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Pairing structural reconstruction with catalytic competence to evaluate the mechanisms of key enzymes in the folate-mediated one-carbon pathway

Zhao, Li Na and Kaldis, Philipp LU orcid (2023) In The FEBS Journal 290(9). p.2279-2291
Abstract

Mammalian metabolism comprises a series of interlinking pathways that include two major cycles: the folate and methionine cycles. The folate-mediated metabolic cycle uses several oxidation states of tetrahydrofolate to carry activated one-carbon units to be readily used and interconverted within the cell, which are required for nucleotide synthesis, methylation and metabolism, particularly for proliferation of cancer cells. Based on the latest progress in genome-wide CRISPR loss-of-function viability screening of 789 cell lines, we focus on the most cancer dependent enzymes in this pathway, especially those that are hyperactivated in cancer, to provide new insight into the chemical basis for cancer drug development. Since the complete... (More)

Mammalian metabolism comprises a series of interlinking pathways that include two major cycles: the folate and methionine cycles. The folate-mediated metabolic cycle uses several oxidation states of tetrahydrofolate to carry activated one-carbon units to be readily used and interconverted within the cell, which are required for nucleotide synthesis, methylation and metabolism, particularly for proliferation of cancer cells. Based on the latest progress in genome-wide CRISPR loss-of-function viability screening of 789 cell lines, we focus on the most cancer dependent enzymes in this pathway, especially those that are hyperactivated in cancer, to provide new insight into the chemical basis for cancer drug development. Since the complete 3D structure of several of these enzymes in their active form are not available, we used homology modeling integrated with the interpretation of the reaction mechanism, and have reconstructed the most likely scenario for the reactions to take place paired with their catalytic cycle that provides a testable framework for this pathway.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The FEBS Journal
volume
290
issue
9
pages
2279 - 2291
publisher
Wiley-Blackwell
external identifiers
  • pmid:35303396
  • scopus:85127373403
ISSN
1742-464X
DOI
10.1111/febs.16439
language
English
LU publication?
yes
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This article is protected by copyright. All rights reserved.
id
bf22bb6f-06d8-49e8-8a1e-cf29ec6f004e
date added to LUP
2022-03-22 09:36:27
date last changed
2024-06-13 11:37:49
@article{bf22bb6f-06d8-49e8-8a1e-cf29ec6f004e,
  abstract     = {{<p>Mammalian metabolism comprises a series of interlinking pathways that include two major cycles: the folate and methionine cycles. The folate-mediated metabolic cycle uses several oxidation states of tetrahydrofolate to carry activated one-carbon units to be readily used and interconverted within the cell, which are required for nucleotide synthesis, methylation and metabolism, particularly for proliferation of cancer cells. Based on the latest progress in genome-wide CRISPR loss-of-function viability screening of 789 cell lines, we focus on the most cancer dependent enzymes in this pathway, especially those that are hyperactivated in cancer, to provide new insight into the chemical basis for cancer drug development. Since the complete 3D structure of several of these enzymes in their active form are not available, we used homology modeling integrated with the interpretation of the reaction mechanism, and have reconstructed the most likely scenario for the reactions to take place paired with their catalytic cycle that provides a testable framework for this pathway.</p>}},
  author       = {{Zhao, Li Na and Kaldis, Philipp}},
  issn         = {{1742-464X}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{2279--2291}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{The FEBS Journal}},
  title        = {{Pairing structural reconstruction with catalytic competence to evaluate the mechanisms of key enzymes in the folate-mediated one-carbon pathway}},
  url          = {{http://dx.doi.org/10.1111/febs.16439}},
  doi          = {{10.1111/febs.16439}},
  volume       = {{290}},
  year         = {{2023}},
}