Figure 2
Regulation of HIF-1α in response to mutations in metabolic enzymes. (A) HIF-1α is hydroxylated at proline residues by the
PHD enzymes, a reaction that requires α-ketoglutarate and produces succinate. Hydroxylated HIF-1α is ubiquitinated by a VHL-containing
ubiquitin ligase. (B) Mutations in SDH or FH enzymes trigger accumulation of succinate, impairing HIF-1α hydroxylations. Increased
HIF-1α drives increased glycolysis. (C) Mutant forms of IDH1 or IDH2 (marked with an asterisk) may reduce the availability
of α-ketoglutarate, restricting HIF-1α hydroxylation and activating glycolysis. An alternative model proposes that mutated
IDH enzymes acquire a novel activity, producing increased 2-hydroxyglutarate. The effects of 2-hydroxyglutarate on the signal
transduction and metabolism of transformed cells are not yet well described.