cooh I

I z ch2

Homocysteine cpOOH H3N"<j;H


Cystathionine beta-synthase (plp)

serine h3o hjn—ch

Cystathionine gam ma-lyase (plp)

Cystathionine h,0


HS k


CH—NHj HOOC Cysteine

Figure 8. J? Thu* trartjiuffuration pathway h'°c.aad h,co,-nadh n-Keto acid dehydrogenase


(jHa ch3


More than 600mg Met is filtered by the kidney per day. Mel is quantitatively reabsorbed from the proximal tubular lumen by amino acid transporter B", and returned across the basolateral membrane into blood by amino acid transport system A. Transport is augmented by the heterodimeric transport system b"'4 (consisting of BAT! and rBAT) at the luminal side, and LAT2 4F2 at the basolateral side (Wagner et ai, 2001).


The main events impacting Met homeostasis are utilization ofSAM as a methyl group donor, remethvlation of homocysteine, and the rate of conversion to cysteine I Mato etal,.

2002). Glycine N-metliyltransferase is the major SAM-utilizing enzyme 111 liver that helps lo metabolize excess Met. An inborn lack of the enzyme is associated with elevated Met concentration in blood.


Protein synthesis; Mel is a constituent of practically all proteins and peptides synthesized in the body. Methioninc-tKNA ligase (EC6.1.L10) loads Met onto a specific t-RNA in an ATP magnesium-dependent reaction. About 2.1 mgkg body weight are incorporated into bodv proteins per day (Rag uso el ul.. 2000). Energy füel Most (90% or more) Met is eventually metabolized to carbon dioxide, water and urea. The complete oxidation of Met (\ia cysteine and propionyl-CoA) requires adequate availability of thiamin, riboflavin, niacin, \ itamin lib, vitamin B12, pantothenate, biotin. lipoate, ubiquinone, iron, and magnesium; disposal of the sulfur in Met requires molybdenum. Met prov ides 5.3 kcal/g (May and Hill, 1990). Methyl-group transfer ATP: I -melh ion ine-S-adenosy I transferase (EC2.5.L6) generates (he essential methyl-group donor S-adenosylmethionine (SAM). Genetically distinct isoforms of this enzyme exist, which arc expressed in a tissue-specific manner. A large number of enzyme-catalyzed reactions depend on adequate supplies of SAM. Important examples are the synthesis of phosphatidylcholine, carnitine, catecholamines. and melatonine. SAM-dependent creatine synthesis constitutes a very significant drain on methyl group donors, drawing about 70",. of the available pool (Wyss and Kaddurah-Daouk. 2000). Methylation silences the expression of specific segments ofDNA and regulates gene function. Inadequate SAM availability may impair proper DNA methylation and thereby increase risk of some cancers and other diseases. However, adequacy of the nutrients enabling methionine remelhylation (folate, vitamin U12) are likely to be more important than Met availability. Indeed, increased risk of cancer of the colon (Giovannucci et«/., 19931, stomach (La Veechia et ul., 1097). or other sites may be associated with high Mel intake.

Homocysteine: Use of SAM as a methyl donor generates homocysteine. When re methylation does not keep pace with production, homocysteine will spill over into extracellular fluid and blood circulation. Homocysteine is a potent oxidant, since it circulates in blood almost exclusively as homocystine, homocysteine-cysteine mixed disulfide, and protein-bound disulfides. Less than 2% is present in the thiol form (Lenlz, 2002). Elevated blood homocysteine concentrations and increased homocysteine excretion are associated with increased cardiovascular risk (atherosclerosis, thrombosis, myocardial infarction) and accelerated cognitive decline. Cysteine synthesis: The transsulfuiation pathway contributes a significant percentage to the body sCys input. When cysteine intakes are low. a greater percentage of the available Met is melaboli/ed via the transsulfuiation pathway. Adequate Cys intakes minimize this draw on Met supplies (Di Buono et ul.. 2001). Cys is also an important precursor for the synthesis of glutathione, coenzyme A. taurine, sulfate (for phosphoadenosyl phosphosulfate synthesis), and reactive sulfur compounds.

