Cystathionine and cysteine

The answer is A. The constellation of symptoms exhibited by this patient is characteristic of homocystinuria. The impairment of her cognitive function could be attributed to many conditions, but the key findings are ectopia lentis with downward lens dislocation and osteoporosis in a female of this age. Homocystinuria is produced by inherited deficiency of one of the enzymes in the pathway of Met conversion to Cys. The most common form is cystathionine P-synthase deficiency, which results in accumulation of all upstream components of the pathway, including homocysteine, which is responsible for the toxic effects, and Met, which becomes elevated in the blood. Cystathionine and cysteine, which are both downstream of the block in the pathway caused by cystathionine P Synthase deficiency, would be decreased. Metabolic pathways for lactate and urea are not involved in this disease mechanism. 

Homocyslinuiia is an autosomal recessive condition caused by a deficiency of the enzyme, cystalhionine-p-synthase (CBS), which results in the accumulation of homocysteine and methionine and a deficiency of cystathionine and cysteine. There are other disorders to consider when an elevated homocysteine concentration is identified. These disorders include vitanun Bn uptake or activation defects, which may or may not have associated elevated methylmalonic acid, severe 5,10-methylenetetrahydrofolate reductase deficiency, and 5-methyl-THF-homocysteine meth-yltransferase deficiency. The latter two are typically associated with an elevated homocysteine, but low methionine concentrations, so it is relatively easy to disaiminate these conditions from homocystinuria. It is also important to consider that nongenetic causes of hyperhomocyste-inemia exist, such as dietary deficiencies, end-stage renal disease, and administration of several drugs [6]. 

This pyridoxal-phosphate-dependent enzyme [EC 4.2.99.9], also known as cystathionine y-synthase, catalyzes the reaction of O-succinyl-L-homoserine with L-cysteine to produce cystathionine and succinate. The enzyme can also use hydrogen sulfide and methanethiol as substrates, producing homocysteine and methionine, respectively. In the absence of a thiol, the enzyme can also catalyze a /3,y-elimination reaction to form 2-oxobu-tanoate, succinate, and ammonia. 

Cysteine is synthesized by two consecutive reactions in which homocysteine combines with serine, forming cystathionine, which, in turn, is hydrolyzed to a-ketobutyrate and cysteine (see Figure 20.8). Homocysteine is derived from methionine as described on p. 262. Because methionine is an essential amino acid, cysteine synthesis can be sustained only if the dietary intake of methionine is adequate. 

When present in excess methionine is toxic and must be removed. Transamination to the corresponding 2-oxoacid (Fig. 24-16, step c) occurs in both animals and plants. Oxidative decarboxylation of this oxoacid initiates a major catabolic pathway,305 which probably involves (3 oxidation of the resulting acyl-CoA. In bacteria another catabolic reaction of methionine is y-elimination of methanethiol and deamination to 2-oxobutyrate (reaction d, Fig. 24-16 Fig. 14-7).306 Conversion to homocysteine, via the transmethylation pathway, is also a major catabolic route which is especially important because of the toxicity of excess homocysteine. A hereditary deficiency of cystathionine (3-synthase is associated with greatly elevated homocysteine concentrations in blood and urine and often disastrous early cardiovascular disease.299,307 309b About 5-7% of the general population has an increased level of homocysteine and is also at increased risk of artery disease. An adequate intake of vitamin B6 and especially of folic acid, which is needed for recycling of homocysteine to methionine, is helpful. However, if methionine is in excess it must be removed via the previously discussed transsulfuration pathway (Fig. 24-16, steps h and z ).310 The products are cysteine and 2-oxobutyrate. The latter can be oxidatively decarboxylated to propionyl-CoA and further metabolized, or it can be converted into leucine (Fig. 24-17) and cysteine may be converted to glutathione.2993... 

