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PMID:19764817

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Citation

McGrath, AP, Hilmer, KM, Collyer, CA, Shepard, EM, Elmore, BO, Brown, DE, Dooley, DM and Guss, JM (2009) Structure and inhibition of human diamine oxidase. Biochemistry 48:9810-22

Abstract

Humans have three functioning genes that encode copper-containing amine oxidases. The product of the AOC1 gene is a so-called diamine oxidase (hDAO), named for its substrate preference for diamines, particularly histamine. hDAO has been cloned and expressed in insect cells and the structure of the native enzyme determined by X-ray crystallography to a resolution of 1.8 A. The homodimeric structure has the archetypal amine oxidase fold. Two active sites, one in each subunit, are characterized by the presence of a copper ion and a topaquinone residue formed by the post-translational modification of a tyrosine. Although hDAO shares 37.9% sequence identity with another human copper amine oxidase, semicarbazide sensitive amine oxidase or vascular adhesion protein-1, its substrate binding pocket and entry channel are distinctly different in accord with the different substrate specificities. The structures of two inhibitor complexes of hDAO, berenil and pentamidine, have been refined to resolutions of 2.1 and 2.2 A, respectively. They bind noncovalently in the active-site channel. The inhibitor binding suggests that an aspartic acid residue, conserved in all diamine oxidases but absent from other amine oxidases, is responsible for the diamine specificity by interacting with the second amino group of preferred diamine substrates.

Links

PubMed PMC2791411 Online version:10.1021/bi9014192

Keywords

Amine Oxidase (Copper-Containing)/antagonists & inhibitors; Amine Oxidase (Copper-Containing)/chemistry; Amine Oxidase (Copper-Containing)/genetics; Amine Oxidase (Copper-Containing)/metabolism; Animals; Binding Sites; Calcium/metabolism; Copper/metabolism; Crystallography, X-Ray; Dimerization; Diminazene/analogs & derivatives; Diminazene/metabolism; Drosophila/enzymology; Humans; Kinetics; Metallothionein/genetics; Models, Molecular; Pentamidine/metabolism; Promoter Regions, Genetic; Protein Conformation; Substrate Specificity; X-Ray Diffraction

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:AOC1

enables

GO:0005507: copper ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AOC1

enables

GO:0005509: calcium ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AOC1

enables

GO:0008131: primary amine oxidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AOC1

enables

GO:0008201: heparin binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AOC1

enables

GO:0042803: protein homodimerization activity

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P19801

F

Seeded From UniProt

complete

HUMAN:AOC1

enables

GO:0044877: protein-containing complex binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AOC1

enables

GO:0048038: quinone binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AOC1

involved_in

GO:0046677: response to antibiotic

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AOC1

involved_in

GO:0071504: cellular response to heparin

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:AOC3

enables

GO:0005507: copper ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AOC3

enables

GO:0005509: calcium ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AOC3

enables

GO:0008131: primary amine oxidase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:AOC3

involved_in

GO:0046677: response to antibiotic

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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