Polyamine synthesis: Decarboxylation of SAM by adenosy I methionine decarboxylase (EC4.1.1,50) generates methyl-S-adenosylthiopropylamine. Spermidine synthase nh, cooh hooc-ch—c—c—c—nr, I Hp Hp nh,

Ornithine h:in-ch

Ornithine decarboxylase nh, cooh h:in-ch

oh oh S-Adenosylmethionine co2

oh oh S-Adenosylmethionine


Spermidine synthase

Methylthio-adenosine H?

Adenosy I me thi o n i n e decarboxylase (pyruvoyl)

h3n-ch, m;> - orvi u hin—c—c—c—c—n—c—c—c—nh, . •_/ \

ij n^ rij Spermidine

Adenosy I me thi o n i n e decarboxylase (pyruvoyl)

Spermini synthase

Methylthio* " adenosine

OH OH S-Adenosylmethionine 3-aminopropyl methyl sulfonate hjn-c —c —c-n-c —c—c—c-n-c —c-c"—nh2 hr h;j h^ h ht h? h3 h h;


Figur* 8.48 S-aiienosyfinethionine is a precursor for polyamirte synthesis

(EC2.5.1.16) generates spermidine by transferring the aminopropyi moiety of this SAM metabolite to putrescine (decarboxylation product of ornithine), Spermine synthase (EC2.5.I.22) is a different en/yme that can add another aminopropyi group to spermine. The polycations spermidine and spermine Lire essential grow th factors for ail cells, but it is not yet known how they act. The residua) metabolite 5'-methyIthioadenosine (MTAi has itself distinct biological properties, such as promotion of apoptosis in abnormal (transformed) cells (Ansorena el <//.. 2002). Both 5'-mefhy Ithioadenosine phosphorylase(EC2.4.2.28)and adenosylhomocysteinase (EC33.1.1) can salvage the nucleoside moiety ofMTA (Smolensk! eta!.. 1992).

Acidity: A large portion of tjtratable acid in urine comes from the production of sulfuric acid from Met and Cys, High intake of sulfur-containing amino acids drains amino groups (used for neutralization in the kidneys) and may accelerate bone mineral loss (Marsh end.. I9SS).


Amorena E, Garcia-Trevtjano LR. Martinez-Chan tar ML. Huang ZZ. then L. Mato JM. Irahuru M. Lu SC. Avila MA. S-ade nosy Imct h ion i nc and me thy 1th i oadenos ine are antiapoptotic in cultured rat hepatocytes but proapoptotic in human hepatoma cells. Hepatology 200235:274 80 Chen J. Zhu V. Hu M. Mechanisms and kinetics of uptake and efflux of L-methionine in an intestinal epithelial model (Caeo-2). J Nutr 1994;124:1907-16 Cramer S. Beveridge M. Kilberg M. Novak D. Physiological importance of system A-mediated amino add transport to rat fetal development, ,-lm J Physiol Cell Physio! 2(H)2;282:CI53-60

Di Ruono M. VVykes I J. Bail RO. Pencharz PB. Dietary cysteine reduces the methionine requirement in men Am J Clin Nuir 2001;74:761 6 Duel I j R, Enerson BE, Gcrhart DZ. Drewes LR. Expression of large amino acid transporter LAT1 in rat brain endothelium. J Cereh Blood Flow Metah 2000: 20:1557 62

Dworschak I". Nonenzyme browning and its effect on protein nutrition. Crit Rev Food Sci Nutr 1980:13:1-40

