The potency of oxalyl amino acid derivatives as inhibitors of prolyl 4-hydroxylase was studied in vitro, in isolated microsomes and in chicken embryonic-tissue culture. These compounds represent structural analogues of 2-oxoglutarate in which the -CH2- moiety at C-3 is replaced by -NH-, with or without further structural modifications. The most efficient inhibitor of purified prolyl 4-hydroxylase was oxalylglycine. Its mode of inhibition was competitive with respect to 2-oxoglutarate. The Ki value varied between 1.9 and 7.8 microM, depending on the variable substrate used. Oxalylalanine inhibited purified enzyme with a Ki of 40 microM. Other oxalyl amino acid derivatives showed little inhibitory activity. In microsomes isolated from embryonic chicken bone, oxalylglycine and oxalylalanine inhibited prolyl hydroxylation with IC50 values of 23 and 120 microM respectively. Dimethyloxalylglycine was not an inhibitor of purified prolyl 4-hydroxylase and only weakly active in the microsomal system, but efficiently suppressed hydroxyproline synthesis in embryonic chicken calvaria and lung. The data suggest that dimethyloxalyl amino acids are converted into active inhibitors in intact cells, most likely in the cytoplasmic compartment.
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Research Article|
June 01 1994
Inhibition of prolyl 4-hydroxylase by oxalyl amino acid derivatives in vitro, in isolated microsomes and in embryonic chicken tissues
E Baader;
E Baader
1Hoechst AG H 821, 65926 Frankfurt/Main, Federal Republic of Germany
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G Tschank;
G Tschank
1Hoechst AG H 821, 65926 Frankfurt/Main, Federal Republic of Germany
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K H Baringhaus;
K H Baringhaus
1Hoechst AG H 821, 65926 Frankfurt/Main, Federal Republic of Germany
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H Burghard;
H Burghard
1Hoechst AG H 821, 65926 Frankfurt/Main, Federal Republic of Germany
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V Günzler
V Günzler
1Hoechst AG H 821, 65926 Frankfurt/Main, Federal Republic of Germany
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Publisher: Portland Press Ltd
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 1994 The Biochemical Society, London
1994
Biochem J (1994) 300 (2): 525–530.
Citation
E Baader, G Tschank, K H Baringhaus, H Burghard, V Günzler; Inhibition of prolyl 4-hydroxylase by oxalyl amino acid derivatives in vitro, in isolated microsomes and in embryonic chicken tissues. Biochem J 1 June 1994; 300 (2): 525–530. doi: https://doi.org/10.1042/bj3000525
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