi k, Ito IT, Takeda t, Fndou H, kanai Y. Identification of an amino acid transporter associated with the cystinuria-rclated type II membrane glycoprotein J Biol Chem 1999:274:28845 8 Dworsehak F., Nonenzyme browning and its effect on protein nutrition. Crit Rev Fond Sej Nutr 1980:13:1- 40

El-Khoury AE, Pereini PC. Borgonha S, Basile-Filho A. Beaumier L. Wang SY, MetgesCT . Ajami AM. Young VR. Twenty-four-hour oral tracer studies with L-fM3C]lysme at a low (I5mg kg (-1) - d l-l)) and intermediate (29mg - kg (-l)-d(-l)) lysine intake in healthy adults, dm J Clin Nutr 2000;72:122 -30 EI-Khoury AE. Basile A. Beaumier L, Wang SY. Al-Amiri HA. Selvaraj A. Wong S. Atkinson A. Ajami AM, Young VR. Twenty-four-hour intravenous and oral tracer studies with L-[l-' Cj-2-aminoadtpic acid and L-[l-l5C]lysine as tracers at generous nitrogen and lysine intakes in healthy adults. Am J Clin Nutr 1998;68:827-39 Fernandez 1M. Silva M, Schuch R. Walker WA, Siber AM, Maurelli AT, McCormick HA. Cadaverine prevents the escape of Shigella Jiexneri from the phagolysosome: a connection between bacterial dissemination and neutrophil transepithelial signaling. JJnf Dist 2001 ;184:743-53 Fiermonte (i. Dolce V, Ralmien I.. Ventura M, Runswick MJ, Palmieri F, Walker .IF. Identification of the human mitochondrial oxodicarhoxylate carrier. Bacterial expression. reconstitution, functional characterization, tissue distribution, and chromosomal location../ Biol Chem 2001:276:8225-30 Galli A, J av ant hi l.D, Ramsey IS. Miller JW, Fremeau RT Jr, DeFclice LJ. 1.-proline and L-pipecolate induce enkephahn-sensitive currents in human embryonic kidney 243 cells transfccted with the high-affinity mammalian brain L-proline transporter. JNeurosct 1994; |9( I5):6240 7 Ulst L. de kromnie I. Oosthcim W. Wanders RJ. Molecular cloning and expression of human I -pipecolate oxidase. Bioehem Biophvs Res Cnmm 2000:270:1101 5

Indivcri C. Tonaz/i A, Siipaui I, Palmieri I". The pun lied and reconstituted ornithine citruilinc carrier from rai liver mitochondria catalyses a second transport mode: ornithine H ' exchange, BiochemJ 1999:341:705 11 May ME, Hill JO, Energy content of diets of variable amino acid composition. Am J Clin Nutr 1990:52:770 6

Peters AH. Mermoud Jf, O'Carroll D, Pagani M. Schweizer D. Bruckdorf!' N, Jenuwein T. Histone H3 lysine 9 methylation is an epigenetic imprint of facultative hcterochro-matin. Nature Genet 2002:30:77 X0 Sachan DS, Daily JW III. Munroe SO. Beauchenne RE. Vegetarian elderly women may risk compromised carnitine status. Veg Nutr 1997:1:64 9 Smith RH. Comparative amino acid requirements. Prot NutrSoc t980;39:71 X Tews J K. Greenwood J. Pratt OP. Harper A P. Dietary amino acid analogues and transport of lysine or valine across the blood-brain barrier in rats../ Nutr 1LJXK: 11 K:75fi (t3

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.

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