2VRM

Structure of human MAO B in complex with phenyethylhydrazine

Summary for 2VRM

• Entry DOI: 10.2210/pdb2vrm/pdb
• Related: 1GOS 1H8R 1OJ9 1OJA 1OJB 1OJC 1OJD 1S2Q 1S2Y 1S3B 1S3E 2BK3 2BK4 2BK5 2BYB 2C64 2C65 2C66 2C67 2C70 2C72 2C73 2C75 2C76 2V5Z 2V60 2V61 2VRL
• Descriptor: AMINE OXIDASE [FLAVIN-CONTAINING] B, FLAVIN-ADENINE DINUCLEOTIDE, PHENYLETHANE, ... (4 entities in total)
• Functional Keywords: oxidoreductase, fad, flavin, membrane, hydrazine, acetylation, flavoprotein, mitochondrion, transmembrane, inhibitor binding, membrane protein, monoamine oxidase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Mitochondrion outer membrane; Single-pass type IV membrane protein; Cytoplasmic side: P27338
• Total number of polymer chains: 2
• Total formula weight: 119458.89

Authors

Binda, C.,Wang, J.,Li, M.,Hubalek, F.,Mattevi, A.,Edmondson, D.E. (deposition date: 2008-04-09, release date: 2008-04-22, Last modification date: 2024-11-13)

Primary citation

Binda, C.,Wang, J.,Li, M.,Hubalek, F.,Mattevi, A.,Edmondson, D.E.
Structural and Mechanistic Studies of Arylalkylhydrazine Inhibition of Human Monoamine Oxidases a and B
Biochemistry, 47:5616-, 2008

PubMed Abstract: The structure and mechanism of human monoamine oxidase B (MAO B) inhibition by hydrazines are investigated and compared with data on human monoamine oxidase A (MAO A). The inhibition properties of phenylethylhydrazine, benzylhydrazine, and phenylhydrazine are compared for both enzymes. Benzylhydrazine is bound more tightly to MAO B than to MAO A, and phenylhydrazine is bound weakly by either enzyme. Phenylethylhydrazine stoichiometrically reduces the covalent FAD moieties of MAO A and of MAO B. Molecular oxygen is required for the inhibition reactions, and the level of O2 consumption for phenylethylhydrazine is 6-7-fold higher with either MAO A or MAO B than for the corresponding reactions with benzylhydrazine or phenylhydrazine. Mass spectral analysis of either inhibited enzyme shows the major product is a single covalent addition of the hydrazine arylalkyl group, although lower levels of dialkylated species are detected. Absorption and mass spectral data of the inhibited enzymes show that the FAD is the major site of alkylation. The three-dimensional (2.3 A) structures of phenylethylhydrazine- and benzylhydrazine-inhibited MAO B show that alkylation occurs at the N(5) position on the re face of the covalent flavin with loss of the hydrazyl nitrogens. A mechanistic scheme is proposed to account for these data, which involves enzyme-catalyzed conversion of the hydrazine to the diazene. From literature data on the reactivities of diazenes, O2 then reacts with the bound diazene to form an alkyl radical, N2 and superoxide anion. The bound arylalkyl radical reacts with the N(5) of the flavin, while the dissociated diazene reacts nonspecifically with the enzyme through arylalkylradicals.

PubMed: 18426226
DOI: 10.1021/BI8002814

Experimental method

X-RAY DIFFRACTION (2.3 Å)