An isotope-dilution, GC–MS assay for formate and its application to human and animal metabolism

Lamarre, Simon G.; MacMillan, Luke; Morrow, Gregory P.; Randell, Edward; Pongnopparat, Theerawat; Brosnan, Margaret E.; Brosnan, John T.

doi:10.1007/s00726-014-1738-7

Cited by 49 publications

(40 citation statements)

References 16 publications

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“…To prove the link between AICAR and formyl unit availability, we fed cells 1 mM formate, which is present in human serum at 20-30 μM (Hanzlik et al, 2005;Lamarre et al, 2014). Although addition did not rescue the modest growth defects of the SHMT2 and ALDH1L2 knockout cells (Figure 1c), it fully reversed the AICAR elevation in each of the mitochondrial folate pathway deletion lines (Figure 1g), but not in the MTHFD1 hypomorphic line ( Figure S1l).…”

Section: Mitochondrial Folate Pathway Knockout Depletes 10-formyl-thfmentioning

confidence: 99%

Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway

Ducker¹,

Chen²,

Morscher³

et al. 2016

Cell Metabolism

120

234

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SummaryOne-carbon (1C) units for purine and thymidine synthesis can be generated from serine by cytosolic or mitochondrial folate metabolism. The mitochondrial 1C pathway is consistently overexpressed in cancer. Here we show that most but not all proliferating mammalian cell lines use the mitochondrial pathway as the default for making 1C units. CRISPR-mediated mitochondrial pathway knockout activates cytosolic 1C-unit production. This reversal in cytosolic flux is triggered by depletion of a single metabolite, 10-formyl-THF, and enables rapid cell growth in nutrient-replete conditions. Loss of the mitochondrial pathway, however, renders cells dependent on extracellular serine to make 1C units and on extracellular glycine to make glutathione. HCT-116 colon cancer xenografts lacking mitochondrial 1C pathway activity generate the 1C units required for growth by cytosolic serine catabolism. Loss of both pathways precludes xenograft formation. Thus, either mitochondrial or cytosolic 1C metabolism can support tumorigenesis with the mitochondrial pathway required in nutrient poor conditions. eTOC blurbUsing genetic and metabolomic approaches, Ducker et al. dissect the roles of cytosolic and mitochondrial folate metabolism in cell proliferation, revealing that most cells default to mitochondria for making 1C units, simultaneously generating glycine, NADH and NADPH. Upon loss of the mitochondrial pathway, however, cytosolic metabolism supports tumor growth.

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Section: Mitochondrial Folate Pathway Knockout Depletes 10-formyl-thfmentioning

confidence: 99%

Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway

Ducker¹,

Chen²,

Morscher³

et al. 2016

Cell Metabolism

120

234

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“…Plasma was obtained by centrifugation and derivatized, and the tracer-to-tracee ratio (TTR) (see Ref. 15 for terminology) was determined as described (14). The TTR of the derivatized zero time sample was subtracted to correct for natural abundance of heavier isotopes, as described by Wolfe (15).…”

Section: Methodsmentioning

confidence: 99%

“…Preliminary experiments showed that the rate of formate production was linear with mitochondrial protein under our experimental conditions. Formate was measured by GC-MS (14).…”

Section: Methodsmentioning

confidence: 99%

In Vivo Kinetics of Formate Metabolism in Folate-deficient and Folate-replete Rats

Morrow

MacMillan

Lamarre

et al. 2015

Journal of Biological Chemistry

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Background:The mitochondrial production of formate is critical to the generation of one-carbon groups. Results: We have shown that the in vivo production of formate is markedly reduced in folate deficiency. Conclusion: Folate deficiency reduces both the production and utilization of one-carbon groups. Significance: Folate status affects the production and utilization of one-carbon groups and the role of choline metabolites as precursors of these groups.

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“…Second, many studies did not include information regarding vitamin levels, or assessed folate plasma levels of determining folate status. Plasma folate levels may not be the best parameter for assessing folate deficiency or intake [43,51,52] . Erythrocyte folate or serum methylmalonic acid levels are better indicators of folate status, because they reflect folate turnover over the preceding 2 to 3 mo [23,43] .…”

Section: Studymentioning

confidence: 99%

“…Erythrocyte folate or serum methylmalonic acid levels are better indicators of folate status, because they reflect folate turnover over the preceding 2 to 3 mo [23,43] . Lamarre et al [52] recently showed that formate levels provide important information regarding folate metabolism, and that increased Hcy levels can be caused by defects in the remethylation and transsulfuration pathways. Finally, some studies have demonstrated an association of the MTHFR polymorphisms and HHcy in different cases and diseases.…”

Section: Studymentioning

confidence: 99%

Elevated homocysteine levels in human immunodeficiency virus-infected patients under antiretroviral therapy: A meta-analysis

Deminice

Silva

Oliveira

2015

WJV

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AIM:To evaluate the association between the levels of homocysteine (Hcy), folate, vitamin B12 in human immunodeficiency virus (HIV)-infected patients who were treated with antiretroviral therapy (ART) or not treated with ART. METHODS:The PubMed and Scielo databases were searched. Eligible studies regarding plasma Hcy level in HIV-infected patients were firstly identified. After careful analysis by two independent researches, the identified articles were included in the review according to two outcomes (1) Hcy, folate and vitamin B12 blood concentration in HIV-infected subjects vs health controls and; (2) Hcy blood concentration in HIV-infected subjects under ART vs not treated with ART. RevMan (version 5.2) was employed for data synthesis. RESULTS:A total of 12 studies were included in outcome 1 (1649 participants, 932 cases and 717 controls). Outcome 1 meta-analysis demonstrated higher plasma Hcy (2.05 µmol/L; 95%CI: 0.10 to 4.00, P < 0.01) and decreased plasma folate concentrations (-2.74 ng/mL; 95%CI: -5.18 to -0.29, P < 0.01) in HIV-infected patients compared to healthy controls. No changes in vitamin B12 plasma concentration were observed between groups. All studies included in the outcome 2 meta-analysis (1167 participants; 404 HIVinfected exposed to ART and 757 HIV-infected non-ART patients) demonstrated higher mean Hcy concentration in subjects HIV-infected under ART compared to non-ART HIV subjects (4.13 µmol/L; 95%CI: 1.34 to 6.92, P < 0.01). CONCLUSION:This meta-analysis demonstrated that the levels of Hcy and folate, but not vitamin B12, were associated with HIV infection. In addition, Hcy levels were higher in HIV-infected patients who were under ART compared to HIV-infected patients who were not exposed to ART. Our results suggest that hyperhomocysteinemia should be included among the several important metabolic disturbances that are associated with ART in patients with HIV infection. 147 META-ANALYSIS

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An isotope-dilution, GC–MS assay for formate and its application to human and animal metabolism

Cited by 49 publications

References 16 publications

Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway

Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate Pathway

In Vivo Kinetics of Formate Metabolism in Folate-deficient and Folate-replete Rats

Elevated homocysteine levels in human immunodeficiency virus-infected patients under antiretroviral therapy: A meta-analysis

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