Journal article
The impact of single nucleotide polymorphisms on human aldehyde oxidase
Drug metabolism and disposition, Vol.40(5), pp.856-864
05/2012
Handle:
https://hdl.handle.net/2376/109576
PMID: 22279051
Abstract
Aldehyde oxidase (AO) is a complex molybdo-flavoprotein that belongs to the xanthine oxidase family. AO is active as a homodimer, and each 150-kDa monomer binds two distinct [2Fe2S] clusters, FAD, and the molybdenum cofactor. AO has an important role in the metabolism of drugs based on its broad substrate specificity oxidizing aromatic aza-heterocycles, for example, N(1)-methylnicotinamide and N-methylphthalazinium, or aldehydes, such as benzaldehyde, retinal, and vanillin. Sequencing the 35 coding exons of the human AOX1 gene in a sample of 180 Italian individuals led to the identification of relatively frequent, synonymous, missense and nonsense single-nucleotide polymorphisms (SNPs). Human aldehyde oxidase (hAOX1) was purified after heterologous expression in Escherichia coli. The recombinant protein was obtained with a purity of 95% and a yield of 50 μg/l E. coli culture. Site-directed mutagenesis of the hAOX1 cDNA allowed the purification of protein variants bearing the amino acid changes R802C, R921H, N1135S, and H1297R, which correspond to some of the identified SNPs. The hAOX1 variants were purified and compared with the wild-type protein relative to activity, oligomerization state, and metal content. Our data show that the mutation of each amino acid residue has a variable impact on the ability of hAOX1 to metabolize selected substrates. Thus, the human population is characterized by the presence of functionally inactive hAOX1 allelic variants as well as variants encoding enzymes with different catalytic activities. Our results indicate that the presence of these allelic variants should be considered for the design of future drugs.
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Details
- Title
- The impact of single nucleotide polymorphisms on human aldehyde oxidase
- Creators
- Tobias Hartmann - Department of Molecular Enzymology, Institute of Biochemistry and Biology, University of Potsdam, Karl-Liebknecht-Strasse 24-25, 14476 Potsdam, GermanyMineko TeraoEnrico GarattiniChristian TeutloffJoshua F AlfaroJeffrey P JonesSilke Leimkühler
- Publication Details
- Drug metabolism and disposition, Vol.40(5), pp.856-864
- Academic Unit
- Chemistry, Department of
- Publisher
- United States
- Grant note
- R01 GM100874 / NIGMS NIH HHS GM100874 / NIGMS NIH HHS
- Identifiers
- 99900546913601842
- Language
- English
- Resource Type
- Journal article