Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.4.1.1 (cystathionine gamma-lyase)
528 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rhodopseudomonas spheroides can grow in a defined medium with either light or oxygen as an energy source. Cells grown anaerobically or at very low oxygen tensions are rich in the photosynthetic pigment bacteriochlorophyll, whereas this pigment is virtually absent in cells grown under high oxygen tensions. Aminolaevulinate synthetase, the first enzyme on the pathway to bacteriochlorophyll, appears to play an important role in the control of bacteriochlorophyll synthesis. Thus, the enzyme has a high activity in extracts of pigmented cells and a low activity in extracts of non-pigmented cells. Further, oxygenation of a pigmented culture causes immediate cessation of pigment synthesis and produces a rapid fall in the activity of aminolaevulinate synthetase. This loss of activity appears to be due to the loss of an endogenous activator of the enzyme. Thus, pigmented cells contain cystine trisulphide, which at muM concentrations is an activator of aminolaevulinate synthetase, while oxygenation causes a rapid fall in the cellular content of this trisulphide. Cystathionase (EC 4.2.1.15) extracted from pigmented cells can catalyse the formation of cystine trisulphide from cystine, while rhodanese (EC 2.8.1.1) extracted from the same cells can catalyse the degradation of cystine trisulphide in the presence of sulphite to form cystine and thiosulphate. It is proposed that the cellular content of cystine trisulphide is controlled by changes in the levels of substrates for cystathionase and possibly rhodanese rather than changes in the amounts of these enzymes. Cystine trisulphide controls the activity of aminolaevulinate synthetase by converting a low-activity form of the enzyme (b-form) into a high-activity form (a-form). The fall in aminolaevulinate synthetase activity on oxygenation appears to be the result of cessation of conversion of b-form into a-form, along with a conversion of a-form into b-form. Factors affecting the equilibrium between the forms and the possible mechanisms for their interconversion are discussed.
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PMID:Control of 5-aminolaevulinate synthetase activity in Rhodopseudomonas spheroides. 0 44

The administration of ethionine results in a rapid and marked increase in rat liver cysteine desulfhydrase activity. However, this antimetabolite of methionine does not affect the hepatic levels of homoserine dehydratase and gamma-cystathionase.
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PMID:Effect of ethionine on gamma-cystathionase, homoserine dehydratase and cysteine desulfhydrase activities. 9 23

L-Propargylglycine, a naturally occurring gamma, delta-acetylenic alpha-amino acid, induces mechanism-based inactivation of two pyridoxal phosphate dependent enzymes of methionine metabolism: (1) cystathionine gamma-synthease, which catalyzes a gamma-replacement reaction in methionine biosynthesis, and (2) methionine gamma-lyase, which catalyzes a gamma-elimination reaction in methionine breakdown. Biphasic pseudo-first-order inactivation kinetics were observed for both enzymes. Complete inactivation is achieved with a minimum molar ratio ([propargylglycine]/[enzyme monomer]) of 4:1 for cystathionine gamma-synthase and of 8:1 for methionine gamma-lyase, consistent with a small number of turnovers per inactivation event. Partitioning ratios were determined directly from observed primary kinetic isotope effects. [alpha-2H]Propargylglycine displays kH/kD values of about 3 on inactivation half-times. [alpha-3H]-Propargylglycine gives release of tritium to solvent nominally stoichiometric with inactivation but, on correction for the calculated tritium isotope discrimination, partition ratios of four and six turnovers per monomer inactivated are indicated for cystathionine gamma-synthase and methionine gamma-lyase, respectively. The inactivation stoichiometry, using [alpha-14C]-propargylglycine, is four labels per tetramer of cystathionine gamma-synthase but usually only two labels per tetramer of methionine gamma-lyase (half-of-the-sites reactivity). Two-dimensional urea isoelectrofocusing/NaDodSO4 electrophoresis suggests (1) that both native enzymes are alpha 2 beta 2 tetramers where the subunits are distinguishable by charge but not by size and (2) that, while each subunit of a cystathionine gamma-synthase tetramer becomes modified by propargylglycine, only one alpha and one beta subunit may be labeled in an inactive alpha 2 beta 2 tetramer of methionine gamma-lyase. Steady-state spectroscopic analyses during inactivation indicated that modified cystathionine gamma-synthase may reprotonate C2 of the enzyme--inactivator adduct, so that the cofactor is still in the pyridoxaldimine oxidation state. Fully inactivated methionine gamma-lyase has lambda max values at 460 and 495 nm, which may represent conjugated pyridoximine paraquinoid that does not reprotonate at C2 of the bound adduct. Either species could arise from Michael-type addition of an enzymic nucleophile to an electrophilic 3,4-allenic paraquinoid intermediate, generated initially by propargylic rearrangement upon a 4,5-acetylenic pyridoximine structure, as originally proposed for propargylglycine inactivation of gamma-cystathionase [Abeles, R., & Walsh, C. (1973) J. Am. Chem. Soc. 95, 6124]. It is reasonable that cystathionine gamma-synthase is the major in vivo target for this natural acetylenic toxin, the growth-inhibitory effects of which are reversed by methionine.
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PMID:Suicide inactivation of bacterial cystathionine gamma-synthase and methionine gamma-lyase during processing of L-propargylglycine. 38 77

