Tracing Metabolic Fate of Mitochondrial Glycine Cleavage System Derived Formate In Vitro and In Vivo
Abstract
:1. Introduction
2. Results
2.1. Tracing Metabolic Fate of C2-Carbon of Glycine via GCS in 1C Metabolism
2.2. Tracing Metabolic Fate of Serine 2-Carbon via GCS in 1C Metabolism
2.3. Metabolic Fate of 2-Carbon from Glycine and Serine via GCS in Cell Models
2.4. Restoring GNMT Expression Decreased Formate Generation from Glycine 2-Carbon via GCS
2.5. Tracing Metabolic Fate of 3-Carbon of Serine in 1C Metabolism
2.6. Utilization of the Glycine 2-Carbon in dTMP Synthesis via Mitochondrial GCS In Vivo
3. Discussion
3.1. Metabolic Fate of C2-Carbon of Glycine and Serine via GCS
3.2. Restoring GNMT Expression Decreased Formate Generation from Glycine 2-Carbon via GCS
3.3. Nutritional Supply Affect the Utilization of GCS-Derived Formate
3.4. The Partitioning of GCS-Derived 1C Unit Utilization is Tissue-Specific
3.5. Limitations of the Study
4. Materials and Methods
4.1. Chemicals and Materials
4.2. Cell-Lines and Culture Conditions
4.3. Stable Isotopic Experiments In Vitro
4.4. Tracing Metabolic Fate of Glycine 2-Carbon, Serine 2-Carbon, and 3-Carbon In Vivo
4.5. Gas Chromatography/Mass Spectrometry Analysis
4.6. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
References
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From GCS Derived Formate 3 | ||||||
---|---|---|---|---|---|---|
[2-13C]-glycine | Leu + 1 + 2 + 3 | Gly + 1 | Ser + 1 4 | Ser + 24 | dT + 14 | Met + 14 |
L02 | 0.262 ± 0.001 | 0.573 ± 0.018 | 0.250 ± 0.002 | 0.000 ± 0.000 | 0.003 ± 0.001 | 0.000 ± 0.000 |
Skep1 | 0.211 ± 0.004 | 0.641 ± 0.014 | 0.116 ± 0.001 | 0.000 ± 0.000 | 0.000 ± 0.000 | 0.002 ± 0.002 |
HepG2 | 0.216 ± 0.001 | 0.573 ± 0.005 | 0.306 ± 0.003 | 0.000 ± 0.000 | 0.001 ± 0.001 | 0.000 ± 0.000 |
An042 | 0.213 ± 0.002 | 0.436 ± 0.010 | 0.296 ± 0.006 | 0.008 ± 0.001 | 0.016 ± 0.003 | 0.000 ± 0.000 |
GNMT+ | 0.239 ± 0.006 | 0.489 ± 0.010 | 0.377 ± 0.004 | 0.035 ± 0.001 | 0.049 ± 0.002 | 0.012 ± 0.001 |
GNMT− | 0.233 ± 0.001 | 0.510 ± 0.002 | 0.420 ± 0.010 | 0.124 ± 0.002 | 0.157 ± 0.004 | 0.000 ± 0.000 |
L-[2-13C]-serine | Leu + 1 + 2 + 3 | Gly + 1 | Ser + 1 4 | Ser + 2 4 | dT + 1 4 | Met + 1 4 |
L02 | 0.237 ± 0.001 | 0.463 ± 0.011 | 0.591 ± 0.016 | 0.000 ± 0.000 | 0.004 ± 0.0003 | 0.000 ± 0.000 |
Skep1 | 0.228 ± 0.004 | 0.539 ± 0.012 | 0.687 ± 0.002 | 0.000 ± 0.000 | 0.000 ± 0.000 | 0.000 ± 0.000 |
HepG2 | 0.215 ± 0.001 | 0.398 ± 0.004 | 0.484 ± 0.006 | 0.000 ± 0.000 | 0.000 ± 0.000 | 0.000 ± 0.000 |
An042 | 0.212 ± 0.002 | 0.351 ± 0.009 | 0.365 ± 0.008 | 0.000 ± 0.000 | 0.004 ± 0.002 | 0.001 ± 0.002 |
GNMT+ | 0.255 ± 0.000 | 0.429 ± 0.001 | 0.514 ± 0.002 | 0.000 ± 0.000 | 0.012 ± 0.001 | 0.000 ± 0.000 |
GNMT− | 0.229 ± 0.000 | 0.407 ± 0.028 | 0.505 ± 0.013 | 0.018 ± 0.002 | 0.041 ± 0.001 | 0.000 ± 0.000 |
From GCS Derived Formate 3 | |||||||
