Cystathionine /?-synthase function

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. 

Cystathionine y-synthase (CGS) is a rather unique PLP-enzyme that catalyzes a transsulfuration reaction important in microbial methionine biosynthesis. It is the only known enzyme whose function is the catalysis of a PLP-dependent replacement reaction at the y-carbon of the amino acid substrate the succinyl moiety of O-succinyl-L-homoserine is replaced by i-Cys to give the thioether linkage of L,/.-cystathionine (scheme II). In the absence of L-Cys, the enzyme catalyzes a net y-elimination reaction from OSHS (scheme II). Because both reactions require the elimination of succinate, the catalytic pathways must diverge from a common reaction intermediate. It was originally hypothesized that a vinylglycine quinonoidal intermediate (structure 11)... 

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)] ... 

The deficiencies of cystathionine )5-synthase (CBS), sulfite oxidase, and methylenetetrahydrofolate reductase (MTHFR) may all result in central nervous system dysfunction, in particular mental retardation [1-3]. Defects of CBS and sulfite oxidase both cause dislocated lenses of the eyes, but the phenotypes are different otherwise. The manifestations of CBS deficiency, the most common of these disorders, and MTHFR deficiency range from severely affected to asymptomatic patients both may cause vascular occlusion. Deficiency of sulfite oxidase is clinically uniform, but genetically heterogeneous, and functional deficiency of the enzyme can result from several inherited defects of molybdenum cofactor biosynthesis [2, 4]. Hereditary folate malabsorption and defects of cobalamin transport (transcobala-min II deficiency) or cobalamin cofactor biosynthesis (cblC-G diseases) may cause megaloblastic anemia, in addition to CNS dysfunction [3, 5, 6]. 

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