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:1.1.1.3 (HSD)
3,464 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A mutant of Salmonella typhimurium was selected for its spontaneous resistance to the lysine analog, thialysine (S-2-aminoethyl cysteine). This strain, JB585, exhibits a number of pleiotropic properties including a partial growth requirement for threonine, resistance to thiaisoleucine and azaleucine, excretion of lysine and valine, and inhibition of growth by methionine. Genetic studies show that these properties are caused by a single mutation in the thrA gene which encodes the threonine-controlled aspartokinase-homoserine dehydrogenase activities. Enzyme assays demonstrated that the aspartokinase activity is unstable and the threonine-controlled homoserine dehydrogenase activity absent in extracts prepared from the mutant. These results explain the growth inhibition by methionine because the remaining homoserine dehydrogenase isoenzyme would be repressed by methionine, causing a limitation for threonine. The partial growth requirement for threonine during growth in glucose minimal medium may also, by producing an isoleucine limitation, cause derepression of the isoleucine-valine enzymes and provide an explanation for both the valine excretion, and azaleucine and thiaisoleucine resistance. The overproduction of lysine may confer the thialysine resistance.
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PMID:Thialysine-resistant mutant of Salmonella typhimurium with a lesion in the thrA gene. 78 77

The kinase activity of the threonine-sensitive aspartokinase-homoserine dehydrogenase enzyme complex of Escherichia coli was selectively inactivated by Co(III) incorporation. Incubation of the enzyme with Co(II) in the presence of oxygen or H2O2 resulted in incorporation of one Co(III) per subunit. The cobalt(III) bound to the enzyme was not removable by dialysis and presumably results from formation of "inert" coordination complexes with ligands contributed by the enzyme. Cobalt was released from the enzyme by incubation with dithiothreitol but not by metal chelating agents. The Co(III)-labeled enzyme was aspartokinase inactive but still retained 60% of its original homoserine dehydrogenase activity. Studies of the time course of inactivation showed aspartokinase inactivation paralleled Co(III) incorporation. The residual dehydrogenase activity of aspartokinase inactive enzyme was still inhibited by threonine Thus, Co(III) incorporation seems to result in a specific inactivation of kinase activity which permits enumeration of the number of aspartokinase sites. Limited alpha-chymotrypsin digestion of Co(III)-enzyme produced homoserine dehydrogenase-active fragments devoid of Co(III), further confirming the specificity of the labeling procedure. Aspartokinase inactivation obtained without concomitant desensitization of homoserine dehydrogenase to threonine inhibition suggests that kinase active site integrity is not required for threonine binding and inhibition of homoserine dehydrogenase.
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PMID:Cobalt(III) labeled aspartokinase-homoserine dehydrogenase of Escherichia coli. 110 Jan 5

Three genes from Pseudomonas aeruginosa involved in threonine biosynthesis, hom, thrB and thrC, encoding homoserine dehydrogenase (HDH), homoserine kinase (HK) and threonine synthase (TS), respectively, have been cloned and sequenced. The hom and thrc genes lie at the thr locus of the P. aeruginosa chromosome map (31 min) and are likely to be organized in a bicistronic operon. The encoded proteins are quite similar to the Hom and TS proteins from other bacterial species. The thrB gene was located by pulsed-field gel electrophoresis experiments at 10 min on the chromosome map. The product of this gene does not share any similarity with other known ThrB proteins. No phenotype could be detected when the chromosomal thrB gene was inactivated by an insertion. Therefore the existence of isozymes for this activity is postulated. HDH activity was feedback inhibited by threonine; the expression of all three genes was constitutive. The overall organization of these three genes appears to differ from that in other bacterial species.
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PMID:Isolation, organization and expression of the Pseudomonas aeruginosa threonine genes. 133 66

