General Information:

Id: 6,362 (click here to show other Interactions for entry)
Diseases: Cancer
Diabetes mellitus, type II - [OMIM]
Insulin resistance
Mammalia
review
Reference: Anastasiou D and Cantley LC(2012) Breathless cancer cells get fat on glutamine Cell Res. 3: 443-446 [PMID: 22212478]

Interaction Information:

Comment Under hypoxic conditions, which are frequently encountered in the tumor environment, pyruvate enters mitochondria at reduced rates. This is, in part, because hypoxia induces the stabilization of the transcription factor HIF-1a (hypoxia-inducible factor-1a). One of the transcriptional targets of HIF-1a is pyruvate dehydrogenase kinase 1 (PDK1), which limits conversion of pyruvate into acetyl-CoA in mitochondria by phosphorylating the E1 subunit of PDH and thus inactivating the enzyme. Limiting pyruvate entry into mitochondria will also reduce glucose-derived carbons available for acetyl-CoA and ultimately lipid synthesis.
Formal Description
Interaction-ID: 59785

decreases_quantity of

drug/chemical compound

Pyruvate

in mitochondrion
Comment Under hypoxic conditions, which are frequently encountered in the tumor environment, pyruvate enters mitochondria at reduced rates. This is, in part, because hypoxia induces the stabilization of the transcription factor HIF-1a (hypoxia-inducible factor-1a). One of the transcriptional targets of HIF-1a is pyruvate dehydrogenase kinase 1 (PDK1), which limits conversion of pyruvate into acetyl-CoA in mitochondria by phosphorylating the E1 subunit of PDH and thus inactivating the enzyme. Limiting pyruvate entry into mitochondria will also reduce glucose-derived carbons available for acetyl-CoA and ultimately lipid synthesis.
Formal Description
Interaction-ID: 59786

increases_activity of

gene/protein

HIF1A

Drugbank entries Show/Hide entries for HIF1A
Comment The dependence on glutamine for proliferation persists even under hypoxic conditions, against the prediction that limited activity of the respiratory chain should alleviate the need for anaplerosis. Cells cultured under hypoxia took up glutamine at higher rates than under normoxia and use it for lipid synthesis.
Formal Description
Interaction-ID: 59789

NOT decreases_activity of

process

anaplerosis

Comment The dependence on glutamine for proliferation persists even under hypoxic conditions, against the prediction that limited activity of the respiratory chain should alleviate the need for anaplerosis. Cells cultured under hypoxia took up glutamine at higher rates than under normoxia and use it for lipid synthesis.
Formal Description
Interaction-ID: 59791

increases_transport of

drug/chemical compound

Glutamine

into the cell
Comment Rather than generating citrate going through the forward, oxidative, direction of the TCA cycle, glutamine utilizes another route that involves the reductive carboxylation of glutamine-derived alpha-ketoglutarate (alpha-KG). As much as 25% of acetyl-CoA utilized for lipid synthesis was generated by this route of glutamine catabolism in various cell lines under normoxic conditions, the rest of the carbons being contributed by glucose. When the source of lipogenic acetyl-CoA was probed under hypoxia, less glucose is used for lipid synthesis, consistent with the notion that hypoxia limits pyruvate entry into mitochondria. Under these conditions, however, glutamine took over the role of the major carbon source for lipogenesis via the reductive carboxylation route. Treatment of cells with dichloroacetate (DCA), which inhibits PDK1 and therefore alleviates inhibition of PDH, partly restored glucose-dependent lipogenesis and diminished reductive glutamine metabolism under hypoxia.
Formal Description
Interaction-ID: 59792

increases_activity of

process

reductive glutamine metabolism