Cystathionine /?-synthase

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). 

CBS Domain in cystathionine /3-synthase and other proteins. E(MFP)AB 9(20) 9(20) 1B30... 

CYSTATHIONINE /3-LYASE CYSTATHIONINE /3-SYNTHASE CYSTEINE CONJUGATE /3-LYASE CYSTEINE LYASE... 

The homocystinurias are a group of disorders involving defects in the metabolism of homocysteine. The diseases are inherited as autosomal recessive illnesses, characterized by high plasma and urinary levels of homocysteine and methionine and low levels of cysteine. The most common cause of homocystinuria is a defect in the enzyme cystathionine /3-synthase, which converts homocysteine to cystathionine (Figure 20.21). Individuals who are homozygous for cystathionine [3-synthase deficiency exhibit ectopia lentis (displace ment of the lens of the eye), skeletal abnormalities, premature arte rial disease, osteoporosis, and mental retardation. Patients can be responsive or non-responsive to oral administration of pyridoxine (vitamin B6)—a cofactor of cystathionine [3-synthase. Bg-responsive patients usually have a milder and later onset of clinical symptoms compared with B6-non-responsive patients. Treatment includes restriction of methionine intake and supplementation with vitamins Bg, B, and folate. 

Beta replacement is catalyzed by such enzymes of amino acid biosynthesis as tryptophan synthase (Chapter 25),184 O-acetylserine sulfhydrylase (cysteine synthase),185 186a and cystathionine (3-synthase (Chapter 24).187 188c In both elimination and (3 replacement an unsaturated Schiff base, usually of aminoacrylate or aminocrotonate, is a probable intermediate (Eq. 14-29). Conversion to the final products is usually assumed to be via hydrolysis to free aminoacrylate, tautomerization to an imino acid, and hydrolysis of the latter, e.g., to pyruvate and ammonium ion (Eq. 14-29). However, the observed stereospecific addition of a... 

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

Homocysteine is a nonprotein-building amino acid formed as a metabolite in the methionine cycle. It was first associated with disease in 1962 (1,2). Individuals with a mutation in cystathionine-(3-synthase (CBS) develop classical homocystin-uria with extremely elevated plasma tHcy (> 100 xmol/L) (3). Homocystinuria is characterized by early atherosclerosis and thromboembolism as well as mental retardation and osteoporosis and is ameliorated by vitamin supplementation aimed at reducing the blood concentration of homocysteine (4). 

Pyridoxine (vitamin B6) Transsulfuration pathway cofactor for cystathionine-(3-synthase and cystathionine "/-lyase Folate cycle methylation of tetrahydrofolate cofactor for serine hydroxymethyltransferase... 

Homocystinuria is a genetic disease lhal usually results from defects In the gene coding for cystathionine 3-synthase, and the consequent lack of activity of this enzyme. Typically, the resulting levels of enzyme activity are from 0 to 5 K> the normal value. The disease w as named because of the increased levels of homocysteine in the urine that arise because the plasma levels of this amino acid increase to over 100 jjlM. Actually, urinary homocysteine occurs as the disulfide-linked... 

Studies of plasma homocysteine and supplements with vitamins that are relevant to enzymes of the pathway of homocysteine breakdown. These enzymes are cystathionine 3-synthase (vitamin Bh), methionine synthase (vitamin Bi ), and 5,10-methylerie-H4folate reductase (folic acid). The associated vitamins are listed,... 

Beta replacement is catalyzed by such enzymes of amino acid bios5mthesis as tryptophan synthase (Chapter 25), O-acetylserine sulfhydrylase (cysteine synihase), and cystathionine 3-synthase (Chapter In both elimination and (I replace-... 

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. 

In /3-replacement reactions, the /3-substituent of an amino acid substrate is replaced by a new /3-substituent. For the three enzymes (TRPS, OASS, and cystathionine /3-synthase (CBS)) whose mechanisms are discussed in this section, the catalytic reaction is composed of two distinct half-reactions. The /3-elimination is followed by a /3-addition where nucleophilic agents, indole, sulfide, and homocysteine, respectively, react with the ci-aminoacrylate Schiff base to form the final product, L-tryptophan, L-cysteine, and L-cystathionine, respectively. 

