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Metabolites
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Folate Homeostasis and Metabolism
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Folate Homeostasis and Metabolism

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Nutrition and Metabolism".

Deadline for manuscript submissions: closed (15 December 2022) | Viewed by 15578

Special Issue Editors

Dr. Boryana Petrova

E-Mail Website
Guest Editor
1. Department of Pathology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
2. Harvard Medical School, Boston, MA, USA
Interests: mass spectrometry; metabolomics; folate homeostasis and metabolism
Dr. Naama Kanarek

E-Mail Website
Guest Editor
1. Department of Pathology, Boston Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
2. Harvard Medical School, Boston, MA, USA
3. Broad Institute of Harvard and MIT, Cambridge, MA, USA
Interests: mass spectrometry; metabolomics; folate homeostasis and metabolism, cancer

Special Issue Information

Dear Colleagues,

Vitamin B9 or folate is an enzymatic cofactor essential in all cell types for the biosynthesis of RNA and DNA. The importance of folate is underlined by the consequences of folate deprivation, which include anemia and birth defects. While both proliferating and quiescent cells depend on folate, folate requirements of proliferating cells such as activated immune or cancer cells are higher because of the increased rate of RNA and DNA synthesis and are a targetable vulnerability with anti-folate therapies being the standard of care in various autoimmune diseases and blood cancers.

Folate is further central to multiple metabolic processes, such as methionine regeneration, DNA methylation, mitochondrial translation, and redox homeostasis. and it is no surprise that it has been linked to a myriad of diseases. Despite that, our understanding of folate homeostasis is rudimentary, and essential gaps remain in our understanding of folate metabolism in different tissues and cell types. With this Special Issue, we will focus on current advances in the field and aim to attract interest in folate homeostasis and metabolism. 

Dr. Boryana Petrova
Dr. Naama Kanarek
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • folate
  • anti-folate therapy
  • methotrexate
  • one-carbon metabolism
  • purine and pyrimidine metabolism
  • redox
  • methylation
  • homocysteine
  • cancer
  • auto-immune disease

Published Papers (4 papers)

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Research

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22 pages, 5070 KiB  
Article
Cycloguanil and Analogues Potently Target DHFR in Cancer Cells to Elicit Anti-Cancer Activity
by Jennifer I. Brown, Peng Wang, Alan Y. L. Wong, Boryana Petrova, Rosanne Persaud, Sepideh Soukhtehzari, Melanie Lopez McDonald, Danielle Hanke, Josephine Christensen, Petar Iliev, Weiyuan Wang, Daniel K. Everton, Karla C. Williams, David A. Frank, Naama Kanarek and Brent D. G. Page
Metabolites 2023, 13(2), 151; https://doi.org/10.3390/metabo13020151 - 19 Jan 2023
Cited by 3 | Viewed by 2169
Abstract
Dihydrofolate reductase (DHFR) is an established anti-cancer drug target whose inhibition disrupts folate metabolism and STAT3-dependent gene expression. Cycloguanil was proposed as a DHFR inhibitor in the 1950s and is the active metabolite of clinically approved plasmodium DHFR inhibitor Proguanil. The Cycloguanil scaffold [...] Read more.
Dihydrofolate reductase (DHFR) is an established anti-cancer drug target whose inhibition disrupts folate metabolism and STAT3-dependent gene expression. Cycloguanil was proposed as a DHFR inhibitor in the 1950s and is the active metabolite of clinically approved plasmodium DHFR inhibitor Proguanil. The Cycloguanil scaffold was explored to generate potential cancer therapies in the 1970s. Herein, current computational and chemical biology techniques were employed to re-investigate the anti-cancer activity of Cycloguanil and related compounds. In silico modeling was employed to identify promising Cycloguanil analogues from NCI databases, which were cross-referenced with NCI-60 Human Tumor Cell Line Screening data. Using target engagement assays, it was found that these compounds engage DHFR in cells at sub-nanomolar concentrations; however, growth impairments were not observed until higher concentrations. Folinic acid treatment rescues the viability impairments induced by some, but not all, Cycloguanil analogues, suggesting these compounds may have additional targets. Cycloguanil and its most promising analogue, NSC127159, induced similar metabolite profiles compared to established DHFR inhibitors Methotrexate and Pyrimethamine while also blocking downstream signaling, including STAT3 transcriptional activity. These data confirm that Cycloguanil and its analogues are potent inhibitors of human DHFR, and their anti-cancer activity may be worth further investigation. Full article
(This article belongs to the Special Issue Folate Homeostasis and Metabolism)
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Review

