Inactivation of monoamine oxidase A by the monoamine oxidase B inactivators 1-phenylcyclopropylamine, 1-benzylcyclopropylamine, and N-cyclopropyl-.alpha.-methylbenzylamine

Abstract

Three known mechanism-based inactivators of beef liver mitochondrial monoamine oxidase (MAO) B are tested as inactivators of human placental mitochondrial MAO A. 1-Phenylcyclopropylamine (1-PCPA), 1-benzylcyclopropylamine (1-BCPA), and N-cyclopropyl-alpha-methylbenzylamine (N-C alpha MBA) are time-dependent irreversible inactivators of MAO A. The KI values for 1-PCPA and N-C alpha MBA, analogues of the MAO B substrate benzylamine, are much higher with MAO A than with MAO B. Evidence is presented to show that 1-PCPA inactivates MAO A by attachment to the flavin cofactor, unlike the reaction with MAO B in which 1-PCPA can attach to both a cysteine residue and the flavin [Silverman, R.B., & Zieske, P.A. (1985) Biochemistry 24, 2128-2138]. The reaction of 1-BCPA with MAO A was too slow to study in detail. N-C alpha MBA exhibits the same properties toward inactivation of MAO A that it does for inactivation of MAO B. Attachment in both cases is shown to be to one cysteine residue per enzyme molecule. The results with 1-PCPA indicate that the active site topographies of MAO A and MAO B are different. The ability of N-C alpha MBA to undergo attachment to a cysteine residue in both MAO A and MAO B may lead the way toward peptide mapping of the two isozymes in order to determine differences in their primary structures.

Quantum chemical modeling of the inhibition mechanism of monoamine oxidase by oxazolidinone and analogous heterocyclic compounds

“…Since the calculated stability trend of adduct models in the aqueous phase confirms experimental findings, rather than in the gas phase, it is reasonable to assume that the proposed adducts can form with residues that are close to the surface of MAOs, which are expected to be in more hydrophilic environment. According to Silverman & Hiebert 23 , cys365 in MAO-B and the corresponding amino acid cys374 in MAO-A are logical candidates which are on the surface of the protein. The results of our calculations in aqueous solution are consistent with this rationale.…”

“…Although the structure of the inactivated enzyme adduct (4) has not known, the X group in (4) could be either the flavin semiquinone formed in the first step or an amino acid radical generated from hydrogen atom transfer from the amino acid to the flavin semiquinone. Two experiments identified this amino acid to be a cysteine residue 22 , cys365 in MAO-B being a logical candidate 23,24 . However, elucidation of the structure of human MAO-B 25 and MAO-A 26,27 and of rat MAO-A 28 by X-ray revealed that there is no cysteine in the active site; cys365 in MAO-B and the corresponding amino acid cys374 in MAO-A are on the surface of the protein.…”

Monoamine Oxidases: The Biochemistry of the Proteins As Targets in Medicinal Chemistry and Drug Discovery

“…Right: the C4a adduct as deduced from the MAO Atranylcypromine crystal structure [122]. several interpretations [276][277][278][279], but the crystal structure of TCP-MAO B at 1.9 Å resolution is clearly C4a [122]. Studies on flavin modification continues in other flavoenzymes, providing insight into the formation of N5 and C4a adducts.…”

“…The adduct formed changes with the derivative used and can be different for MAO A. With MAO B, 1-phenylcyclopropylamine (1-PCPA) forms a mixture of the N5 and cysteine adducts [284]; with MAO N, it forms some C4a but mainly the N5 adduct [280]; and with MAO A it forms the N5 adduct [179,279]. As discussed above, inactivation of MAO B with 2-PCPA gives the C4a adduct in the crystal structure despite evidence for a mixture of adducts from the spectral and radioligand binding experiments.…”

Fluorinated Phenylcyclopropylamines as Inhibitors of Monoamine Oxidases

“…In contrast, nonfluorinated 38 is known to be a weak and moderately selective (A:B = 0.26:1) inhibitor of MAO B. [64] Thus, introduction of a fluorine substituent in position 2, trans to the amino group, caused a dramatic reversal of isoform selectivity to give A versus B selectivity of 135:1.…”