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The polar neutral amino acid L-methionine (2-amino-4-(methylthioJbutyric acid, alpha-amino-gamma-methylmercaptobutyric acid, 2-amino-4-methylthiobutanoic acid gamma-methylthio-alpha-aminobutyric acid one-letter code M: molecular weight 149) contains 9.4% nitrogen and 21.5% sulfur (one sulfhydry] group).


Csn L-cystine

Cys L-cysteine

Met L-merhionine

MTA S'-mechylthioadenosine

PLP pyridoxal 5'*phosphate

RDA recommended dietary allowance

SAM S-adenosylmerhionine

Nutritional summary

Function: The essential amino acid L-methioninc (Met I is needed for the synthesis of proteins and is a precursor for L-cysteine (Cys). It has a special role as the precursor of S-adenosylmethionine (SAM). SAM provides methyl groups for the synthesis of adrenaline (epinephrine), creatine, melatonin, phosphatidylcholine, carnitine, and numerous other essential compounds and is the precursor of essential polyamincs. Met is also an energy fuel; its complete oxidation requires thiamin, riboflavin, niacin, vitamin B6. vitamin B12. pantothenate, ¡notin, lipoate, ubiquinone, iron, and magnesium; disposal of the sulfur in Met requires molybdenum.

Food sources: Plant-derived foods contain much less Met than meats and other animal-derived foods. Nonetheless, all foods are likely to pro\ ide adequate amounts as long as total protein intakes meet recommendations. The body cannot produce additional amounts from other amino acids.

Requirements Combined daily Met and Cys intake of healthy adults should be at feast 13 mg/kg.

Deficienty: Prolonged lack of Met as of all essential amino acids or a lack of protein causes growth 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 risk of renal glomerular sclerosis and accelerate osteoporosis. Consumption of Met greatly in excess of recommendations or of high-dosed SAM supplements may increase potentially damaging homocysteine concentrations and promote bone mineral loss. Long-term health risks from the consumption of such supplements have not been adequately evaluated.

Dietary sources flic Mct-content of proteins varies considerably depending on the food source. Foods w ith a particularly high percentage include eggs (3) mg g protein), cod (30mg g). and chicken (28mg/g). Intermediate content is in beef (26mg/g), pork (26mg/g), milk (25 mg g). and rice (24 nig g>. Grains and Other plant-derived protein sources tend to contain a lower percentage. Examples are corn (21 mg'g), wheat and oats (lSmgg). rye and beans (15 rng g). and cauliflower 114 mg g), Cooking foods at high temperatures (browning) can decrease Met bioavailability due to oxidation (Dworschak, 1980).


s ch3

Figure 8.4J


Since Mel cannot be synthesized in the body, adequate amounts have to be supplied. Met and Cys are closely linked mctabolieally. and recommendations arc often given for the sum of both sulfur amino acids (SA A), therefore. Healthy adults should gel at least 13mg/kg per day in combination (Raguso el til., 2000). Adequate Cys intake minimizes Met requirements (Di Buono ei til., 2001), bin high Cys intake has no sparing efTcct beyond that in healthy people (Raguso et al., 2000).

Average daily Mei intake in elderly non-vegetarian Americans was estimated at I450mg. that ofovo-lacto-vegetarians al 770mg (Sachan el u!, 1997}

Digestion and absorption

Proteases and aminopeptidascs from stomach, pancreas, and small-intestinal wall digest Met-containing proteins. Several small intestinal brush border enzymes act on small peptides.

Met-containing di - and tripeptides are taken up \ ia the hydrogen ion peptide cotrans-porters 1 (SLC15A1) and, toa lesser extent. 2 (SLCI5A2).

Kree Met is taken up from the proximal small intestine by the sodium-dependent transporters B° {ASCT2. SLC1A5 ) and ASC. but the evidence for the latter is controversial (Chen etal.. 1994; Munck etui. 2000). In addition, theglycoprotein-anchored transport system ba + (consisting of BATI ■ SLC7A9 and rBAT/SI.C3AI) can take up Met in exchange for a neutral amino acid (Wagner etal.. 2001). Sodium-coupled amino acid transport system A (ATAl, SLC38A1) moves Met across the basolateral membrane

membrane membrane endothelium

Figure H. 4*1 lnl«nn.if ahïorptuin of I mrl I-, ion me membrane membrane endothelium

Figure H. 4*1 lnl«nn.if ahïorptuin of I mrl I-, ion me towards the pericapillary space, when the intracellular concentration is high after a meal. Between meals the flux tends to reverse and Met from blood is supplied for the emerocytes own high needs. The heterodimeric transporter LAT2 + 4F2 (SLC7A8 + SLC3A2) augments Met transport in either direction through exchange for another neutral amino acid.

Transport and cellular uptake

Blood circulation: Plasma concentration of free Met is about 25 jamol I. ATA2 (Halanaka ei ul., 2000) mediates the sodium-driven uptake of Met into skeletal and heart muscle and other tissues. AT A3 (Halanaka el ul.. 2lM>l | is important for uptake into (he liver. Blood brain barrier: The hetemexchanger LA'IT. and to a lesser extent LAT2. at both sides of the brain capillary cell epithelial cell (Duelli etui. 2000) moves Met across the blood brain barrier (Kill tan and Chikhale. 2(101). The sodium-dependent system A is a minor contributor to Met transport (Kitazawa et ul.. 2001), Materno-fetal transfer: Transport of Met from maternal circulation into the syntro-phoblast uses mainly the sodium-dependent ATA2 (SLC38A2; Cramer et ul.. 2002). Members of system A then mediate Met movement along its concentration gradient to the fetal side (Jansson. 2001).