An antifungal antibiotic (S) 2-amino-4-oxo-5-hydroxypentanoic acid, inhibited the biosynthesis of the aspartate family of amino acids (methionine, isoleucine and threonine) followed by the inhibition of protein biosynthesis in Saccharomyces cerevisiae. This inhibition was effected by impeding the biosynthesis of their common intermediate precursor, homoserine. The inhibition of biosynthesis of homoserine by the antibiotic was attributable to inactivation of homoserine dehydrogenase [EC 1.1.1.3], which is involved in the conversion of aspartate semialdehyde to homoserine in the metabolic pathway leading to threonine, methionine and isoleucine. Since such enzymic activity is not present in animal cells, the selective antifungal activity of the antibiotic is thus explained.
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PMID:Mechanism of action of an antifungal antibiotic, RI-331, (S) 2-amino-4-oxo-5-hydroxypentanoic acid; kinetics of inactivation of homoserine dehydrogenase from Saccharomyces cerevisiae. 135 15

The hom-thrB operon (homoserine dehydrogenase/homoserine kinase) and the thrC gene (threonine synthase) of Corynebacterium glutamicum ATCC 13,032 and the homFBR (homoserine dehydrogenase resistant to feedback inhibition by threonine) alone as well as homFBR-thrB operon of C. glutamicum DM 368-3 were cloned separately and in combination in the Escherichia coli/C. glutamicum shuttle vector pEK0 and introduced into different corynebacterial strains. All recombinant strains showed 8- to 20-fold higher specific activities of homoserine dehydrogenase, homoserine kinase, and/or threonine synthase compared to the respective host. In wild-type C. glutamicum, amplification of the threonine genes did not result in secretion of threonine. In the lysine producer C. glutamicum DG 52-5 and in the lysine-plus-threonine producer C. glutamicum DM 368-3 overexpression of hom-thrB resulted in a notable shift of carbon flux from lysine to threonine whereas cloning of homFBR-thrB as well as of homFBR in C. glutamicum DM 368-3 led to a complete shift towards threonine or towards threonine and its precursor homoserine, respectively. Overexpression of thrC alone or in combination with that of homFBR and thrB had no effect on threonine or lysine formation in all recombinant strains tested.
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PMID:Amplification of three threonine biosynthesis genes in Corynebacterium glutamicum and its influence on carbon flux in different strains. 136 20

Isotope exchange kinetics at chemical equilibrium have been used to investigate the kinetic mechanism of homoserine dehydrogenase (EC 1.1.1.3) of the (Thr-sensitive) aspartokinase/homoserine dehydrogenase-I multifunctional enzyme from E. coli. For the reaction (L-ASA + NADPH + H+ = L-Hse + NADP+), at pH 9.0, 37 degrees C, Keq = 100 (+/- 20). Under these conditions, the rate for exchange of [14C]-L-homoserine (Hse) in equilibrium L-aspartate-beta-semialdehyde (ASA) is nearly twice that for the [3H]-NADP+ in equilibrium NADPH exchange. This indicates that covalent interconversion between reactants and products bound in the active site cannot be rate-limiting. Upon variation of the concentrations of all four substrates in constant ratio at equilibrium (to minimize dead-end complex formation), the Hse in equilibrium ASA exchange increased smoothly toward a maximum. In contrast, the NADP+ in equilibrium NADPH exchange rate increased to a maximum value at partial saturation, then decreased to approximately half the maximum rate. These data are consistent with a preferred-order random kinetic mechanism in which the dominant pathway involves association of NADPH prior to L-ASA and dissociation of L-Hse prior to NADP+.
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PMID:Preferred order random kinetic mechanism for homoserine dehydrogenase of Escherichia coli (Thr-sensitive) aspartokinase/homoserine dehydrogenase-I: equilibrium isotope exchange kinetics. 154 69