The L-cyst(e)ine requirements of normal and malignant cells are reviewed and expanded within the context of establishing whether the measurement of gamma-cystathionase levels constitutes a predictive test for tumor sensitivity to L-cyst(e)ine depletion. The ability of both purified L-cysteine desulfhydrase and gamma-cystathionase to inhibit the growth of the L-cystine-dependent L1210 leukemia in culture is presented, as well as approaches to circumvent the limitations of these enzymes for in vivo therapy. The ability of proparagylglycine to inhibit L-cysteine biosynthesis in vivo is reviewed for its possible use in combination therapy. In addition, the ability of poly D,L-alanine modification of Escherichia coli L-asparaginase to increase the plasma half-life in mice tenfold as well as to decrease the immunogenicity of the enzyme is presented.
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PMID:L-cyst(e)ine requirements of malignant cells and progress toward depletion therapy. 46 47

Theoretic and experimental arguments are surveyed which justify the setting up, within the family of pyridoxal-P-dependent lyases, of a special subgroup that comprizes several enzymes catalyzing exclusively beta-replacement reactions of alpha-aminoacids with electronegative substituents in the beta-position. The authors and their associates have studied the physico-chemical and catalytic properties of four high purity enzymes belonging to this subgroup, namely: cysteine lyase (EC 4.1.1.10) from embryonic chicken yolk-sac, serine sulfhydrase from chicken liver and the closely analogous or synonymic cystathionine beta-synthase (EC 4.4.1.8) from rat liver, and beta-cyanoalanine synthase (EC 4.4.1.9) from lupine seedlings, in comparison with some pyridoxal-P-requiring lyases differing in reaction specificity, for example, gamma-specific, alphabeta-eliminating or plurifunctional lyases such as gamma-cystathionase (EC 4.4.1.1) of animal tissues. The results of these studies, relating to subtrate and cosubstrate specificities of the enzymes mentioned, their interactions with some selective inhibitors, catalysis of isotopic exchange of hydrogen atoms in substrates and substrate analogs, etc., indicate that lyases of the exclusively beta-replacing type substantially differ in reaction mechanism from other subgroups of this enzyme family. Thus, it appears highly improbable that transient formation of an alphabeta-unsaturated, coenzyme-substrate imine, considered as an obligatory step in the action of lyases in the alphabeta-eliminating and other subgroups, should occur in the sequences of reaction intermediates in the case of beta-replacing lyases. Suggested features of the presumable catalytic mechanism of these lyases are discussed, such as : fixed conformation of the aminoacid substrate in the ES complex (protein-bound pyridoxal-P aldimine), with beta-substituent in orientation cis (rather than trans) to the Halpha atom ; role of the binding of appropriate cosubstrates (nucleophilic replacing agent, Cs) inducing essential electronic and/or steric transitions in the catalytic site of the ternanry CsES complexes, etc.
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PMID:The pyridoxal-phosphate-dependent enzymes exclusively catalyzing reactions of beta-replacement. 78 60

