Physiologic and Genetic Factors Influencing Use or Production of Cysteine, Homocysteine, and Taurine
Cys uptake can be diminished and its loss from the plasma increased by defects in cystine transport. Cystinuria is an inherited disorder of cystine and dibasic amino acid transport by the system b0,+
transporter that is expressed by the kidney and small intestine (39
). Because other intestinal amino acid and peptide transporters are not affected, these amino acids are generally absorbed from the intestine in sufficient amounts. The defect in the renal transporter results in elevated levels of lysine, ornithine, arginine, and cystine in the urine, however, because of the lack of reabsorption of these amino acids by the proximal tubular cells of the kidney (42
). The major complication of cystinuria is the formation of cystine kidney stones because cystine is a highly insoluble amino acid with an aqueous solubility limit of 250 mg/L (1 mmol/L).
In another genetic disorder of cystine transport, cystinosis, cystine reutilization is prevented, and this leads to the accumulation of cystine in lysosomes. In cystinosis, mutations in the gene for cystinosin give rise to the lack of a functional lysosomal cystine transporter (43
). This situation causes cystine from degraded proteins to accumulate inside the lysosomes of cells and leads to tissue damage. Malfunctioning kidneys and corneal crystals are the main initial features of the disorder. Patients with cystinosis are usually treated by administration of the thiol cysteamine to reduce intracellular cystine. Cysteamine enters the lysosome and reacts with cystine to form Cys and a Cyscysteamine disulfide, which are both able to leave the lysosome through other transport systems.
Methionine Metabolism to Homocysteine and Cysteine
Because Cys can be synthesized in the body from Met (Hcy) sulfur and serine, Cys levels can be affected by Met intake and by various factors that influence Met metabolism, including the pathways for Met transmethylation, Hcy remethylation, and Hcy transsulfuration, which are summarized in Figure 33.2
. Met is metabolized
by formation of S
-adenosylmethionine (SAM), transfer of the methyl group to various substrates forming S
-adenosylhomocysteine (SAH), and the hydrolysis of SAH to form Hcy. Thus, Hcy formation depends on Met intake and on the regulation and function of the Met transmethylation pathway that leads to Hcy formation. The liver is uniquely able to respond to elevated intake or plasma concentration of Met with increased SAM formation because hepatocytes express a liver-specific high Michaelis-Menten constant (Km
) isozyme of Met adenosyltransferase that is encoded by the gene MAT1A.
Other tissues, as well as the liver, express the low-Km
isozyme encoded by the gene MAT2.
Although the equilibrium of SAH hydrolase actually favors formation of SAH, the reaction is normally driven forward by rapid removal of the products Hcy and adenosine. Accumulation of SAH can impair transmethylation reactions by allosteric inhibition of methyltransferases.
Methionine metabolism. Numbered reactions are catalyzed by the following enzymes: (1)
Met adenosyltransferase; (2)
various methyltransferases; (3)
adenosylhomocysteine hydrolase; (4)
-methyl-THF-homocysteine methyltransferase; (5)
-methylene-THF reductase; (6)
betaine-homocysteine methyltransferase; (7)
cystathionine β-synthase; (8)
cystathionine γ-lyase; (9)
enzymes involved in polyamine synthesis; and (10)
enzymes involved in methylthioadenosine salvage pathway. FAD,
flavin adenine dinucleotide; Pi,
free pyrophosphate; NADP+
, nicotinamide adenine dinucleotide phosphate; NADPH
, reduced nicotinamide adenine dinucleotide phosphate; PLP
, pyridoxal 5′-phosphate; THF
The Hcy generated by hydrolysis of SAH has two likely metabolic fates, remethylation and transsulfuration. In remethylation, Hcy acquires a methyl group from N5-methyltetrahydrofolate (N5-methyl-THF) or from betaine to form Met. In transsulfuration, the sulfur is transferred to serine to form Cys, and the remainder of the Hcy molecule is catabolized to α-ketobutyrate and ammonium. Disorders of Hcy remethylation to Met result in Hcy accumulation and reduced regeneration of Met (and hence SAM) by using methyl groups donated directly by N5-methyl-THF or betaine. Remethylation disorders may result from genetic mutations causing a lack of functional Met synthase, a lack of functional coenzyme (methylcobalamin), or a lack of synthesis of the cosubstrate (N5-methyl-THF). Alternatively, a lack of vitamin B12 or folate coenzymes secondary to vitamin deficiency resulting from malabsorption or inadequate intake can also cause a lack of Hcy remethylation. The decrease in SAM levels that accompanies impaired remethylation of Hcy may also lead to decreased transsulfuration and Hcy accumulation because SAM is an important allosteric activator of the transsulfuration enzyme cystathionine β-synthase.
Transsulfuration is the pathway for removal of the Hcy carbon chain as well as for transfer of Met sulfur to serine to synthesize Cys. This pathway is catalyzed by two pyridoxal 5′-phosphate-(PLP)-dependent enzymes: cystathionine β-synthase, which condenses Hcy and serine to form cystathionine; and cystathionine γ-lyase, which hydrolyzes cystathionine to release Cys, α-ketobutyrate, and ammonium. Although all cells are capable of transmethylation and remethylation, the catabolism of Hcy through transsulfuration is restricted to the tissues that express both transsulfuration enzymes. In the rat and mouse, transsulfuration occurs in liver, kidney, pancreas, and intestine (44
). Tissues that are not capable of transsulfuration require an exogenous source of Cys and also must export Hcy for further metabolism and removal by other tissues.
