The pathway to pyrimidines : The essential focus on dihydroorotate dehydrogenase, the mitochondrial enzyme coupled to the respiratory chain
(2020) In Nucleosides, Nucleotides and Nucleic Acids 39(10-12). p.1281-1305- Abstract
This paper is based on the Anne Simmonds Memorial Lecture, given by Monika Löffler at the International Symposium on Purine and Pyrimidine Metabolism in Man, Lyon 2019. It is dedicated to H. Anne Simmonds (died 2010) - a founding member of the ESSPPMM, since 2003 Purine and Pyrimidine Society - and her outstanding contributions to the identification and study of inborn errors of purine and pyrimidine metabolism. The distinctive intracellular arrangement of pyrimidine de novo synthesis in higher eukaryotes is important to cells with a high demand for nucleic acid synthesis. The proximity of the enzyme active sites and the resulting channeling in CAD and UMP synthase is of kinetic benefit. The intervening enzyme dihydroorotate... (More)
This paper is based on the Anne Simmonds Memorial Lecture, given by Monika Löffler at the International Symposium on Purine and Pyrimidine Metabolism in Man, Lyon 2019. It is dedicated to H. Anne Simmonds (died 2010) - a founding member of the ESSPPMM, since 2003 Purine and Pyrimidine Society - and her outstanding contributions to the identification and study of inborn errors of purine and pyrimidine metabolism. The distinctive intracellular arrangement of pyrimidine de novo synthesis in higher eukaryotes is important to cells with a high demand for nucleic acid synthesis. The proximity of the enzyme active sites and the resulting channeling in CAD and UMP synthase is of kinetic benefit. The intervening enzyme dihydroorotate dehydrogenase (DHODH) is located in the mitochondrion with access to the ubiquinone pool, thus ensuring efficient removal of redox equivalents through the constitutive activity of the respiratory chain, also a mechanism through which the input of 2 ATP for carbamylphosphate synthesis is balanced by Oxphos. The obligatory contribution of O2 to de novo UMP synthesis means that DHODH has a pivotal role in adapting the proliferative capacity of cells to different conditions of oxygenation, such as hypoxia in growing tumors. DHODH also is a validated drug target in inflammatory diseases. This survey of selected topics of personal interest and reflection spans some 40 years of our studies from tumor cell cultures under hypoxia to in vitro assays including purification from mitochondria, localization, cloning, expression, biochemical characterization, crystallisation, kinetics and inhibition patterns of eukaryotic DHODH enzymes.
(Less)
- author
- Löffler, Monika ; Carrey, Elizabeth A. and Knecht, Wolfgang LU
- organization
- publishing date
- 2020-02-11
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- dihydroorotate, drugs, hypoxia, inborn errors, mitochondria, Pyrimidine de novo synthesis
- in
- Nucleosides, Nucleotides and Nucleic Acids
- volume
- 39
- issue
- 10-12
- pages
- 25 pages
- publisher
- Taylor & Francis
- external identifiers
-
- pmid:32043431
- scopus:85079489947
- ISSN
- 1525-7770
- DOI
- 10.1080/15257770.2020.1723625
- language
- English
- LU publication?
- yes
- id
- 03dee9c5-9989-425f-8d48-264e908fae30
- date added to LUP
- 2020-02-28 11:50:57
- date last changed
- 2024-04-17 05:11:44
@article{03dee9c5-9989-425f-8d48-264e908fae30,
abstract = {{<p>This paper is based on the Anne Simmonds Memorial Lecture, given by Monika Löffler at the International Symposium on Purine and Pyrimidine Metabolism in Man, Lyon 2019. It is dedicated to H. Anne Simmonds (died 2010) - a founding member of the ESSPPMM, since 2003 Purine and Pyrimidine Society - and her outstanding contributions to the identification and study of inborn errors of purine and pyrimidine metabolism. The distinctive intracellular arrangement of pyrimidine de novo synthesis in higher eukaryotes is important to cells with a high demand for nucleic acid synthesis. The proximity of the enzyme active sites and the resulting channeling in CAD and UMP synthase is of kinetic benefit. The intervening enzyme dihydroorotate dehydrogenase (DHODH) is located in the mitochondrion with access to the ubiquinone pool, thus ensuring efficient removal of redox equivalents through the constitutive activity of the respiratory chain, also a mechanism through which the input of 2 ATP for carbamylphosphate synthesis is balanced by Oxphos. The obligatory contribution of O<sub>2</sub> to de novo UMP synthesis means that DHODH has a pivotal role in adapting the proliferative capacity of cells to different conditions of oxygenation, such as hypoxia in growing tumors. DHODH also is a validated drug target in inflammatory diseases. This survey of selected topics of personal interest and reflection spans some 40 years of our studies from tumor cell cultures under hypoxia to in vitro assays including purification from mitochondria, localization, cloning, expression, biochemical characterization, crystallisation, kinetics and inhibition patterns of eukaryotic DHODH enzymes.</p>}},
author = {{Löffler, Monika and Carrey, Elizabeth A. and Knecht, Wolfgang}},
issn = {{1525-7770}},
keywords = {{dihydroorotate; drugs; hypoxia; inborn errors; mitochondria; Pyrimidine de novo synthesis}},
language = {{eng}},
month = {{02}},
number = {{10-12}},
pages = {{1281--1305}},
publisher = {{Taylor & Francis}},
series = {{Nucleosides, Nucleotides and Nucleic Acids}},
title = {{The pathway to pyrimidines : The essential focus on dihydroorotate dehydrogenase, the mitochondrial enzyme coupled to the respiratory chain}},
url = {{http://dx.doi.org/10.1080/15257770.2020.1723625}},
doi = {{10.1080/15257770.2020.1723625}},
volume = {{39}},
year = {{2020}},
}