Cystathionine-y-lyase

Pyridoxamine phosphate serves as a coenzyme of transaminases, e.g., lysyl oxidase (collagen biosynthesis), serine hydroxymethyl transferase (Cl-metabolism), S-aminolevulinate synthase (porphyrin biosynthesis), glycogen phosphoiylase (mobilization of glycogen), aspartate aminotransferase (transamination), alanine aminotransferase (transamination), kynureninase (biosynthesis of niacin), glutamate decarboxylase (biosynthesis of GABA), tyrosine decarboxylase (biosynthesis of tyramine), serine dehydratase ((3-elimination), cystathionine 3-synthase (metabolism of methionine), and cystathionine y-lyase (y-elimination). 

Hydrogen sulfide is a well known general metabolite produced on sulfate reduction by certain bacteria. Moreover, organic forms of sulfur can give rise to HS , hence H2S in certain bacteria. Thus, cysteine desulfhydrase (EC 4.4.1.1, cystathionine y-lyase) converts L-cysteine to H2S, pyruvate, and NH3. This enzyme shows a requirement for pyridoxal phosphate and the unstable ami-noacrylic acid is an intermediate (Equation 1) in the reaction ... 

CYSTATHIONINE yS-LYASE CYSTATHIONINE y-LYASE CYSTATHIONINE yS-SYNTHASE Oystathionine y-synthase,... 

CYSTATHIONINE y-LYASE HOMOSERINE DEHYDROGENASE ASPARTATE KINASE HOMOSERINE SUCCINYLTRANSFERASE HomotopIc,... 

Aspartate y-decarboxylase Selenocysteine lyase NifS protein of nitrogenase Gamma elimination and replacement Cystathionine y-synthase Cystathionine y-lyase Threonine synthase... 

Cysteine Methionine S-Adenosylmethionine synthase a-Methyltransferase S-Adenosylhomocysteinase Cystathionine- /3-synthase Cystathionine- y- lyase... 

The transsulfuration pathway involves conversion of homocysteine to cysteine by the sequential action of two pyridoxal phosphate (vitamin B6)-dependent enzymes, cystathionine- 5-synthase (CBS) and cystathionine y-lyase (Fig. 21-2). Transsulfuration of homocysteine occurs predominantly in the liver, kidney, and gastrointestinal tract. Deficiency of CBS, first described by Carson and Neill in 1962, is inherited in an autosomal recessive pattern. It causes homocystinuria accompanied by severe elevations in blood homocysteine (>100 (iM) and methionine (>60 (iM). Homocystinuria due to deficiency of CBS occurs at a frequency of about 1 in 300,000 worldwide but is more common in some populations such as Ireland, where the frequency is 1 in 65,000. Clinical features include blood clots, heart disease, skeletal deformities, mental retardation, abnormalities of the ocular lens, and fatty infiltration of the fiver. Several different genetic defects in the CBS gene have been found to account for loss of CBS activity. 

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.

In the biosynthesis of cysteine, the sulfur comes from methionine by transsulfuration, and the carbon skeleton and the amino group are provided by serine (Figure 17-16). Cysteine regulates its own formation by functioning as an allosteric inhibitor of cystathionine y-lyase, a-Ketobutyrate is metabolized to succinyl-CoA by way of propionyl-CoA and methylmalonyl-CoA. 

A third sulfurtransferase, cystathionase (cystathionine y-lyase EC 4.4.1.1), which is a cytosohc enzyme, may play a role in CN detoxification in the kidney and rhombencephalon (Wrobel et al., 2004). A product of the cystathionase reaction, bis(2-amino-2-carboxylethyl)trisulfide (thiocystine), may serve as a sulfur substrate donor for rhodanese. Another reaction product, 3-(thiosulpheno)-alanine (thiocysteine), may be an additional link between cystathionase and CN biodetoxification. In addition, cystathionase also functions as a sulfane sulfur carrier. 

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 cysfeine info homocysfeine, 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. 

Toxicity Causes neurolathyrism and cystathionuria by inhibition of cystathionine y-lyase (EC 4.4.1.1). Biosynthesis metabolism From serine or cysteine and cyanide catalyzed by 3-cyanoalanine synthase (EC 4.4.1.9). 3-Cyanoalanine hydratase (EC 4.2.1.65) hydrates C. to asparagine. ... 

Reaction 3 is the cysteine desulfhydrase reaction which by -elimination produces HjS, pyruvate, and NH3. This reaction is catalyzed by cystathionine-y-lyase, the B protein of tryptophan synthetase (E.C. 4.2.1.20), or crystalline tryptophanase (E.C. 4.1.99.1) (Meister, 1965). According to Meister cysteine desulfhydrase reactions are probably catalyzed by other enzymes. Cystathionine-y-lyase has not been found in higher plants (Giovanelli et al., this volume. Chapter 12). 

Fig. 20.3 Pathway of methionine metabolism. The numbers represent the following enzymes or sequences (1) methionine adenosyltransferase (2) S-adenosylmethionine-dependent transmethylation reactions (3) glycine methyltransferase (4) S-adenosylhomocysteine hydrolase (5) betaine-homocysteine methyltransferase (6) 5-methyltetrahydrofolate homocysteine methyltransferase (7) serine hydroxymethyltransferase (8) 5,10-methylenetetrahydrofolate reductase (9) S-adenosylmethionine decarboxylase (10) spermidine and spermine synthases (11) methylthio-adenosine phosphorylase (12) conversion of methylthioribose to methionine (13) cystathionine P-synthase (14) cystathionine y-lyase (15) cysteine dioxygenase (16) cysteine suplhinate decarboxylase (17) hypotaurine NAD oxidoreductase (18) cysteine sulphintite a-oxoglutarate aminotransferase (19) sulfine oxidase. MeCbl = methylcobalamin PLP = pyridoxal phosphate...

Transsulfuration is facilitated by the action of two vitamin Be-dependent enzymes, cystalhionine-p-synthase (CBS), the enzyme deficient in homocystinuria, and cystathionine-Y-lyase (CTH). CBS catalyzes the condensation of homocysteine and serine to cystathionine, and CTH subsequently catalyzes the hydrolysis of cystathionine to cysteine and a-ketobutyrale. Cysteine is important in protein synthesis and taurine synthesis and is a precursor to glutathione, a strong antioxidant and essential compound in detoxification of many xenobiotics [8,10,11]. 

Cystathionase (homoserine dehydratase, cystathionine y-lyase) (EC 4.4.1.1). High urinary cystathionine. Increased concentrations of cystathionine in serum and tissues. See Cysteine. 

Another probe (25) for the discrimination of Cys from Hey and GSH was also designed by utilizing remarkable difference in reactivity toward Cys, Hey and GSH. The reaction between 25 and Cys produces an amino-substituted BODIPY, exhibiting a yellow turn-on fluorescence response. In contrast, the response of 25 to Hey or GSH introduces a red turn-on fluorescence signal, due to the formation of sulfenyl-substituted BODIPY. These distinguishable fluorescence turn-on responses allow the differentiation of Cys over Hey and GSH (Scheme 7.22b). Moreover, probe 25 was successfully utilized for the detection of Cys in living cells and in monitoring cystathionine y-lyase activity in vitro. 

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