As may be predicted, the overexpression of cystathionine β-synthase (on chromosome 21) in children with Down syndrome results in significantly reduced plasma levels of Hcy, Met, SAH, and SAM and in significant increases in plasma cystathionine and Cys (46
). In contrast, inborn errors of metabolism that lead to a lack of functional cystathionine β-synthase result in dramatic elevation of tissue and plasma levels of Hcy. Lack of the second enzyme in the transsulfuration pathway, cystathionine γ-lyase, results in accumulation of cystathionine in tissues and the loss of cystathionine in the urine, but no apparent disorder. Nevertheless, a lack of either enzyme impairs the synthesis of Cys from Met (Hcy) sulfur and decreases the supply of Cys to the body.
Met intake provides the substrate for Hcy formation. At typical intakes of SAAs, Hcy formation in men was approximately 19 mmol/day, and Cys formation by transsulfuration of part of this Hcy was approximately 12 mmol/day. In men fed an SAA-free diet, Hcy formation was reduced to 6 mmol/day, and Cys formation was reduced to 2 mmol/day (17
). The balance of the Hcy was remethylated back to Met. A major mechanism for regulation of Hcy remethylation versus transsulfuration in response to Met or methyl group availability is the allosteric effects of SAM (48
). SAM is both an inhibitor of N5,10
-methylene-THF reductase and an activator of cystathionine β-synthase (see also the chapter on folic acid). Hence, when the cellular SAM concentration is low, the synthesis of N5
-methyl-THF proceeds uninhibited, and cystathionine synthesis is suppressed, thus favoring Hcy remethylation or Met synthesis. Conversely, when the SAM concentration is high, inhibition of N5
-methyl-THF synthesis and stimulation of transsulfuration favor Hcy catabolism and Cys biosynthesis.
Normal adult subjects given a control diet with a betaine supplement had increased rates of Met transmethylation and transsulfuration (49
). This finding suggests that an increased dietary supply of methyl groups in the form of choline or betaine may increase Met catabolism by transmethylation and transsulfuration. Presumably, increased remethylation induced by betaine would increase SAM concentration, which would, in turn, result in inhibition of N5
-methyl-THF-dependent remethylation and stimulation of cystathionine β-synthase-dependent Hcy catabolism. Thus, a high dietary intake of betaine coupled with a marginal intake of Met could possibly disrupt the normal regulation of Met metabolism and precipitate a Met deficiency state. The importance of betaine or its precursor choline in promoting Hcy remethylation is also supported by the observation that treatment of patients with metabolic syndrome or diabetes mellitus with fibrates resulted in abnormal renal excretion of betaine and a rise in plasma total Hcy (tHcy) (50
). Analysis of data obtained in the Framingham Offspring Study (1995 to 1998) that spanned the period before and after folic acid fortification in the United States was analyzed for
the association of choline plus betaine intake and plasma tHcy. During the period before supplementation, a higher intake of choline plus betaine was associated with lower concentrations of both fasting tHcy and post-Met-load tHcy, but this association was no longer present in the period after fortification (51
Cyst(e)ine is said to have a Met-sparing effect by reducing Met catabolism through the transsulfuration pathway, and this process appears to occur with intakes of typical food proteins in which the Met-to-Cys ratio ranges from approximately 1:1 to 2:1 (52
). Maximal sparing of Met is approximately 64%, as judged by observations on subjects consuming excess cyst(e)ine and minimal Met (53
). The action of supplemental cyst(e)ine when it is added to an SAA-free diet or to a low-Met diet may be explained at least partially by promotion of the incorporation of Met into protein such that less Met is catabolized (54
). The action of cyst(e)ine, when it is used to replace part of the dietary Met, thus keeping the total SAA level the same, may be explained by a reduction in the hepatic concentrations of Met and SAM and, hence, less activation and reduced activity of hepatic cystathionine β-synthase. When the Met-to-cyst(e)ine ratio of the diet was increased from 1:0 to 1:1 to 1:3, the ratio of metabolism of Hcy by remethylation versus transsulfuration increased from 0.75 to 1.3 to 1.9 (53
). Less catabolism of Hcy by transsulfuration would result in an increase in the recycling of Hcy to Met by using methyl groups generated by the folate coenzyme system (see the chapter on folic acid).
Other mechanisms of regulation of transsulfuration may also play a role in the conversion of Hcy to Cys. Redox regulation of cystathionine β-synthase may provide a means to promote transsulfuration at the expense of remethylation, independently of methylation status, when the body has an increased need for Cys for GSH synthesis. Flux of Hcy through transsulfuration appears to be increased under oxidizing conditions, and this upregulation of transsulfuration has been associated with oxidation of the heme moiety in the N-terminal domain or targeted proteolysis of the C-terminal domain of cystathionine β-synthase (56
). In addition, hepatic cystathionine β-synthase gene expression is increased by glucagon and glucocorticoids and decreased by insulin (58
). Hormonal regulation of hepatic cystathionine β-synthase expression may serve to conserve Met for protein synthesis in the fed state and to promote catabolism of the Met/Hcy carbon chain to α-ketobutyrate, a gluconeogenic substrate, in the starved state.
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