I z ch2
Homocysteine cpOOH H3N"<j;H
Cystathionine beta-synthase (plp)
serine h3o hjn—ch
Cystathionine gam ma-lyase (plp)
CH—NHj HOOC Cysteine
Figure 8. J? Thu* trartjiuffuration pathway h'°c.aad h,co,-nadh n-Keto acid dehydrogenase
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 decarboxylase nh, cooh h:in-ch
oh oh S-Adenosylmethionine co2
oh oh S-Adenosylmethionine
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)
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
(EC220.127.116.11) 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(EC18.104.22.168)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).
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L-Cysli'ine and Lcystim*
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