Inhibitory substrate

Active site directed P-lactam-derived inhibitors have a competitive component of inhibition, but once in the active site they form an acyl en2yme species which follows one or more of the pathways outlined in Figure 1. Compounds that foUow Route C and form a transiendy inhibited en2yme species and are subsequendy hydroly2ed to products have been termed inhibitory substrates or competitive substrates. Inhibitors that give irreversibly inactivated P-lactamase (Route A) are called suicide inactivators or irreversible inhibitors. The term progressive inhibitor has also been used. An excellent review has appeared on inhibitor interactions with P-lactamases (28). 

Adriaens P, DD Focht (1991a) Evidence for inhibitory substrate interactions during cometabolism of 3,4-dichlorobenzoate hy Acinetobacter sp. strain 4-CBl. FEMS Microbiol Ecol 85 293-300. 

Finally, in the case of inhibitory substrate analogues such as allo-xanthine, strong evidence has recently been presented that these bind to molybdenum in reduced xanthine oxidase (33). If the enzyme is reduced with xanthine, then treated anaerobically with alloxanthine and finally exposed to air, catalytic activity is lost. Though flavin and iron in the final product are in the oxidized state, there are significant spectral differences between it and the native enzyme. These are believed (33) due to reduction of molybdenum from Mo(VI) to Mo(IV) and complexing of... 

A rate equation for cell growth with an inhibitory substrate is assumed to be of the form (Andrews, Biotechnol Bioeng 10 707, 1968)... 

INHIBCONT - Continuous Bioreactor with Inhibitory Substrate System... 

Inhibitory substrates at high concentrations reduce the specific growth rate below that predicted by the simple Monod equation. The inhibition function may... 

Transient Holdup Profiles in an Agitated Extractor 459 Homogeneous Free-Radical Polymerisation 310 Batch Reactor Hydrolysis of Acetic Anhydride 247 Continuous Bioreactor with Inhibitory Substrate 543 Dynamic Oxygen Electrode 462... 

J. Andrews. A mathematical model for the continous culture of microorganisms utilizing inhibitory substrates. Biotechnol. Bioeng., 10 707-723, 1968. 

Gaudy, A. F., Jr, Lowe, W., Rozich, A. Colvin, R. (1988). Practical methodology for predicting critical operating range of biological systems treating inhibitory substrates. Journal Water Pollution Control Federation, 60, 77-85. 

Several monobactams have been reported to be inhibitory substrates for type 1 Cephases. 

Andrews, J. F., "A Mathematical Model for the Continuous Culture of Microorganisms Utilizing Inhibitory Substrates," Biotechnol. Bioeng. 10(1968) 707-723. 

Fig. 26. (A) Schematic diagram of one subunit of horse liver alcohol dehydrogenase. Znl is the active-site zinc. Designed by B. Furugren, from the work of Branden and colleagues [55], (B) Schematic diagram of a section through the horse liver alcohol dehydrogenase dimer. The catalytic zinc atoms are shown, with the inhibitory substrate analogue DMSO and coenzyme molecules indicated. The dimer has two active sites, each composed of parts of both subunits. From the work of Branden and colleagues [123].

Fig. 31. Horse liver alcohol dehydrogenase ternary complex with NADH and the inhibitory substrate analogue dimethyl sulphoxide. Stereo drawing from the work of Branden and colleagues.

Animal proteases, particularly those involved in blood clotting, can be also regulated by endogenous protease inhibitory proteins that act as inhibitory substrate analogues. These inhibitor proteins bind at the active site through key inhibitory sequences in which the key residues about the peptide bond contribute to inhibition and are denoted (N-terminal side)—P2—PI—(peptide bond to be hydrolysed)-PT-P2 -(C-terminal side) or simply P2-P1-PT-P2. A large number of plant PI proteins also act as peptide substrate mimetics. 

Andrews (13) has discussed the basis for the use of this function, and a more detailed treatment of its properties is given by Dixon and Webb (14). Yano and Koga (15) and Edwards (16) have discussed the properties of other functions which may be used to reflect inhibition by substrate. Figure 3 illustrates the properties of the inhibition function with the Monod function shown for comparison. For low values of substrate concentration or high values of Ki (less inhibitory substrates) the inhibition function reduces to the Monod function. There is a considerable reduction in the maximum growth rate attainable as compared with the case without inhibition. The maximum rate attainable may be obtained by setting the first derivative of Equation 9 equal to zero and can be expressed as ... 

Microorganisms Utilizing Inhibitory Substrates, Biotechnol. Bioeng. (1968) 10,707. 

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