Selective Inhibition of PLP-Dependent Enzymes by Hydroxylamine Derivatives

Khomutov, Alex R.; Gabibov, A. G.; Khurs, Elena N.; Tolosa, E.A.; Shuster, Alexander M.; Goryachenkova, E.V.; Khomutov, R. M.

doi:10.1007/978-3-0348-9308-4_54

Cited by 5 publications

(2 citation statements)

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“…They react readily with the cofactor of the enzyme to form oximes (Scheme 1). The monocarboxylic hydroxylamine derivatives mimic amino acids that lack the a-carboxylate group (Khomutov et al, 1961(Khomutov et al, , 1963(Khomutov et al, , 1987Karpeisky et al, 1963). The oxime with aminooxyacetate, the aspartate analogue, has been studied particularly well.…”

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confidence: 99%

Crystal Structures and Solution Studies of Oxime Adducts of Mitochondrial Aspartate Aminotransferase

Marković-Housley

Schirmer

Hohenester

et al. 1996

European Journal of Biochemistry

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The interaction of mitochondrial aspartate aminotransferase with hydroxylamine and five derivatives (in which the hydroxyl hydrogen is replaced by the side chain of naturally occurring amino acids) was investigated by X-ray diffraction as well as by kinetic and spectral measurements with the enzyme in solution. The inhibitors react with pyridoxal 5'-phosphate in the enzyme active site, both in solution and in the crystalline state, in a reversible single-step reaction forming spectrally distinct oxime adducts. Dissociation constants determined in solution range from lo-' M to M depending on the nature of the side-chain group.The crystal structures of the adducts of mitochondrial aspartate aminotransferase with the monocarboxylic analogue of L-aspartate in the open and closed enzyme conformation were determined at 0.23-nm and 0.25-nm resolution, respectively. This inhibitor binds to both the open and closed crystal forms of the enzyme without disturbing the crystalline order. Small differences in the conformation of the cofactor pyridoxal phosphate were detected between the structures of both oxime complexes and the 2-methylaspartate adduct. The crystal structures indicate that the interaction between the w-carboxylate of the inhibitor and Arg292* of the neighbouring subunit is mainly responsible for the attainment of nearcoplanarity of the aldimine bond with the pyridine ring in the oxime adducts. Studies with a fluorescent probe aimed to detect shifts in the open/closed conformational equilibrium of the enzyme in oxime complexes showed that the hydroxylamine-derived inhibitors, even those containing a carboxylate group, do not induce the 'domain closure' in solution. This is probably due to the absence of the a-carboxylate group in the monocarboxylic hydroxylamine-derived inhibitors, emphasizing that both carboxylates of the substrates L -A s~ and L -G~ are essential for stabilizing the closed form of aspartate aminotransferase.

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confidence: 99%

Crystal Structures and Solution Studies of Oxime Adducts of Mitochondrial Aspartate Aminotransferase

Marković-Housley

Schirmer

Hohenester

et al. 1996

European Journal of Biochemistry

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“…Attention was therefore focused on blocking three potential biosynthetic points. These points, and the specific inhibitors tested, were (a) blocking transamination with transaminase inhibitors (aminooxyacetic acid (AOAA), 11 (22)(23)(24), and 2-methylglutamate (MeGlu), 12 (25)) or amidotransferase inhibitors (azaserine, 13 (26), and 6-diazo-5-0x0-Lnorleucine (DON), 14 (27)); (b) blocking the availability of La-arginine with a L-a-arginine biosynthetic inhibitors (L-arginine hydroxamate (ArgH), 15 (28,29), and 12); and (c) blocking N-methylation with a methyltransferase inhibitor (L-ethionine (Eth), 16 (30, 3 1)).…”

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confidence: 99%

Nucleoside intermediates in blasticidin S biosynthesis identified by the in vivo use of enzyme inhibitors

Gould¹,

Guo²,

Geitmann³

et al. 1994

Can. J. Chem.

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s . Can. J. Chem. 72,6 (1994).Intermediates in the biosynthesis of blasticidin S and its nucleoside co-metabolites were detected by altering fermentation conditions. Inhibitors of specific types of biochemical reactions that were expected to be involved in blasticidin biosynthesis were fed to Streptomyces griseochromogenes, in some cases with the inclusion of large quantities of the primary precursors of blasticidin S. The types of reactions and inhibitors used were (1) transaminase (aminooxyacetic acid and 2-methylglutamate), (2) amidotransferase (azaserine and 6-diazo-5-0x0-L-norleucine), (3) arginine biosynthesis (arginine hydroxamate), and (4) methyltransferase (ethionine). These manipulations apparently distorted the pools of precursors and (or) intermediates, and led to substantial accumulations of three known, previously minor, metabolites of S. griseochromogenes, cytosylglucuronic acid, pentopyranine C, and demethylblasticidin S, and of two new ones, pentopyranone and isoblasticidin S. New cytosyl metabolites were detected by HPLC with photodiode array detection. Fermentations to which arginine hydroxamate and cytosine had been added also produced three aberrant metabolites that were derived from pentopyranone and arginine hydroxamate. [Traduit par la redaction]

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Blasticidin S and Related Peptidyl Nucleoside Antibiotics

Gould¹

1997

Drugs and the Pharmaceutical Sciences

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Selective Inhibition of PLP-Dependent Enzymes by Hydroxylamine Derivatives

Abstract: Compounds of the general formula RONH 2 containing structural fragments of the products or the substrates of enzymatic reactions are suggested as· a means for effective and specific inhibition of corresponding carbonyl dependent enzymes.

Cited by 5 publications

References 2 publications

Crystal Structures and Solution Studies of Oxime Adducts of Mitochondrial Aspartate Aminotransferase

Crystal Structures and Solution Studies of Oxime Adducts of Mitochondrial Aspartate Aminotransferase

Nucleoside intermediates in blasticidin S biosynthesis identified by the in vivo use of enzyme inhibitors

Blasticidin S and Related Peptidyl Nucleoside Antibiotics

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