Cystathionine-P-synthase

The most common cause of homocystinuria is a congenital deficiency of cystathionine-p-synthase, a pyridoxine-dependent enzyme that condenses homocysteine and... 

Biochemical findings are variable. The blood cobala-min and folate levels often are normal. Patients often have homocysteinemia with hypomethioninemia, the latter finding discriminating this group from homocystinuria secondary to cystathionine- P-synthase deficiency. Urinary excretion of methylmalonic acid may be high, reflecting the fact that vitamin B12 serves as a cofactor for the methyl-malonyl-CoA (coenzyme A) mutase reaction. 

Figure 22.7 Homocysteine formation from methionine and formation of thiolactone from homocysteine. The homocysteine concentration depends upon a balance between the activities of homocysteine methyltransferase (methionine synthase) and cystathionine p-synthase. Both these enzymes require vitamin B12, so a deficiency can lead to an increase in the plasma level of homocysteine. (For details of these reactions, see Chapter 15.) Homocysteine oxidises spontaneously to form thiolactone, which can damage cell membrane.

Enzyme (1) is methionine synthase enzyme (2) is cystathionine P-synthase... 

Further to this, the enzyme cystathionine P-synthase is involved in the catabolism of homocysteine, so that a deficiency of this enzyme also results in an elevated level of homocysteine in the blood. Consequently, patients with a deficiency, even a partial deficiency, could also suffer an increased risk of coronary artery disease. 

Serine dehydratase Enoyl-CoA hydratase Methylglutaconyl-CoA hydratase Cystathionine p-synthase [PLP]... 

Gonversion of homocysteine to Gys occurs in two reactions catalyzed by two pyridoxal phosphate-requiring enzymes, cystathionine p-synthase and y-cystathionase. 

Figure 9-5. Pathway for formation of cysteine from methionine. Only the enzymes involved in known diseases of this pathway are shown. Cystathionase is deficient in cysthioninuria, which leads to accumulation of cystathionine without producing frank symptoms. Cystathionine p-synthase deficiency causes homocystinuria.

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. 

Cyclohexanedione, reaction with guanidinium groups, 126 Cyclophilin 488 human 488s D-Cycloserine 739s Cyclosporin 488, 488s p Cylinders 65, 66, 686 Cystathionine, 746s formation 746 Cystathionine p lyase 742 Cystathionine p-synthase 744 Cystathionine y-synthase 743, 746 Cystatins 622, 629... 

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. 

Figure 21-2. Metabolism of homocysteine. BHMT, betaineihomocysteine methyl-transferase CBS, cystathionine P-synthase Cob, cobalamin CTH, cystathionine y-lyase DHF, dihydrofolate DMG, dimethylglycine FAD, flavin adenine dinucleotide MAT, methionine adenosyltransferase 5-MTHF, 5-methyltetrahydrofolate 5,10-MTHF, 5,10-methylenetetrahydrofolate MTHFR, methylenetetrahydrofolate reductase MS, methionine synthase MTRR, methionine synthase reductase MTs, methyl transferases PLE pyridoxal phosphate SAH, S-adenosylhomocysteine SAHH, SAH hydrolase SAM, 5-adenosylmethionine SHMT, serine hydroxymethyltransferase THF, tetrahydrofolate Zn, zinc.

Homocystinuria Cystathionine P-synthase Scoliosis, muscle weakness, mental retardation, thin blond hair... 

Homocystinuria is a genetic disease that usually results from defects in the gene coding for cystathionine P-synthase, and the consequent lack of activity of this enzyme. Typically, the resulting levels of enzyme activity are from 0 to 5% the normal value. The disease was 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 iM. Actually, urinary homocysteine occurs as the disulfide-linked... 

Studies of plasma homocysteine and supplements with vitamins that are relevant to enz)nnes of the pathway of homocysteine breakdown. These enzymes are cystathionine P-synthase (vitamin Be), methionine synthase (vitamin B12), and 5,10-methylene-H4folate reductase (folic acid). The associated vitamins are listed. 

These studies are detailed in what follows. Although the severe increases in plasma homocysteine that occur with homozygous cystathionine P-synthase deficiency can be clearly treated with vitamin Bs, the moderate increases of homocysteine (which are widespread in the population and do not lead to mental retardation) can be treated best with folate. 