About half of all Met metabolism takes place in liver (Mato et ul., 2002). The main pathway for Met breakdown is transsulfuration to Cys. It must be kept in mind that the first part of this pathway is partially cyclical because half or more of the generated homocysteine reverts to Met. Decarboxylation of the central metabolite S-adenosyl-methionine (SAM) by S-adenosylmcthionine decarboxylase (EC4.I.I.50, contains pyruvate) and use for the synthesis of spermidine and spermine accounts for less than 10% of total turnover (Mato ef ul.. 2002). Transamination of Met to a-keto-y-methiol-butyrate is quantitatively of little significance (Raguso et ul.. 2000). Met can act as donor m the reactions catalyzed by cytoplasmic and mitochondrial glutamine-pyru-vatc aminotransferase (EC2.6.1.I5) and to a minor extent phenylalanine(histidine) aminotransferase (EC2.6.I.5K).

The SAM cycle: Met is activated by ATP:L-methionine-S-adenosyltransferase (methionine adenosyltransferase. MAT, EC2.5.1.6), lsoforms 1 and III are expressed in the liver, isoform II is present in kidneys, brain, and other tissues. Hydrolysis of the pyrophosphate from the adenosylation reaction by ubiquitous pyrophosphatase (EC3.6.1.I) keeps the equilibrium in favor of SAM synthesis, Many methy It raits (erases, of which glycine N -methy [trans ferase (EC2.1.1,20) is the most abundant in liver, use SAM as methyl group donor, Adenosylhomoeysteinase (EC3.3.1.1) hydrolyzes the resulting adenosyl homocysteine. 5 -Methy Itetrahy drofo I ate-ho mocyste ine methy ¡transferase (M fR, methionine synthase; IX provides the main pathway for the regeneration of Met. Cob(I)alamin in the active center of the enzyme receives the methyl group from 5-methy Itetrahy drofo late (5-methyl-1 III I and moves it to homocysteine.








H..O • ATP

^ p. - pp.

<i-Keto^d^ amino acid

ArTnnolranstorases (PLP>

OH ÖH S ■ Adenosy trrielhioiK ne substrate r

X^meltiyiai«! substrate

<i-Keto^d^ amino acid

ArTnnolranstorases (PLP>

Actenosyimeth lonine decarboxylase (pynjwyl)

Actenosyimeth lonine decarboxylase (pynjwyl)


«-KolD-( -rnathiolbutyrale

OH OH S ■ ActenosytmeLtiiontno 3.aminopropyl methyl sulfonate (to spermidine synthesis)




Figure H.45 Metabolic fates of L-meihioninc


S-Aöenosymomocysieine Homocysfaine

Figure H.45 Metabolic fates of L-meihioninc

Oxidation of the enzyme-bound cob(l)alamin without methyl group transfer, which occurs in a small percentage of reaction cycles and possibly with high oxidative stress (McC'addon ei al„ 2002 f. inactivates MTR. In this case the enzyme has to be remethy-lated by methionine synthase reductase (EC2.1.1.135). which uses both FAD and FMN as cofactors (Lcclere et ai. I99K). SAM serves as the methyl-group donor and cytochrome b5 provides the reducing potential. Cytochrome b5 is regenerated by NADl'l [-dependent cytochrome P450 reductase (EC 1.6,2.4). another enzyme with bolh I AD and FMN as prosthetic groups. Inhalation of nitrous oxide irrev ersibly inactivates MTR (Home et ai., 1989: Riedel et ai, 1999). Low MTR activity causes the accumulation of 5-mcthyl-11 IF because there are no other major uses for this folate metabolite.

Liver and kidneys have an additional route for Met remethylation that uses the zinc-enzyme be same-homocysteine S-methy (transferase (EC2.I.I.5). The choline metabolite betaine can regenerate Met directly without requiring folate or vitamin






Betaine-homocy steine S-methyl tränst

MTR reductase (FAD * FMN)


MTR reductase (FAD * FMN)


reduced cyt b + SAM



Fijcw« 8,46 Homocysteine rcmethytation

BI2 like the main rcmelhylatioii pathway. However, the metabolism of the di methyl-glycine arising from this reaction generates 3mol of 5-methyl-THF. and this causes an even greater sequestration (trapping) and potential functional deficiency of folate. Transsulfuratton The successive actions of cystathionine beta-synthase (EC4.2.1.22) and cystathionine-gamma-lyase (EC4.4.1.I) convert homocysteine to Cys and a-ketobutyrate. Both enzymes contain pyridoxal phosphate as a prosthetic group. The main fate of Cys is metabolism to pyruvate via eysteinesullinate. CssC. mercaptopv-ruvate, or directly. Much smaller amounts of Cys are convened to taurine. L-alanine, and cysteamine. Detoxification of (lie sullite produced by Cys oxidation depends on the molybdenum enzyme sulfite oxidase (EC

Repair of oxidative damage The sulfur in Met is highly susceptible to oxidation. Exposure of proteins to molecular oxygen or other reactix e oxygen species, particularly in the mitochondrial matrix, can result in their mactivation. therefore. A thioredoxin-using enzyme. protein-methionine-S-oxide reductase (EC 1,8.4.6), can repair such oxidative damage in proteins, but it does not work on free Met.

Body proteins on average contain about 120mgg (Raguso vt a/., 2000). Small amounts of Met (2.1 mglig body weight) are released with normal turnover of tissue proteins. Very iow intake may promote breakdown of protein from muscle and other tissues.

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