Homocystinuria <0.5 Methionine degradation Cystathionine /3-synthase Faulty bone development mental retardation... 

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. 

An increased plasma level of homocysteine is regarded as a risk factor for cardiovascular disease and the development of arteriosclerosis. Homocysteine concentrations in plasma are reduced by remethylation and transsulfuration (Komarnisky et al. 2003). The remethylation is catalyzed by methionine synthase, which in turn is influenced by vitamin B12 and folate. The transsulfura-tions depend on cystathionine 3-synthase. A dietary deficiency of vitamins B, B12 and folate, accompanied by a high protein intake, can cause hyperhomocystinemia in humans (Jacobsen 1998). Furthermore, a genetic disorder of enzymes involved in the metabolism of homocysteine leads to hypercystinuria (Mudd et al. 1989). 

The carbons and nitrogen for cysteine synthesis are provided by serine, and the snlfur is provided by methionine (Fig. 39.7). Serine reacts with homocysteine (which is prodnced from methionine) to form cystathionine. This reaction is catalyzed by cystathionine 3-synthase. Cleavage of cystathionine by cystathionase prodnces cysteine and a-ketobntyrate, which forms snccinyl CoA via propionyl CoA. Both cystathionine 3-synthase ( 3-eliminaiion) and cystathionase (y-elimination) require PLP. 

Cysteine inhibits cystathionine 3-synthase and, therefore, regulates its own production to adjust for the dietary supply of cysteine. Because cysteine derives its sulfur from the essential amino acid methionine, cysteine becomes essential if the supply of methionine is inadequate for cysteine synthesis. Conversely, an adequate dietary source of cysteine spares methionine that is, it decreases the amount that must be degraded to produce cysteine. 

Homer Sistine. The most characteristic biochemical featnres of the disor-J der affecting Homer Sistine, a cystathionine 3-synthase deficiency, are the — presence of an accnmnlation of both homocyst(e)ine and methionine in the blood. Becanse renal tnbnlar reabsorption of methionine is highly efficient, this... 

Treatment is directed toward early reduction of the elevated levels of homocysteine and methionine in the blood. In addition to a diet low in methionine, very high oral doses of pyridoxine (vitamin B6) have significantly decreased the plasma levels of homocysteine and methionine in some patients with cystathionine 3-synthase deficiency. (Genetically determined responders to pyridoxine treatment make up approximately 50% of type I homocystinurics.) PLP serves as a cofactor for cystathionine (3-synthase however, the molecular properties of the defective enzyme that confer the responsiveness to B6 therapy are not known. 

The terms hypermethioninemia, homocystinuria (or -emia), and cystathionin-uria (or -emia) designate biochemical abnormalities and are not specific clinical diseases. Each may be caused by more than one specific genetic defect. For example, at least seven distinct genetic alterations can cause increased excretion of homocystine in the urine. A deficiency of cystathionine (3-synthase is the most common cause of homocystinuria more than 600 such proven cases have been studied. 

Fig. 40.10. Reaction pathways involving homocysteine. Defects in numbered enzymes (1 = methionine synthase, 2 = N, methylene FH4 reductase, 3 = cystathionine-(3-synthase) lead to elevated homocysteine. Recall that as cysteine accumulates, there is feedback inhibition on cystathionine-P-synthase to stop further cysteine production.

H2S can be produced via the metabolism of sulfhydryl-bearing amino acids, specifically by several enzymes found in the methionine-homocysteine-cysteine pathway such as cystathionine 3 synthase (CBS) and cystathionine lyase (CGL) (Fig. 8.1) [6, 10, 11]. The sequence of CBS has been identified in genomes from bacteria to humans [12-14], and a gene similar to the sulfide quinone oxidoreductase gene has been identified in the genome of flies, worms, mice, rats, and humans [15], indicating that cellular H2S and its regulation may be widespread and essential. 

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