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[Enzymology and function of the gamma-glutamyl moiety (author's transl)].
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Glutathione and related gamma-glutamyl compounds: biosynthesis and utilization.
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Gluthatione turnover and the transport of amino acids. The gamma-glutamyl cycle (author's transl).
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5-Oxo-L-prolinase (L-pyroglutamate hydrolase). Purification and catalytic properties.
5-Oxo-L-prolinase, an enzyme that catalyzes the conversion of 5-oxo-L-proline (L-pyroglutamate; L-2-pyrrolidone-5-carboxylate) to L-glutamate coupled with the cleavage of ATP to ADP and Pi, has been purified about 1600-fold from rat kidney. Purification was carried out in the presence of 5-oxo-L-proline which protects the enzyme under a variety of conditions. An estimate of the molecular weight (about 325,000) was made by gel filtration on Sephadex G-200. K+ (or NH4+) and Mg2+ were required for activity. GTP, ITP, CTP, and UTP were much less active than ATP; dATP was 43% as active as ATP. ADP inhibited and addition of pyruvate kinase and phosphoenolpyruvate activated the reaction. The enzyme, which is protected during storage by dithiothreitol, is inhibited by p-hydroxymercuribenzoate, N-ethylmaleimide, and iodoacetamide. The apparent Km values for 5-oxo-L-proline and ATP are, respectively, 0.05 and 0.17 mM. The pH profile indicates a broad range of activity from about pH 5.5 to pH 11.2 with apparent maxima at about pH 7 and pH 9.7. The formation of Pi and glutamate was equimolar over a wide pH range. When the enzyme was incubated with ATP, Mg2+, K+, and L-2-imidazolidone-4-carboxylate or L-dihydroorotate, cleavage of ATP to ADP and Pi occurred, but no cleavage of the imino acid substrates was observed; when the enzyme was incubated under these conditions with 2-piperidone-6-carboxylate, 4-oxy-5-oxoproline, and 3-oxy-5-oxoproline, the corresponding dicarboxylic amino acids were formed, but the molar ratio of Pi to amino acid formation was significantly greater than unity.
Primary structural analysis of sulfhydryl protease inhibitors from pineapple stem.
Pineapple stem acetone powder provides a rich source of the sulfhydryl protease bromelain and of a family of compositionally similar but chromatographically distinct polypeptide inihibtors of this enzyme. The isoinhibitors have molecular weights of 5600, and they contain five disulfide bonds and about 50 amino acids each (Perlstein, S. H., AND Kezdy, F.J. (1973) J. Supramol. Struct. 1, 249-254). Primary structural analysis of one of the seven inhibitor fractions (VII) revealed extensive microheterogeneity. Each of the inhibitor molecules in Fraction VII was shown to be composed of two peptide chains joined by disulfide bonds. These chains, designated A and B on the basis of size, comprise 41 and 10-11 residues, respectively, and the amino acid sequence of one of each are given below: (see article for formular). On the basis of ionization properties and yields of the A and B chains, it would appear that one of the major inhibitor species in Fraction VII is the covalently linked complex of the two chains shown, namely [A-1, B-2]. The second major inhibitor component of Fraction VII is identical in structure with [A-1, B-2i1 except that residues 1 and 8 in the A chain are pyroglutamate and threonine, respectively, and in the B chain glutamine 11 is replaced by arginine. The third inhibitor in Fraction VII is a minor constituent identical with the second, except that residue 1 in the A chain is glutamate rather than pyroglutamate. This microheterogeneity in the inhibitors of Fraction VII is further increased by the fact that B chains may lack threonine 1, in which case they are decapeptides beginning with alanine. On the basis of the striking homology of the cysteine residues with those of other protease inhibitors, it is proposed that the bromelain inhibitors are generated enzymatically from single chain precursors by excision of a "bridge" paptide which links the NH-2 termal A chain to the COOH-terminal B chain.
Metabolism of thyrotropin releasing hormone in brain extracts. Isolation and characterization of an imidopeptidase for histidylprolineamide.
