Structural basis for the role of mammalian aldehyde oxidases in the metabolism of drugs and xenobiotics

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

Research output: Contribution to journalReview article

11 Citations (Scopus)

Abstract

Aldehyde oxidases (AOXs) are molybdo-flavoenzymes characterized by broad substrate specificity, oxidizing aromatic/aliphatic aldehydes into the corresponding carboxylic acids and hydroxylating various heteroaromatic rings. Mammals are characterized by a complement of species-specific AOX isoenzymes, that varies from one in humans (AOX1) to four in rodents (AOX1, AOX2, AOX3 and AOX4). The physiological function of mammalian AOX isoenzymes is unknown, although human AOX1 is an emerging enzyme in phase-I drug metabolism. Indeed, the number of therapeutic molecules under development which act as AOX substrates is increasing. The recent crystallization and structure determination of human AOX1 as well as mouse AOX3 has brought new insights into the mechanisms underlying substrate/inhibitor binding as well as the catalytic activity of this class of enzymes.

Original languageEnglish
Pages (from-to)39-47
Number of pages9
JournalCurrent Opinion in Chemical Biology
Volume37
DOIs
Publication statusPublished - 1 Apr 2017

Fingerprint

Aldehyde Oxidase
Xenobiotics
Metabolism
Pharmaceutical Preparations
Isoenzymes
Substrates
Mammals
Enzymes
Substrate Specificity
Carboxylic Acids
Crystallization
Aldehydes
Rodentia
Catalyst activity
Molecules

Keywords

  • SINGLE-NUCLEOTIDE POLYMORPHISMS
  • XANTHINE-OXIDASE
  • MOLYBDENUM COFACTOR
  • CLASSICAL XANTHINURIA
  • SUBSTRATE-SPECIFICITY
  • INHIBITOR BINDING
  • CRYSTAL-STRUCTURE
  • LIVER
  • DEHYDROGENASE
  • MECHANISM

Cite this

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title = "Structural basis for the role of mammalian aldehyde oxidases in the metabolism of drugs and xenobiotics",
abstract = "Aldehyde oxidases (AOXs) are molybdo-flavoenzymes characterized by broad substrate specificity, oxidizing aromatic/aliphatic aldehydes into the corresponding carboxylic acids and hydroxylating various heteroaromatic rings. Mammals are characterized by a complement of species-specific AOX isoenzymes, that varies from one in humans (AOX1) to four in rodents (AOX1, AOX2, AOX3 and AOX4). The physiological function of mammalian AOX isoenzymes is unknown, although human AOX1 is an emerging enzyme in phase-I drug metabolism. Indeed, the number of therapeutic molecules under development which act as AOX substrates is increasing. The recent crystallization and structure determination of human AOX1 as well as mouse AOX3 has brought new insights into the mechanisms underlying substrate/inhibitor binding as well as the catalytic activity of this class of enzymes.",
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author = "Rom{\~a}o, {Maria Jo{\~a}o} and Catarina Coelho and Teresa Santos-Silva and Alessandro Foti and Mineko Terao and Enrico Garattini and Silke Leimk{\"u}hler",
note = "M. Romao would like to thank the Fundagao para a Ciencia e Tecnologia, through project PTDC/BBB-BEP/1185/2014, UID/Multi/04378/2013, grant SFRH/BPD/84581/2012 (C.C.) and the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007728) for financial support, E. Garattini and M. Terao thank The Associazione Italiana per la Ricerca contro it Cancro (AIRC) and the Fondazione Italo Monzino for their financial support, and S. Leimkuhler thanks the Deutsche Forschungsgemeinschaft (DFG) for the support with grant LE1171/8.",
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Structural basis for the role of mammalian aldehyde oxidases in the metabolism of drugs and xenobiotics. / Romão, Maria João; Coelho, Catarina; Santos-Silva, Teresa; Foti, Alessandro; Terao, Mineko; Garattini, Enrico; Leimkühler, Silke.

In: Current Opinion in Chemical Biology, Vol. 37, 01.04.2017, p. 39-47.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Structural basis for the role of mammalian aldehyde oxidases in the metabolism of drugs and xenobiotics

AU - Romão, Maria João

AU - Coelho, Catarina

AU - Santos-Silva, Teresa

AU - Foti, Alessandro

AU - Terao, Mineko

AU - Garattini, Enrico

AU - Leimkühler, Silke

N1 - M. Romao would like to thank the Fundagao para a Ciencia e Tecnologia, through project PTDC/BBB-BEP/1185/2014, UID/Multi/04378/2013, grant SFRH/BPD/84581/2012 (C.C.) and the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007728) for financial support, E. Garattini and M. Terao thank The Associazione Italiana per la Ricerca contro it Cancro (AIRC) and the Fondazione Italo Monzino for their financial support, and S. Leimkuhler thanks the Deutsche Forschungsgemeinschaft (DFG) for the support with grant LE1171/8.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - Aldehyde oxidases (AOXs) are molybdo-flavoenzymes characterized by broad substrate specificity, oxidizing aromatic/aliphatic aldehydes into the corresponding carboxylic acids and hydroxylating various heteroaromatic rings. Mammals are characterized by a complement of species-specific AOX isoenzymes, that varies from one in humans (AOX1) to four in rodents (AOX1, AOX2, AOX3 and AOX4). The physiological function of mammalian AOX isoenzymes is unknown, although human AOX1 is an emerging enzyme in phase-I drug metabolism. Indeed, the number of therapeutic molecules under development which act as AOX substrates is increasing. The recent crystallization and structure determination of human AOX1 as well as mouse AOX3 has brought new insights into the mechanisms underlying substrate/inhibitor binding as well as the catalytic activity of this class of enzymes.

AB - Aldehyde oxidases (AOXs) are molybdo-flavoenzymes characterized by broad substrate specificity, oxidizing aromatic/aliphatic aldehydes into the corresponding carboxylic acids and hydroxylating various heteroaromatic rings. Mammals are characterized by a complement of species-specific AOX isoenzymes, that varies from one in humans (AOX1) to four in rodents (AOX1, AOX2, AOX3 and AOX4). The physiological function of mammalian AOX isoenzymes is unknown, although human AOX1 is an emerging enzyme in phase-I drug metabolism. Indeed, the number of therapeutic molecules under development which act as AOX substrates is increasing. The recent crystallization and structure determination of human AOX1 as well as mouse AOX3 has brought new insights into the mechanisms underlying substrate/inhibitor binding as well as the catalytic activity of this class of enzymes.

KW - SINGLE-NUCLEOTIDE POLYMORPHISMS

KW - XANTHINE-OXIDASE

KW - MOLYBDENUM COFACTOR

KW - CLASSICAL XANTHINURIA

KW - SUBSTRATE-SPECIFICITY

KW - INHIBITOR BINDING

KW - CRYSTAL-STRUCTURE

KW - LIVER

KW - DEHYDROGENASE

KW - MECHANISM

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U2 - 10.1016/j.cbpa.2017.01.005

DO - 10.1016/j.cbpa.2017.01.005

M3 - Review article

VL - 37

SP - 39

EP - 47

JO - Current Opinion in Chemical Biology

JF - Current Opinion in Chemical Biology

SN - 1367-5931

ER -