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29 pages, 2586 KiB  
Review
Simplifying the B Complex: How Vitamins B6 and B9 Modulate One Carbon Metabolism in Cancer and Beyond
by Carolina N. Franco, Laurence J. Seabrook, Steven T. Nguyen, Jack T. Leonard and Lauren V. Albrecht
Metabolites 2022, 12(10), 961; https://doi.org/10.3390/metabo12100961 - 11 Oct 2022
Cited by 8 | Viewed by 5671
Abstract
Vitamin B micronutrients are essential regulators of one carbon metabolism that ensures human health. Vitamin B9, or folate, lies at the heart of the folate cycle and converges with the methionine cycle to complete the one carbon pathway. Additionally, vitamin B6 contributes by [...] Read more.
Vitamin B micronutrients are essential regulators of one carbon metabolism that ensures human health. Vitamin B9, or folate, lies at the heart of the folate cycle and converges with the methionine cycle to complete the one carbon pathway. Additionally, vitamin B6 contributes by orchestrating the flux of one carbon cycling. Dysregulation of vitamin B contributes to altered biochemical signaling that manifests in a spectrum of human diseases. This review presents an analysis of the past, present, and future work, highlighting the interplay between folate and vitamin B6 in one carbon metabolism. Emerging insights include advances in metabolomic-based mass spectrometry and the use of live-cell metabolic labeling. Cancer is used as a focal point to dissect vitamin crosstalk and highlight new insights into the roles of folate and vitamin B6 in metabolic control. This collection of vitamin-based research detailing the trends of one carbon metabolism in human disease exemplifies how the future of personalized medicine could unfold using this new base of knowledge and ultimately provide next-generation therapeutics. Full article
(This article belongs to the Special Issue Folate Homeostasis and Metabolism)
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23 pages, 1463 KiB  
Review
The Impact of Maternal Folates on Brain Development and Function after Birth
by Sapna Virdi and Nafisa M. Jadavji
Metabolites 2022, 12(9), 876; https://doi.org/10.3390/metabo12090876 - 16 Sep 2022
Cited by 14 | Viewed by 2827
Abstract
Folate is vital for biological processes within the body, including DNA synthesis, DNA repair, and methylation reactions that metabolize homocysteine. The role of folate is particularly important in pregnancy, where there is rapid cellular and tissue growth. Maternal folate deficiencies secondary to inadequate [...] Read more.
Folate is vital for biological processes within the body, including DNA synthesis, DNA repair, and methylation reactions that metabolize homocysteine. The role of folate is particularly important in pregnancy, where there is rapid cellular and tissue growth. Maternal folate deficiencies secondary to inadequate dietary supplementation are known to produce defects in the neural tube and spinal cord, yet the exact mechanism of folate in neurodevelopment is unknown. The consequences of maternal folate deficiency on offspring brain development and function beyond gestation are not well defined. The objective of this review is to investigate the role of folate deficiency in offspring neurodevelopment, and the complications that arise post-gestation. This was accomplished through a comprehensive review of the data presented in both clinical and preclinical studies. Evidence supports that folate deficiency is associated with altered offspring neurodevelopment, including smaller total brain volume, altered cortical thickness and cerebral white matter, altered neurogenesis, and neuronal apoptosis. Some of these changes have been associated with altered brain function in offspring with memory, motor function, language skills, and psychological issues. This review of literature also presents potential mechanisms of folate deficiency in neurodevelopment with altered metabolism, neuroinflammation, epigenetic modification through DNA methylation, and a genetic deficiency in one-carbon metabolism. Full article
(This article belongs to the Special Issue Folate Homeostasis and Metabolism)
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Other

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10 pages, 441 KiB  
Conference Report
Notes from the 2022 Folate, Vitamin B12, and One-Carbon Metabolism Conference
by Adam G. Maynard, Boryana Petrova and Naama Kanarek
Metabolites 2023, 13(4), 486; https://doi.org/10.3390/metabo13040486 - 28 Mar 2023
Cited by 1 | Viewed by 3706 | Correction
Abstract
Here, we present notes from the Folate, Vitamin B12, and One-Carbon Metabolism Conference organized by The Federation of American Societies for Experimental Biology (FASEB), held in Asheville, North Carolina, USA, 14–19 August 2022. We aim to share the most recent findings in the [...] Read more.
Here, we present notes from the Folate, Vitamin B12, and One-Carbon Metabolism Conference organized by The Federation of American Societies for Experimental Biology (FASEB), held in Asheville, North Carolina, USA, 14–19 August 2022. We aim to share the most recent findings in the field with members of our scientific community who did not attend the meeting and who are interested in the research that was presented. The research described includes discussions of one-carbon metabolism at the biochemical and physiological levels and studies of the role of folate and B12 in development and in the adult, and from bacteria to mammals. Furthermore, the summarized studies address the role of one-carbon metabolism in disease, including COVID-19, neurodegeneration, and cancer. Full article
(This article belongs to the Special Issue Folate Homeostasis and Metabolism)
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