Cysteine is formed in plants and in bacteria from sulfide and serine after the latter has been acetylated by transfer of an acetyl group from acetyl-CoA (Fig. 24-25, step f). This standard PLP-dependent (3 replacement (Chapter 14) is catalyzed by cysteine synthase (O-acetylserine sulfhydrase).446 447 A similar enzyme is used by some cells to introduce sulfide ion directly into homocysteine, via either O-succinyl homoserine or O-acetyl homoserine (Fig. 24-13). In E. coli cysteine can be converted to methionine, as outlined in Eq. lb-22 and as indicated on the right side of Fig. 24-13 by the green arrows. In animals the converse process, the conversion of methionine to cysteine (gray arrows in Fig. 24-13, also Fig. 24-16), is important. Animals are unable to incorporate sulfide directly into cysteine, and this amino acid must be either provided in the diet or formed from dietary methionine. The latter process is limited, and cysteine is an essential dietary constituent for infants. The formation of cysteine from methionine occurs via the same transsulfuration pathway as in methionine synthesis in autotrophic organisms. However, the latter use cystathionine y-synthase and P-lyase while cysteine synthesis in animals uses cystathionine P-synthase and y-lyase. 

RX— may be a thiol, a hydroxyl, or an indole group. In this way, serine, threonine, cysteine, tryptophan, cystathionine, and serine and threonine phosphates may be interconverted or degraded. 

There are two pyridoxal phosphate-requiring enzymes in the homocysteine degradation pathway, which are associated with genetic diseases. In homo-cystinuria, cystathionine synthase is defective, and large amounts of homocystine are excreted in the urine. Some homocystinurics respond to the administration of large doses of vitamin B6. In cystathioninuria, cystathionase is either defective or absent. These patients excrete cystathionine in the urine. Cystathionase is often underactive in the newborns with immature livers, and cysteine and cystine become essential amino acids. Human milk protein is especially rich in cysteine, presumably to prepare the newborn for such a contingency. 

Figure 21-1. Structural and metabolic relationships between methionine, homocysteine, and cysteine. CBS, cystathionine b-synthase CTH, cystathionine y-lyase MAT, methionine adenosyltransferase MS, methionine synthase 5-MTHF, 5-methyltetrahydrofoIate MTs, methyl transferases PLR pyridoxal phosphate SAH, S-adenosylhomocysteine SAHH, SAH hydrolase THF, tetrahydrofolate.

Figure 9.5. Methionine load test for vitamin Be status. Methionine synthetase, EC 2.1.1.13 (vitamin Bi2-dependent) 2.1.1.5 (betaine as methyl donor) cystathionine synthetase, EC 4.2.1.22 and cystathionase, EC 4.4.1.1. Relative molecular masses (Mr) methionine, 149.2 homocysteine, 135.2 cystathionine, 222.3 and cysteine, 121.2.

Homocysteine can also react with serine to form cystathionine. The cleavage of cystathionine produces cysteine, NH4+, and a-ketobutyrate, which is converted to propionyl CoA. 

Methionine, homocysteine, and cysteine are linked by the methylation cycle and transsulfuratlon pathway (Figure 55-9). Conversion of methionine into homocysteine proceeds via the formation of S-adenosyl intermediates including S-adenosylmethionine, die methyl group donor in a wide range of transmethylation reactions. Homocysteine is further condensed with serine by cystathionine 3-synthase to form cystathionine. 

Cystathionine is the first intermediate metabolite in transsulfuration, formed from HCY and serine by cystathionine-fi-synthase, a redox-sensitive, heme-containing enzyme (Banerjee et al., 2003), whose activity is lower in males vs. females (Vitvitsky et al., 2007). The higher levels of cystathionine in human brain reflect a strong diversion of HCY to transsulfuration (i.e., low methionine synthase activity and high cystathionine-f)-synthase activity), in conjunction with a decreased conversion of cystathionine to cysteine. As illustrated in Fig. 1, this indicates impaired transsulfuration in human brain. Low transsulfuration activity relative to other tissues has been described in rat or mouse brain (Finkelstein, 1990), although a... 

The homocysteine can accept a methyl group from betaine or tetrahydrofolate-C 1 to reform methionine. However, much of the homocysteine combines with serine to form cystathionine. The cleavage of cystathionine forms cysteine and homoserine. Thus, cysteine is not an essential amino acid, but it does have a sparing effect on methionine. 

Cystathioninuria occurs when cystathionase is genetically missing. In this disease, cystathionine is excreted in the urine and cysteine becomes an essential amino acid. 