Pulsed Fourier transform proton magnetic resonance was used to study the labilization of protons of various L-amino acids by the enzyme gamma-cystathionase. In the course of the normal reaction, the enzyme labilizes the alpha and beta protons of the substrate, L-homoserine, and promotes elimination of the gamma substituent. It was found that gamma-cystathionase also catalyzes the exchange of the alpha and beta protons of L-amino acids which cannot undergo elimination reactions, but are competitive inhibitors of the enzyme. Both beta protons of L-alpha-aminobutyrate, although not stereochemically equivalent, were exchanged at equal rates, whereas selectivity was shown for one of the beta hydrogens when the carbon length was increased. The data also show that beta-proton exchange cannot occur without alpha-proton exchange. The rate of alpha-proton exchange from amino acids containing a terminal hydroxyl group at the beta, gamma, or lambda carbon is greater than from the corresponding unsubstituted amino acid. Exchange rates of the alpha proton for the inhibitors examined vary from one-seventh that of the normal enzymatic reaction to approximately the same rate as that for the elimination reaction with homoserine. An active site with two areas of substrate-enzyme interaction is proposed. One site contains pyridoxal 5'-phosphate and the base or bases involved in alpha- and beta-proton exchange; the second site contains a base which normally facilitates removal of the gamma substituent and can interact with the gamma and lambda carbons of the substrate molecule.
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PMID:Substrate proton exchange catalyzed by gamma-cystathionase. 83 97

beta,beta-Dichloro- and beta,beta,beta-trifluoroalanine irreversibly inactivate a number of pyridoxal phosphate dependent enzymes which catalyze beta- or gamma-elimination reactions. The inactivation is time dependent and the rate of inactivation is first order in enzyme concentration. This suggests that inactivation is due to covalent modification of the enzyme by a species generated at the active site from the polyhaloalanine (i.e., suicide inactivation). Monohaloalanines are substrates and do not inactivate. For gamma-cystathionase, covalent and stoichiometric attachment of [1-14C]beta,beta,beta-trifluoroalanine was shown. It is proposed that the mechanism of inactivation involves Schiff base formation between inactivator and enzyme-bound pyridoxal and subsequent elimination of HC1 from dichloroalanine or HF from trifluoroalanine. This results in the formation of a beta-halo-alpha,beta unsaturated imine, an activated Michael acceptor. Michael addition of a nucleophile at the active site leads to covalent labeling of the enzyme and inactivation. Alanine racemase is also inactivated by the two polyhaloalanines. Glutamate-pyruvate and gultamate-oxaloacetate transaminase are inactivated by monohaloalanines but not by polyhaloalanines.
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PMID:Inactivation of pyridoxal phosphate dependent enzymes by mono- and polyhaloalanines. 97 85