Gtovanmicci E, Statnpfer MJ. Colditz GA. Rimm Eft. Triehopoulos D. Rosner BA. Speizer FE, Widen WC. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Natl Cancer Inst 1993:85:875 84 Halanaka 1.1 luangW Wang H. Sugawara M. Prasad I'D. I eibach FH.Ganapathy V. Primary structure, functional characteristics and tissue expression pattern of human AIA2. a subtype of amino acid transport system A. Biochim Biophys Acta 2000:1467:1 6 Halanaka T. Huang \V. Ling RH, Prasad PD. Sugawara M. Leihach I'll. Ganapathy V. Evidence for the transport of neutral us well ascationic amino acids by ATA3. a novel and liver-specific subtype of human ATA2, a subtype of amino acid transport system A. Biochim Biophys Acta 2001; 1510:10 17 Home DW, Patterson D. Cook RJ. Effect of nitrous oxide inactivation of vitamin B12-dependent methionine synthetase on the subcellular distribution of folate coenzymes in rat liver, Anh Bioehem Biophys 1989:270:729 33 .lansson T. Amino acid transporters in the human placenta. Pediatr Res 2001:49:141 -7 Killiun DM. Chikhale PJ, Predominant functional activity of the large, neutral amino acid transporter (LATI > isoform at the cerebrovasculature. \eumsd Lett 2001:306:1 4 KilazawaT. Hosya K. Watanabe M, TakashimaT, Ohtsuki S, Takanaga H. Ueda M, Yanai N. Obinata M. Terasaki T. Characterization of the amino acid transport of new immortalized choroid plexus epithelial cell lines: a novel in vitro system for investigating transport functions at the blood-cerebrospinal lluid barrier. Pharmaceut Res 2001;18:16-22

La Vecehia C, Negri E. Franeeschi S, Decarli A. Case-control study on influence of methionine, nitrite, and salt on gastric carcinogenesis in northern Italy. Vu/r Cancer 1997;27:65-8

Leclerc D. W ilson A. Dumas R, Gafuik C. Song D. Watkins D. Heng 11 HQ, Rommens JM, Schcrer SW, Rosenblatt DS. Gravel RA. Cloning and mapping of a cDNA for methionine synthase reductase, a flavoprotein defective in patients w ith homocystin-uria. Proc MatlAcadSci USA 1998:95:3059-64

Lent/ SR. Does homocysteine promote atherosclerosis? Arterioscl Thmmh Ifac Biol 2002:21:1385-6

Marsh AG, Sanchez TV. Michelsen O. Chaffee FL. Fagal SM. Vegetarian lifestyle and bone mineral density. AmJClin Nutr 1988:48:837 41 Mato JM. Corrales FJ, In SC. Avila MA. S-Adenosylmethionine: a control switch that regulates liver function. 2002:16:15 26

May ME, Hill ,IO. Energy content of diets of variable amino acid composition. AmJClin Nun-1990:52:770-6

McCaddon A, Regland H. Hudson I1, Da vies t> Functional \ itamin Bt 12) deficiency and

Alzheimer disease. Neurol 2002;58:1395-9 Munck LK, Grondahl ML. Thorboll IE, Skadhauge E. Munck BG, Transport of neutral, cation¡c and anionic amino acids by systems B. b(o, + ). X(AG). and ASC in sw ine small intestine. Comp Biochem Physio!A Mol Integ Phniol2000; 126:527 37 Raguso CA. Regan MM. Young VR. Cysteine kinetics and oxidation at different intakes of methionine and cystine in young adults. Am J Clin Nutr 2000:71 ;491 9 Riedcl B. Fisk erst rand T, Refsum FL Ueland PM. Co-ordinate variations in me thy 1-malonyl-CoA mutase and methionine synthase, and the cobalamin cofactors in human glioma cells during nitrous oxide exposure and the subsequent recovery phase. Biochem J 1999:341:133 K Sachan DS. Daily JW ¡1!. Munroe SC. Beauchene RF. Vegetarian elderly women may risk compromised carnitine status, keg Nuir 1997; 1:64 4 Smolensk) RT. Fabianowska-Majewska K. MonteroC, Dulcy JA. Fairbanks LD, Marlewski M.

Simmonds HA. A novel route of ATP synthesis. Biochem Pharmacol 1992;43:2053 7 Wagner C A. Lang F, Broer S. Function and structure of heterodtmeric amino acid transporters. Am J Physiol Cell Physiol 2001 ;2X 1 :C 1077-93 Wyss M. Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Re\< 2000: 1107-213




Figure 8.49

L-Cysli'ine and Lcystim*



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