An extract of porcine brain acetone powder incubated with thyrotropin-releasing hormone (TRH; pGlu-His-ProNH2) produces acid TRH (pGlu-His-Pro), histidine, and prolineamide. Fractionation of the brain extract by DEAE-cellulose chromatography produces three protein fractions which metabolize TRH. The activity of these fractions was characterized using TRH with a 3H-label on the histidine or proline as well as [His-3H]His-ProNH2. Fraction I contains pyroglutamate aminopeptidase and Fraction II contains TRH deamidase. Fraction III was found to contain a previously unrecognized enzyme which cleaves His-ProNH2 to histidine and proline. The histidylprolineamide imidopeptidase has been characterized. A competition study using a variety of compounds containing histidine or proline suggests that the best substrates for the imidopeptidase contain a free alpha-amino group on histidine and a blocked carboxyl group on proline, as is found in His-ProNH2. A survey of a variety of polypeptide hormones indicates that many of them inhibit the imidopeptidase activity. A kinetic study of the inhibition of the enzyme by adrenocorticotropic hormone (1-24) shows that the inhibition by polypeptide hormones is noncompetitive. We hypothesize that pituitary hormones may stimulate the production of (cyclo)-His-Pro by inhibiting alternate routes of TRH metabolism.
Conformational analysis of the molecule luteinizing hormone-releasing hormone. 3. Analogue inhibitors and antagonists.
Conformational energy calculations have been carried out on analogues of luteinizing hormone-releasing hormone which have been shown to be potent inhibitors of the release of luteinizing hormone and follicle-stimulating hormone. The analogues included in this study have D-amino acid substitutions in the 2 and/or 3 positions, such as [D-X2]-LH-RH, [D-X2,D-Y3]-LH-RH, [D-X2,Pro3]-lh-rh, and [D-X2,Leu3]-LH-RH. A configurational property which was common to the low-energy conformers of all the analogues is the directional change of the cis-peptide bond of the pyroglutamate ring. Further, there was no overall structural change in the analogues relative to the conformation of native LH-RH, and the orientation of the aromatic side chains relative to one another remained the same throughout this series of analogues.
Enzymes of the gamma-glutamyl cycle in 'aging' WI-38 fibroblasts and in HeLa S3 cells.
gamma-Glutamyltransferase ((5-glutamyl)-peptide:amino-acid 5-glutamyltransferase, EC 2.3.2.2) activity of WI-38 fibroblasts decreased only slightly in relation to a constant amount of cell-associated protein as the cells were carried in culture serially from middle to late passage numbers leading toward senescence, e.g., from population doubling level 27 through 41. Also, when the enzyme activity was expressed on the basis of a unit number of cells or unit amount of DNA, little change occurred over that range of PDLs. As the culture approached 'phase-out', the transferase activity rose sharply regardless of how the activity was expressed. The possibility is considered that the large increase in activity could be a reflection of a significant increase in size of cells and therefore changes in the membranes where the transferase is located. The occurrence of other enzymes of the 'gamma-glutamyl cycle' in WI-38 and HeLa S3 cells also was demonstrated. These included gamma-glutamylcyclotransferase ((gamma-L-glutamyl)-L-amino-acid gamma-glutamyltransferase (cyclizing), EC 2.3.2.4) and 5-oxoprolinase, whose activities showed no large increase comparable to that of the gamma-glutamyltransferase, as the culture approached 'phase-out'.
[Glutathion-synthetase deficiency with 5-oxoprolinuria. Two new cases and a review of the literature (author's transl)].
Hereditary deficiency in glutathion- synthetase is a rare disease presenting up to now either with a congenital non-spherocytic anaemia or with a metabolic acidosis, most often neonatal and accompanied by a pyroglutamic amino-aciduria (5-oxoprolinuria). These two syndrome may be present together or exist independently. Pyroglutamic amino-aciduria is the result of extension of the deficiency to non-haematopoietic cells, in particular renal. Two new cases of glutathion-synthetase deficiency are reported: both with haemolytic anaemia and moderate pyroglutamic amino-aciduria, in the absence of clinical signs of metabolic acidosis. The clinical, haematological and biochemical heterogeneity of the deficiency is illustrated by these two cases and datas from the literature.