L-Methionine sulfoximine is a substrate of L-amino acid oxidase (Crotalus adamanteus), glutamine transaminase, and gamma-cystathionase. In the reaction catalyzed by L-amino acid oxidase, methionine sulfoximine is converted to aplph-imino-gamma-methylsulfoximinylbutyrate, which undergoes rapid gamma elimination yielding methane sulfinimide and 2-imino-3-butenoic acid. Methane sulfinimide is converted to methane sulfonamide, methane sulfinic acid, and methane sulfonic acid; 2-imino-3-butenoic acid is hydrolyzed to vinylglyoxylate, which polymerizes to an insoluble product. When the reaction is carried out in the presence of semicarbazide, the imine formed initially is quantitatively trapped as alpha-keto-gamma-methylsulfoximinylbutyrate semicarbazone, from which the free alpha-keto acid may be obtained. When the reaction is carried out in the presence of a mercaptan (RSH), a gamma exchange reaction occurs leading to formation of a new alpha-keto acid substituted in the gamma position by an SR-group; thus, alpha-keto-gamma-(beta-hydroxyethiol)butyric acid (S-(hydroxyethyl)-2-keto-4-mercaptobutyric acid) was obtained when L-methionine sulfoximine was oxidized in the presence of 2-mercaptoethanol, and enzymatic transamination of this alpha-keto acid with L-glutamine gave the new amino acid, L-omega-hydroxyethionine. The reaction of L-methionine sulfoximine with gamma-cystathionase yields 1 mol each of alpha-ketobutyrate and methane sulfinimide; the latter is hydrolyzed almost exclusively to methane sulfinic acid. Transamination of L-methionine sulfoximine yields the corresponding alpha-keto acid (alpha-keto-gamma-methylsulfoximinylbutyrate), which is stable. Some of these reactions may occur in vivo, and thus contribute to the toxicity of L-methionine sulfoximine.
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PMID:Enzymatic reactions of methionine sulfoximine. Conversion to the corresponding alpha-imino and alpha-keto acids and to alpha-ketobutyrate and methane sulfinimide. 97 92

1. The mode of inhibition of rat liver cystathionine-gamma-lyase [L-cystathionine cysteine-lyase (deaminating), EC 4.4.1.1] was studied by using several unusual sulfur-containing amino acids newly found in this laboratory. Some cysteine conjugates (CMC, Beta-CEC, HCETC and HCPC) inhibited noncompetitively both homoserine dehydratase and diaminopropionate ammonia-lyase activities, and competitively gamma-cystathionase activity. CMTC exhibited a mixed type inhibition on both homoserine dehydratase and gamma-cystathionase activities, and a noncompetitive inhibition on the diaminopropionate ammonia-lyase activity. Some homocysteine conjugates (CMHC, beta-CEHC and HCEHC) inhibited competitively both the activity of homoserine dehydratase and of gamma-cystathionase, and exhibited a mixed type inhibition on the diaminopropionate ammonia-lyase activity. beta-CEC, CMHC and beta-CEHC were also effective inhibitors to cysteine desulfhydrase activity. 2. Among the other amino acids tested, DL-homocysteine and D-cysteine, irrespective of their concentration, exhibited a mixed type inhibition on the homoserine dehydratase activity. However, they promoted gamma-cystathionase activity at their lower concentrations and inhibited at their higher concentrations, more so than cystathionine. DL-alpha-Aminobutyric acid was a weak competitive inhibitor of the homoserine dehydratase, gamma-cystathionase and diaminopropionate ammonia-lyase activities. DL-alpha-Aminopimeric acid has the same chain length as beta-CEC, CMHC and CMTC, but it showed a very weak inhibitory effect compared with the latter sulfur-containing compounds. L-Methionine, DL-methionine sulfoxide, L-ethionine, L-cysteic acid, L-aspartic acid, L-asparagine, L-glutamic acid, L-glutamine, D-alanine, beta-alanine, L-ornithine and L-lysine had little or no effect on any activities of the enzyme preparation. These results were discussed in relation to the catalytic center of cystathionine-gamma-lyase.
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PMID:Effects of several unusual sulfur-containing amino acids on rat liver cystathionine-gamma-lyase. 119 82

Cystathionase activity in a lymphoid cell line extracts from a vitamin B6-responsive patient with cystathioninuria was increased strikingly by pyridoxal phosphate. Immunodiffusion with antiserum to human hepatic cystathionase showed identity between this cystathionase protein and cystathionase from an extract of normal lymphoid cells. Neither an increase in cystathionase activity nor immunochemical identity was found using extract of cells from a B6-unresponsive patient.
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PMID:Vitamin B6-responsive and -unresponsive cystathioninuria: two variant molecular forms. 119 8


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