Abstract
Abstract Cystathionase, an enzyme requiring pyridoxal phosphate as a cofactor, reacts with several cyclic derivatives of α-aminobutyric acid to form complexes. The reaction depends on the presence of the pyridoxal phosphate moiety of the enzyme and is specific for the l form of the cyclic derivatives. Homocysteine thiolactone, α-aminobutyrolactone, α-aminobutyro-γ-selenolactone, and cycloserine competitively inhibit cystathionase activity. Conversely, the substrates homoserine and cystathionine competitively inhibit complex formation. An enzymic group with a pK of 8.6 participates in complex formation, whereas another more acidic group (pK 7.3) does not, but is ionized in the complex. This group apparently does not affect the absorption characteristics of the enzyme. These observations suggest a mechanism for transaldimination, based on a nucleophilic attack of the cyclic compounds on a protonated aldimine situated on the enzyme. Cystathionase normally has an absorption maximum at 420 mµ. When it was combined with α-aminobutyrolactone, homocysteine thiolactone, α-aminobutyro-γ-selenolactone, or cycloserine, the absorption maxima appeared in the range 495 mµ to 530 mµ. The shift to the longer wave lengths apparently corresponds to decreasing electronegativity of the heteroatoms in the cyclic derivatives. Stable enzyme-inhibitor intermediates are possible because of increased resonance energy in the complexes.
Highlights
Mammalian cystathionase (homoserine hydrolase, EC 4.2.1.15), which requires pyridoxal phosphate as a cofactor, catalyzes the deamination of homoserine (LY,8 elimination), the degradation of cystathionine (7 elimination), and the desulfuration of cysteine (/3 elimination)
Cystathionase activity was assayed by measuring cu-ketobutyric acid production with either homoserine or cystathionine as substrate [9]
Phosphate-Addition of homocysteinc thiolactone to solutions of cystathionase resulted in a reddish color, with a concomitant shift in the enzyme absorption maximum from 420 to 525 rnp (Fig. 1)
Summary
Cystathionase, an enzyme requiring pyridoxal phosphate as a cofactor, reacts with several cyclic derivatives of Mammalian cystathionase (homoserine hydrolase (deaminating), EC 4.2.1.15), which requires pyridoxal phosphate as a cofactor, catalyzes the deamination of homoserine (LY, elimination), the degradation of cystathionine (7 elimination), and the desulfuration of cysteine (/3 elimination) Investigating these reactions in brain tissue from various species, we discovered that cystathionase forms complexes with certain heterocyclic amino acid derivatives, with consequent inhibition of activity. When such a complex was formed, there was a concomitant shift from the usual 420 rnp absorbance maximum of the enzyme to various new maxima; these appeared at 495 to 530 rnp, depending on the heterocyclic compound used. We have tried to relate the data obtained from studies of the complexes to a proposed mechanism of action of cystathionase
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