Literature summary for 6.3.4.3 extracted from

Lee, D.; Xu, I.M.; Chiu, D.K.; Lai, R.K.; Tse, A.P.; Lan Li, L.; Law, C.T.; Tsang, F.H.; Wei, L.L.; Chan, C.Y.; Wong, C.M.; Ng, I.O.; Wong, C.C.
Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma (2017), J. Clin. Invest., 127, 1856-1872 .

Application

Application	Comment	Organism
drug development	MTHFD1L overexpression is closely associated with aggressive clinicopathological features of hepatocellular carcinoma (HCC) including the presence of tumor microsatellite formation, venous invasion, and more advanced tumor stages. The enzyme MTHFD1L is a potential target in cancer therapy. Inhibition of the folate cycle sensitizes HCC cells to sorafenib treatment in vitro and in vivo	Homo sapiens

Protein Variants

Protein Variants	Comment	Organism
additional information	MTHFD1L-knockdown in cells is established by shRNA. Knockdown of MTHFD1L causes cell cycle delay	Homo sapiens

Localization

Localization	Comment	Organism	GeneOntology No.	Textmining
mitochondrion	MTHFD1L is a mitochondrial monofunctional enzyme with 10-CHO-THF synthase activity	Homo sapiens	5739	-

Metals/Ions

Metals/Ions	Comment	Organism	Structure
Mg2+	required	Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.	Reac.
ATP + formate + tetrahydrofolate	Homo sapiens	-	ADP + phosphate + 10-formyltetrahydrofolate	-	?

Organism

Organism	UniProt	Comment	Textmining
Homo sapiens	Q6UB35	-	-

Source Tissue

Source Tissue	Comment	Organism	Textmining
breast cancer cell	high expression level of MTHFD1L	Homo sapiens	-
colonic adenocarcinoma cell	-	Homo sapiens	-
colorectal cell line	high expression level of MTHFD1L	Homo sapiens	-
esophageal cancer cell	-	Homo sapiens	-
gastric cancer cell	-	Homo sapiens	-
HEP-3B cell	-	Homo sapiens	-
Hep-G2 cell	-	Homo sapiens	-
hepatocyte	-	Homo sapiens	-
hepatoma cell	-	Homo sapiens	-
Huh-7 cell	-	Homo sapiens	-
liver	-	Homo sapiens	-
lung adenocarcinoma cell	-	Homo sapiens	-
MHCC97-L cell	-	Homo sapiens	-
miR-197 cell	high expression level of MTHFD1L	Homo sapiens	-
miR-9 cell	high expression level of MTHFD1L	Homo sapiens	-
additional information	MTHFD1L overexpression is present in solid cancers including esophageal cancer, stomach adenocarcinoma, bladder cancer, lung adenocarcinoma, breast cancer, colon adenocarcinoma, kidney renal cell carcinoma, and prostate adenocarcinoma	Homo sapiens	-
PLC-PRF-5 cell	-	Homo sapiens	-
prostate adenocarcinoma cell	-	Homo sapiens	-
renal cell carcinoma cell	-	Homo sapiens	-
urinary bladder cancer cell	-	Homo sapiens	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.	Reac.
ATP + formate + tetrahydrofolate	-	Homo sapiens	ADP + phosphate + 10-formyltetrahydrofolate	-	?

Synonyms

Synonyms	Comment	Organism
10-CHO-THF synthase	-	Homo sapiens
methylenetetrahydrofolate dehydrogenase 1-like	-	Homo sapiens
MTHFD1L	-	Homo sapiens

Cofactor

Cofactor	Comment	Organism	Structure
ATP	-	Homo sapiens

Expression

Organism	Comment	Expression
Homo sapiens	MTHFD1L is transcriptionally activated by NRF2, a master regulator of redox homeostasis. MTHFD1L is a transcription target of nuclear factor (erythroid-derived 2)-like 2 (NRF2), a transcription factor that acts as the central regulator for redox homeostasis. NRF2 expression is tightly regulated by kelch-like ECH-associated protein 1 (KEAP1), a negative regulator that targets NRF2 for proteosomal degradation	up

General Information

General Information	Comment	Organism
malfunction	knockdown of MTHFD1L impedes hepatocellular carcinoma (HCC) proliferation through induction of oxidative stress and ROS-associated cell cycle delay. In the MTHFD1L-knockdown HCC cells, the levels of TCA cycle metabolic intermediates derived from pyruvate/acetyl-CoA, including citrate, cis-aconitate, and isocitrate, decrease	Homo sapiens
malfunction	the elevation of oxidative stress through MTHFD1L knockdown or the use of methotrexate, an antifolate drug, sensitizes cancer cells to sorafenib, a targeted therapy for hepatocellular carcinoma	Homo sapiens
metabolism	the folate cycle is an important metabolic pathway that fulfills a number of cancer-specific nutrient demands. Folate (folic acid), or vitamin B9, is commonly found in Western diets and dietary supplements. A 1-carbon (1C) unit from serine is transferred to tetrahydrofolate (THF) by serine hydroxymethyl transferases (SHMTs) to form 5,10-methylenetetrahydrofolate (CH2-THF). The 1C unit is then transferred from one position of THF to another, thus creating the folate cycle. The folate cycle is composed of the cytoplasmic and mitochondrial compartments. The cytoplasmic compartment is carried out by methylenetetrahydrofolate dehydrogenase, cyclohydrolase, and formyltetrahydrofolate synthetase 1 (MTHFD1), while the mitochondrial compartment is carried out by MTHFD2/2L and methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L). MTHFD1 is a cytoplasmic trifunctional enzyme with CH2-THF dehydrogenase (EC 1.5.1.5), 5,10-methenyl-tetrahydrofolate (CH+-THF, EC 3.5.4.9) cyclohydrolase, and 10-formyl-tetrahydrofolate (10-CHO-THF, EC 6.3.4.3) synthase activities	Homo sapiens
physiological function	the folate cycle, through transfer of a carbon unit between tetrahydrofolate and its derivatives in the cytoplasmic and mitochondrial compartments, produces other metabolites that are essential for cell growth, including nucleotides, methionine, and the antioxidant NADPH. Methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L) is the enzyme catalyzing the last step of the mitochondrial compartment generating formate, which subsequently can enter the cytoplasmic compartment. MTHFD1L plays critical roles in folate cycle maintenance and in support of cancer growth. MTHFD1L is transcriptionally activated by NRF2, a master regulator of redox homeostasis. MTHFD1L overexpression is closely associated with aggressive clinicopathological features of hepatocellular carcinoma (HCC) including the presence of tumor microsatellite formation, venous invasion, and more advanced tumor stages. MTHFD1L increased NADPH/NADP+ levels and reduced reactive oxygen species (ROS)	Homo sapiens