Transamination is just one of a wide range of amino acid transformations that are catalyzed by PLP enzymes. The other reactions catalyzed by PLP enzymes at the a-carbon atom of amino acids are decarboxylations, deaminations, racemizations, and aldol cleavages (Figure 23.13). In addition, PLP enzymes catalyze elimination and replacement reactions at the p-carbon atom (e.g., tryptophan synthetase p. 696) and the y-carbon atom (e.g., cystathionine p-synthase, p. 693) of amino acid substrates. Three common features of PLl catalysis underlie these diverse reactions. 

In addition to being a precursor of methionine in the activated methyl cycle, homocysteine is an intermediate in the synthesis of cysteine. Serine and homocysteine condense to form cystathionine. This reaction is catalyzed by cystathionine p-synthase. Cystathionine is then deaminated and cleaved to cysteine and a-ketobutyrate by cystathioninase. Both of these enzymes utilize PLP and are homologous to aspartate aminotransferase. The net reaction is... 

A couple comes to the physician s office after having had two sons affected with a similar disease. The first-born son is tall and thin and has dislocated lenses and an IQ of 70. He has also experienced several episodes of deep vein thromboses. The chart mentions deficiency of the enzyme cystathionine-P-synthase, but a diagnosis is not given. The second son was treated from an early age with pyridoxine (vitamin Bg) and is less severely affected. No other family members are affected. While taking a family history, the physician discovers that the parents are first cousins. The 38-year-old mother is pregnant, and amniocentesis has demonstrated that the fetus has a 46,XY karyotype. The risk that the fetus will be affected with the same disease is... 

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,which probably involves P 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). 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 P Synthase is associated with greatly elevated homocysteine concentrations in blood and urine and often disastrous early cardiovascular disease. ° ° 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 Bg 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 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. ... 

If the blood levels of methionine and homocysteine are very elevated and cystine is low, cystathionine p-synthase could be defective, but a cystathionase deficiency is also a possibility. With a deficiency of either of these enzymes, cysteine could not be synthesized, and levels of homocysteine would rise. Homocysteine would be converted to methionine by reactions that require B12 and tetrahydrofolate (see Chapter 40). In addition, it would be oxidized to homocystine, which would appear in the urine. The levels of cysteine (measured as its oxidation product cystine) would be low. A measurement of serum cystathionine levels would help to distinguish between a cystathionase or cystathionine p-synthase deficiency. 

Homocystinuria is caused by deficiencies in the enzymes cystathionine p-synthase and cystathionase as well as by deficiencies of methyltetrahy-drofolate (CH3-FH4) or of methyl-B12. The deficiencies of CH3-FH4 or of methyl-B12 are due either to an inadequate dietary intake of folate or B12 or to defective enzymes involved in joining methyl groups to tetrahy-drofolate (FH4), transferring methyl groups from FH4 to B12, or passing them from B12 to homocysteine to form methionine (see Chapter 40). 

A biopsy specimen from Homer Sistine s liver was sent to the hospital s biochemistry research laboratory for enzyme assays. Cystathionine p-synthase activity was reported to be 7% of that found in normal liver. 

Methionine Cystathionine p-synthase Flomocysteine Flomocysteinemia Cardiovascular complications and neurologic problems... 

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.

Homocystinuria is a biochemical abnormality caused either by a deficiency of cystathionine P-syn-thase or impaired activity of N -methyltetrahydrofolate-homocysteine methyltransferase. The classical homocystinuria occurs when the conversion of homocysteine to cystathionine is limited by a deficiency of cystathionine P-synthase, with accumulation of methionine and homocysteine and a decrease in cysteine. 

Patients with this most common form of homocystinuria show evidence of involvement of the eye, the skeletal system, the vascular system, and the brain. It is important to note that individuals with cystathionine P-synthase deficiency do not manifest any abnormalities at birth and that the affected pregnancies are uneventful. Thus, this disorder, as opposed to the more rare remethylation defect variants of homocystinuria (described below), is not usually part of the differential diagnosis of the catastrophically ill newborn. Ectopia lentis does not usually appear before the age of 3 years, but most patients have some manifestations by the age of 10. The initial recognition of ocular abnormahties may be an observation by parent or physician that the iris shakes, when the head is moved rapidly. While a predilection for... 

The complication of cystathionine P-synthase deficiency that is of most concern is the prodensity to thromembolism. This involves vessels of all diameters and is unpredictable as to when, where, and if it occurs. The malar flush and erythemous mottling of the extremities are also vascular manifestations of homocystinuria. 

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