Several PLP-dependent enzymes catalyze elimination and replacement reactions at the y-carbon of substrates, an unusual process which provides novel routes for mechanism-based inactivation. An example of this class of enzymes is cystathionine y-synthase [0-succinylhomoserine (thiol)-lyase], which converts (7-succinyl-L-homoserine and L-cysteine to cystathionine and succinate as part of the bacterial methionine biosynthetic pathway (Walsh, 1979, p. 823). Formation of a PLP-stabilized o-carbanion intermediate activates the )8-hydrogen for abstraction, yielding j8-carbanion equivalents and allowing elimination of the y-substituent. The resulting j8,y-unsaturated intermediate serves as an electrophilic acceptor for the replacement nucleophile. Suitable manipulation of the j8-carbanion intermediate allows strategies for the design of inactivators which do not affect enzymes which abstract only the a-hydrogen. 

Cystathionine y-synthase is the best studied enzyme catalyzing both y-replacement and /3,y-elimination reactions. The enzyme is found in plants and bacteria and normally functions to catalyze the formation of cystathionine from 0-acylhomoserine and cysteine during the biosynthesis of methionine (66) [Eq. (57)] ... 

In order to determine the stereochemical course at during the normal replacement reaction, Chang and Walsh converted (Z)-DL-[4- H)vinylglycine and ( )-DL-[3,4- H2]vinylglycine to cystathionine in presence of cystathionine y-synthase Salmonella) and cysteine 280). Stereospecific chemical and enzymic degradation of the resultant samples of cystathionine to homoserine followed by comparison of the NMR spectra with those of authentic (4/ )- and (4S)-l-[4- H]homoserine established that cysteine must add to the si face of the vinyl-... 

A number of enzymes involved in cysteine metabolism have been described in the tapeworm Hymenolepis diminuta (48). In addition to a high cystathionine /3-synthase activity it has low y-cystathionase activity, and contains cysteine aminotransferase, cysteine dioxygenase and cysteine sulphinate aminotransferase the latter two could be involved in the oxidation of cysteine. 

Autotrophic organisms synthesize methionine from asparfafe as shovm in the lower right side of Fig. 24-13. This involves fransfer of a sulfur atom from cysteine info homocysteine, using the carbon skeleton of homoserine, the intermediate cystathionine, and two PLP-dependent enzymes, cystathionine y-synthase and cystathionine p-lyase. This transsulfuration sequence (Fig. 24-13, Eq. 14-33) is essentially irreversible because of the cleavage to pyruvate and NH4+ by the P-lyase. Nevertheless, this transsulfuration pathway operates in reverse in the animal body, which uses two different PLP enzymes, cystathionine P s3mthase (which also contains a bound heme) and cystathionine y-lyase (Figs. 24-13,24-16, steps h and i), in a pathway that metabolizes excess methionine. 

The more complex sulphur requirements of the marine animals are met largely by cysteine, cystine, methionine, biotin, and thiamine (Young and Maw, 1958) (Fig. 4). Cysteine is a component of the tripeptide glutathione and a precursor of taurine. Methionine is as an essential amino acid involved in biosynthesis of proteins, creatine and adrenaline. Adenosylmethionine is considered to be the active part in transmethylation, e.g. of choline. Methionine is part of the pathways to homocysteine, cystathionine and methylthioadenosine (Young and Maw, 1958). Various organisms convert cysteine and/or cystine into mercapturic acids, cysteine sulphinic acid, and thiazolidine derivatives (Zobell, 1963). 

This evidence is consistent with, but does not provide definitive proof for OAS being the physiologically important precursor of cysteine. Only a limited number of O-esters of serine have been tested for activity with cysteine synthase (Section II,B,2), and no systematic studies have been made to determine whether serine O-esters other than OAS are synthesized by plants, or to identify the physiologically important a-aminopropionyl donor for cysteine synthesis. Experiments analogous to those used to identify the a-aminobutyryl donor for cystathionine and homocysteine synthesis (Section III,A,3) and the physiological carrier in sulfate reduction in Chlorella (Section IV,D,3) should be informative in this respect. 

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