Critical overview on the structure and metabolism of human aldehyde oxidase and its role in pharmacokinetics

Cristiano Mota, Catarina Coelho, Silke Leimkühler, Enrico Garattini, Mineko Terao, Teresa Santos-Silva, Maria João Romão

Research output: Contribution to journalReview article

7 Citations (Scopus)

Abstract

Aldehyde oxidases are molybdenum and flavin dependent enzymes characterized by a very wide substrate specificity and performing diverse reactions that include oxidations (e.g., aldehydes and aza-heterocycles), hydrolysis of amide bonds, and reductions (e.g., nitro, S-oxides and N-oxides). Oxidation reactions and amide hydrolysis occur at the molybdenum site while the reductions are proposed to occur at the flavin site. AOX activity affects the metabolism of different drugs and xenobiotics, some of which designed to resist other liver metabolizing enzymes (e.g., cytochrome P450 monooxygenase isoenzymes), raising its importance in drug development. This work consists of a comprehensive overview on aldehyde oxidases, concerning the genetic evolution of AOX, its diversity among the human population, the crystal structures available, the known catalytic reactions and the consequences in pre-clinical pharmacokinetic and pharmacodynamic studies. Analysis of the different animal models generally used for pre-clinical trials and comparison between the human (hAOX1), mouse homologs as well as the related xanthine oxidase (XOR) are extensively considered. The data reviewed also include a systematic analysis of representative classes of molecules that are hAOX1 substrates as well as of typical and well characterized hAOX1 inhibitors. The considerations made on the basis of a structural and functional analysis are correlated with reported kinetic and metabolic data for typical classes of drugs, searching for potential structural determinants that may dictate substrate and/or inhibitor specificities.

Original languageEnglish
Pages (from-to)35-59
Number of pages25
JournalCoordination Chemistry Reviews
Volume368
DOIs
Publication statusPublished - 1 Aug 2018

Fingerprint

Aldehyde Oxidase
Pharmacokinetics
oxidase
metabolism
Aldehydes
aldehydes
Metabolism
drugs
Molybdenum
Amides
inhibitors
Oxides
amides
molybdenum
hydrolysis
enzymes
Hydrolysis
Substrates
Enzymes
Isoenzymes

Keywords

  • Aldehyde oxidase
  • Drug metabolism
  • Hepatic clearance
  • Molybdoenzymes
  • Non-CYP enzymes
  • Xenobiotics

Cite this

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title = "Critical overview on the structure and metabolism of human aldehyde oxidase and its role in pharmacokinetics",
abstract = "Aldehyde oxidases are molybdenum and flavin dependent enzymes characterized by a very wide substrate specificity and performing diverse reactions that include oxidations (e.g., aldehydes and aza-heterocycles), hydrolysis of amide bonds, and reductions (e.g., nitro, S-oxides and N-oxides). Oxidation reactions and amide hydrolysis occur at the molybdenum site while the reductions are proposed to occur at the flavin site. AOX activity affects the metabolism of different drugs and xenobiotics, some of which designed to resist other liver metabolizing enzymes (e.g., cytochrome P450 monooxygenase isoenzymes), raising its importance in drug development. This work consists of a comprehensive overview on aldehyde oxidases, concerning the genetic evolution of AOX, its diversity among the human population, the crystal structures available, the known catalytic reactions and the consequences in pre-clinical pharmacokinetic and pharmacodynamic studies. Analysis of the different animal models generally used for pre-clinical trials and comparison between the human (hAOX1), mouse homologs as well as the related xanthine oxidase (XOR) are extensively considered. The data reviewed also include a systematic analysis of representative classes of molecules that are hAOX1 substrates as well as of typical and well characterized hAOX1 inhibitors. The considerations made on the basis of a structural and functional analysis are correlated with reported kinetic and metabolic data for typical classes of drugs, searching for potential structural determinants that may dictate substrate and/or inhibitor specificities.",
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Critical overview on the structure and metabolism of human aldehyde oxidase and its role in pharmacokinetics. / Mota, Cristiano; Coelho, Catarina; Leimkühler, Silke; Garattini, Enrico; Terao, Mineko; Santos-Silva, Teresa; Romão, Maria João.

In: Coordination Chemistry Reviews, Vol. 368, 01.08.2018, p. 35-59.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Critical overview on the structure and metabolism of human aldehyde oxidase and its role in pharmacokinetics

AU - Mota, Cristiano

AU - Coelho, Catarina

AU - Leimkühler, Silke

AU - Garattini, Enrico

AU - Terao, Mineko

AU - Santos-Silva, Teresa

AU - Romão, Maria João

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PY - 2018/8/1

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AB - Aldehyde oxidases are molybdenum and flavin dependent enzymes characterized by a very wide substrate specificity and performing diverse reactions that include oxidations (e.g., aldehydes and aza-heterocycles), hydrolysis of amide bonds, and reductions (e.g., nitro, S-oxides and N-oxides). Oxidation reactions and amide hydrolysis occur at the molybdenum site while the reductions are proposed to occur at the flavin site. AOX activity affects the metabolism of different drugs and xenobiotics, some of which designed to resist other liver metabolizing enzymes (e.g., cytochrome P450 monooxygenase isoenzymes), raising its importance in drug development. This work consists of a comprehensive overview on aldehyde oxidases, concerning the genetic evolution of AOX, its diversity among the human population, the crystal structures available, the known catalytic reactions and the consequences in pre-clinical pharmacokinetic and pharmacodynamic studies. Analysis of the different animal models generally used for pre-clinical trials and comparison between the human (hAOX1), mouse homologs as well as the related xanthine oxidase (XOR) are extensively considered. The data reviewed also include a systematic analysis of representative classes of molecules that are hAOX1 substrates as well as of typical and well characterized hAOX1 inhibitors. The considerations made on the basis of a structural and functional analysis are correlated with reported kinetic and metabolic data for typical classes of drugs, searching for potential structural determinants that may dictate substrate and/or inhibitor specificities.

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KW - Drug metabolism

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KW - Molybdoenzymes

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KW - Xenobiotics

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JO - Coordination Chemistry Reviews

JF - Coordination Chemistry Reviews

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