In Escherichia coli, Bacillus subtilis and Corynebacterium glutamicum, homoserine dehydrogenase (HD), the enzyme after the branch point of the threonine/methionine and lysine biosynthetic pathways, is allosterically inhibited by L-threonine. To investigate the regulation of the C. glutamicum HD enzyme by L-threonine, the structural gene, hom, was mutated by UV irradiation of whole cells to obtain a deregulated allele, homdr. L-Threonine inhibits the wild-type (wt) enzyme with a Ki of 0.16 mM. The deregulated enzyme remains 80% active in the presence of 50 mM L-threonine. The homdr gene mutant was isolated and cloned in E. coli. In a C. glutamicum wt host background, but not in E. coli, the cloned homdr gene is genetically unstable. The cloned homdr gene is overexpressed tenfold in C. glutamicum and is active in the presence of over 60 mM L-threonine. Sequence analysis revealed that the homdr mutation is a single nucleotide (G1964) deletion in codon 429 within the hom reading frame. The resulting frame-shift mutation radically alters the structure of the C terminus, resulting in ten amino acid (aa) changes and a deletion of the last 7 aa relative to the wt protein. These observations suggest that the C terminus may be associated with the L-threonine allosteric response. The homdr mutation is unstable and probably deleterious to the cell. This may explain why only one mutation was obtained despite repeated mutagenesis.
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PMID:A C-terminal deletion in Corynebacterium glutamicum homoserine dehydrogenase abolishes allosteric inhibition by L-threonine. 174 20

Transduction of the locus of stability to high threonine concentrations (Thrr) into E. coli str M1 and C600 resulted in enhancements of the amino acid production and retardation of the culture development. Besides the mutation caused increase of the specific activity of glutamate synthase, aspartate kinase and homoserine dehydrogenase. The cells of the mutant strains had poorly developed walls and were smaller than those of the parent strains.
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PMID:[Comparative study of E. coli strains producing amino acids]. 177 48

We have reported that a major cause of growth inhibition of Escherichia coli by L-serine is its inhibition of homoserine dehydrogenase I (HDH I), which is involved in the biosyntheses of threonine and isoleucine [Hama, H., Sumita, Y., Kakutani, Y., Tsuda, M., & Tsuchiya, T. (1990) Biochem. Biophys. Res. Commun. 168, 1211-1216]. However, Patte et al. reported that L-serine does not inhibit HDH I [Patte, J.-C., Truffa-Bachi, P., & Cohen, G.N. (1966) Biochim. Biophys. Acta 128, 426-439]. In studies on the reason for these discrepant results, we found that the concentration of K+ and the pH in the assay mixture strongly influenced the inhibitory effect of L-serine. L-Serine strongly inhibited the HDH I activities in both the forward and reverse reactions between aspartate semialdehyde and homoserine at a physiological K+ concentration (100 to 200 mM) and physiological pH (7.5) for E. coli cells. On the other hand, two well-known inhibitors of HDH I, L-threonine and L-cysteine, strongly inhibited the activity regardless of the K+ concentration and pH.
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PMID:Inhibition of homoserine dehydrogenase I by L-serine in Escherichia coli. 190 68

We have explored the mechanism by which an antifungal antibiotic, (S)-2-amino-4-oxo-5-hydroxypentanoic acid, RI-331, preferentially inhibits protein biosynthesis in Saccharomyces cerevisiae, by inhibiting the biosynthesis of the aspartate family of amino acids, methionine, isoleucine and threonine. This inhibition was effected by inhibiting the biosynthesis of their common intermediate precursor homoserine. The target enzyme of RI-331 was homoserine dehydrogenase (EC.1.1.1.3) which is involved in converting aspartate semialdehyde to homoserine in the pathway from aspartate to homoserine. The enzyme is lacking in animals. So the antibiotic is selectively toxic to prototrophic fungi.
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PMID:The mechanism of antifungal action of (S)-2-amino-4-oxo-5-hydroxypentanoic acid, RI-331: the inhibition of homoserine dehydrogenase in Saccharomyces cerevisiae. 197 Jul 30


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