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

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...

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Bibliographic Details
Published in:The FEBS journal Vol. 290; no. 9; pp. 2279 - 2291
Main Authors: Zhao, Li Na, Kaldis, Philipp
Format: Journal Article
Language:English
Published: England Blackwell Publishing Ltd 01.05.2023
Subjects:
Activated carbon
Animals
Antineoplastic Agents
Cancer
Cancer and Oncology
Cancer och onkologi
Carbon
Cell proliferation
Clinical Medicine
CRISPR
DHFR
Drug development
enzyme catalysis
enzyme reaction mechanism
Enzymes
folate
folate metabolism
folate‐mediated one‐carbon pathway
Folic acid
Folic Acid - metabolism
Genomes
Homology
Humans
Klinisk medicin
loss-of-function mutation
mammals
Mammals - metabolism
Medical and Health Sciences
Medicin och hälsovetenskap
Metabolism
Methionine
Methylation
Methylenetetrahydrofolate Dehydrogenase (NADP) - metabolism
MTHFD1
MTHFD2
MTHFD2L
Neoplasms - genetics
Nucleotides
Oxidation
Reaction mechanisms
SHMT2
Tetrahydrofolic acid
TYMS
viability
Vitamin B
DHFR
folate
MTHFD1
MTHFD2
SHMT2
MTHFD2L
enzyme catalysis
TYMS
enzyme reaction mechanism
folate metabolism
folate-mediated one-carbon pathway
ISSN:1742-464X, 1742-4658, 1742-4658
Online Access:Get full text
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Summary: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. They are required for nucleotide synthesis, methylation and metabolism, and 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 of the one‐carbon pathway in their active form are not available, we used homology modelling integrated with the interpretation of the reaction mechanism. In addition, have reconstructed the most likely scenario for the reactions taking place paired with their catalytic competence that provides a testable framework for this pathway. The folate‐mediated metabolic cycle uses several oxidation states of tetrahydrofolate to carry activated one‐carbon units to be used and interconverted within cells, which are required for nucleotide synthesis, methylation and particularly for cancer cell proliferation. We used homology modelling integrated with interpretation of the reaction mechanism, and have reconstructed the most likely scenario for the reactions taking place paired with the catalytic competence of enzymes of the one‐carbon pathway.
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ISSN:1742-464X
1742-4658
1742-4658
DOI:10.1111/febs.16439