The organic chemistry of mechanism‐based enzyme inhibition: A chemical approach to drug design

Silverman, Richard B.; Hoffman, Stephen J.

doi:10.1002/med.2610040305

Cited by 40 publications

(16 citation statements)

References 98 publications

(8 reference statements)

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“…Denaturation of the inactivated enzyme did not lead to reoxidation of the flavin, indicating that attachment was to the flavin, as is the case with 1 -phenylcyclopropylamine (Silverman & Zieske, 1985). Consequently, these results suggest that PCBA is a mechanism-based (enzyme-activated) inactivator (Silverman & Hoffman, 1984;Walsh, 1984;Abeles, 1983;Rando, 1984) of MAO.…”

Section: Resultsmentioning

confidence: 77%

1-Phenylcyclobutylamine, the first in a new class of monoamine oxidase inactivators. Further evidence for a radical intermediate

Silverman¹,

Zieske²

1986

Biochemistry

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1-Phenylcyclobutylamine (PCBA) is shown to be both a substrate and a time-dependent irreversible inactivator of monoamine oxidase (MAO). Inactivation results in attachment to the flavin cofactor. For every molecule of PCBA leading to inactivation, 325 molecules are converted to product. The first metabolite formed is identified as 2-phenyl-1-pyrroline; then after a lag time, 3-benzoylpropanal and 3-benzoylpropionic acid are generated. The 3-benzoylpropanal is a product of MAO-catalyzed oxidation of 2-phenyl-1-pyrroline (presumably, of its hydrolysis product, gamma-aminobutyrophenone). The aldehyde is nonenzymatically oxidized by nascent hydrogen peroxide to the carboxylic acid. These results are consistent with a one-electron oxidation of PCBA to the amine radical cation followed by homolytic cyclobutane ring cleavage. The resulting radical can partition between cyclization (an intramolecular radical trap) to the 2-phenylpyrrolinyl radical and attachment to the flavin. The cyclic radical can be further oxidized by one electron to 2-phenyl-1-pyrroline. PCBA represents the first in the cyclobutylamine class of MAO inactivators and strongly supports involvement of a radical mechanism for MAO-catalyzed amine oxidations.

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Section: Resultsmentioning

confidence: 77%

1-Phenylcyclobutylamine, the first in a new class of monoamine oxidase inactivators. Further evidence for a radical intermediate

Silverman¹,

Zieske²

1986

Biochemistry

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“…9 Their catalytic cycle involves removal of a proton, facilitating activation of many chemical entities. 1,3 We previously described dihydropyridone 1 as an MBI of BioA, 10 a PLP-dependent aminotransferase that conditional knockdown experiments identified as essential in Mycobacterium tuberculosis . 11 Given the presumed four-step mechanism of inactivation (Figure 1A), it was unclear how to further optimize 1 based on the obtained K I and k inact values.…”

mentioning

confidence: 99%

Rational Optimization of Mechanism-Based Inhibitors through Determination of the Microscopic Rate Constants of Inactivation

et al. 2017

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Mechanism-based inhibitors (MBIs) are widely employed in chemistry, biology, and medicine due to their exquisite specificity and sustained duration of inhibition. Optimization of MBIs is complicated due to time-dependent inhibition resulting from multi-step inactivation mechanisms. The global kinetic parameters kinact and KI have been used to characterize MBIs, but provide far less information than is commonly assumed, as shown by derivation and simulation of these parameters. We illustrate an alternative and more rigorous approach for MBI characterization through determination of the individual microscopic rate constants. Kinetic analysis revealed the rate-limiting step of inactivation of the PLP-dependent enzyme BioA by dihydro-(1,4)-pyridone 1. This knowledge was subsequently applied to rationally design a second-generation inhibitor scaffold with a nearly optimal maximum inactivation rate (0.48 min−1).

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“…A mechanism-based inactivator is a chemically unreactive compound that is converted by an enzyme via its catalytic mechanism to a species that, without prior release from the active site, produces inactivation of that enzyme (Silverman & Hoffman, 1984;Walsh, 1984;Abeles & Maycock, 1976;Rando, 1974). The mechanism proposed for the inactivation of M A 0 by N-CBA was described in the preceding paper in this issue .…”

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confidence: 99%

Mechanism for reactivation of N-cyclopropylbenzylamine-inactivated monoamine oxidase by amines

Rb¹,

Rb²

1985

Biochemistry

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The effect of 18 different amines, two mercaptans, and two alcohols on the reactivation of N-cyclopropylbenzylamine- (N-CBA-) inactivated bovine liver monoamine oxidase (MAO) is described. All of the compounds that reactivate the enzyme produce a time-dependent pseudo-first-order return of enzyme activity and exhibit saturation kinetics. There is no direct correlation between the ability of a compound to serve as a substrate for native MAO and its ability to reactivate N-CBA-inactivated MAO. Amines containing an aromatic moiety, in general, are better reactivators than the aliphatic amines. The amine must be primary or secondary in order for reactivation to occur. The distance between the aromatic portion and the amino group is critical to the reactivation properties of the compound. The mercaptans and alcohols do not reactivate N-CBA-inactivated MAO, nor do they interfere with the reactivation reaction by benzylamine. Three mechanisms for the reactivation reaction are considered. One involves initial Schiff base formation with the active site adduct produced by N-CBA inactivation of MAO followed by base-catalyzed beta-elimination to the imine of acrolein. The second mechanism is the same as the first except no prior Schiff base formation is invoked. The third mechanism is an SN2 displacement by the amine of the active site amino acid residue attached to the adduct. Experiments are carried out to exclude the SN2 mechanism. The results of the reactivation experiments favor the Shiff base mechanism.

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The organic chemistry of mechanism‐based enzyme inhibition: A chemical approach to drug design

Cited by 40 publications

References 98 publications

1-Phenylcyclobutylamine, the first in a new class of monoamine oxidase inactivators. Further evidence for a radical intermediate

1-Phenylcyclobutylamine, the first in a new class of monoamine oxidase inactivators. Further evidence for a radical intermediate

Rational Optimization of Mechanism-Based Inhibitors through Determination of the Microscopic Rate Constants of Inactivation

Mechanism for reactivation of N-cyclopropylbenzylamine-inactivated monoamine oxidase by amines

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