---|---|---|---|---|---|---|---|
Gly + 1 | Ser + 1 | deAla + 1 4 | Ser + 23 | deAla + 23,4 | dT + 13 | Met + 13 | |
GNMT+ | |||||||
MEM 2 | 0.567 ± 0.012 | 0.404 ± 0.011 | 0.379 ± 0.015 | 0.044 ± 0.003 | 0.039 ± 0.001 | 0.044 ± 0.001 | 0.001 ± 0.002 |
MEM + B12 2 | 0.489 ± 0.010 | 0.377 ± 0.004 | 0.353 ± 0.006 | 0.035 ± 0.001 | 0.033 ± 0.0002 | 0.049 ± 0.002 | 0.012 ± 0.001 |
MEM + B12 + NEAA 2 | 0.452 ± 0.009 | 0.345 ± 0.005 | 0.322 ± 0.005 | 0.014 ± 0.001 | 0.014 ± 0.001 | 0.012 ± 0.001 | 0.009 ± 0.001 |
GNMT− | |||||||
MEM 2 | 0.579 ± 0.019 | 0.458 ± 0.002 | 0.433 ± 0.003 | 0.116 ± 0.0003 | 0.107 ± 0.0001 | 0.134 ± 0.001 | 0.000 ± 0.000 |
MEM + B12 2 | 0.510 ± 0.002 | 0.420 ± 0.010 | 0.385 ± 0.001 | 0.124 ± 0.002 | 0.109 ± 0.001 | 0.157 ± 0.004 | 0.000 ± 0.000 |
MEM + B12 + NEAA 2 | 0.469 ± 0.004 | 0.390 ± 0.001 | 0.370 ± 0.004 | 0.062 ± 0.0004 | 0.058 ± 0.001 | 0.096 ± 0.001 | 0.001 ± 0.001 |
(A) Isotopic enrichments from [2-13C]glycine in serine, dTMP, and methionine 1,2,3 | |||||||
From GCS Derived Formate3 | |||||||
Nutritional effects 5,7 | Gly + 1 | Ser + 1 | deAla + 1 | Ser + 23 | deAla + 23,4 | dT + 13 | Met + 13 |
GNMT+ | |||||||
MEM + B12 vs. MEM | −14% | −7% | −7% | −20% | −15% | +11% | +1100% |
MEM + B12 + NEAA vs. MEM | −20% | −15% | −15% | −68% | −64% | −73% | +800% |
GNMT− | |||||||
MEM + B12 vs. MEM | −12% | −8% | −11% | 7% | 2% | +17% | ND |
MEM + B12 + NEAA vs. MEM | −19% | −15% | −15% | −47% | −46% | −28% | ND |
(B) Vitamin B12 and NEAA supply affect C2-glycine derived formate utilization in serine, dTMP, methionine 5 | |||||||
From GCS Derived Formate3 | |||||||
GNMT effects 6,7 (GNMT+ vs. GNNT-) | Gly + 1 | Ser + 1 | deAla + 1 | Ser + 23 | deAla + 2 3,4 | dT + 13 | |
in MEM | −2% | −12% | −12% | −62% | −64% | −67% | |
in MEM + B12 | −4% | −10% | −8% | −72% | −70% | −69% | |
in MEM + B12 + NEAA | −4% | −12% | −13% | −77% | −76% | −88% | |
(C) GNMT expression affect C2-glycine derived formate utilization in serine and dTMP 6 |
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Tan, Y.-L.; Sou, N.-L.; Tang, F.-Y.; Ko, H.-A.; Yeh, W.-T.; Peng, J.-H.; Chiang, E.-P.I. Tracing Metabolic Fate of Mitochondrial Glycine Cleavage System Derived Formate In Vitro and In Vivo. Int. J. Mol. Sci. 2020, 21, 8808. https://doi.org/10.3390/ijms21228808
Tan Y-L, Sou N-L, Tang F-Y, Ko H-A, Yeh W-T, Peng J-H, Chiang E-PI. Tracing Metabolic Fate of Mitochondrial Glycine Cleavage System Derived Formate In Vitro and In Vivo. International Journal of Molecular Sciences. 2020; 21(22):8808. https://doi.org/10.3390/ijms21228808
Chicago/Turabian StyleTan, Yee-Ling, Nga-Lai Sou, Feng-Yao Tang, Hsin-An Ko, Wei-Ting Yeh, Jian-Hau Peng, and En-Pei Isabel Chiang. 2020. "Tracing Metabolic Fate of Mitochondrial Glycine Cleavage System Derived Formate In Vitro and In Vivo" International Journal of Molecular Sciences 21, no. 22: 8808. https://doi.org/10.3390/ijms21228808