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Glutamine via α-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis

Joseph S. Burch, Jason R. Marcero, John Alan Maschek, James E. Cox, Laurie K. Jackson, Amy E. Medlock, John D. Phillips and Harry A. Dailey Jr.

Key points

  • During late erythropoiesis exogenous glutamine, rather than TCA cycle intermediates, provides carbons for succinyl-CoA for heme synthesis.

  • Itaconate, a compound manufactured as part of the inflammatory response, inhibits heme synthesis in cells undergoing erythropoiesis.

Abstract

During erythroid differentiation the erythron must remodel its protein constituents so that the mature red cell contains hemoglobin as the chief cytoplasmic protein component. For this approximately 109 molecules of heme must be synthesized, consuming 1010 molecules of succinyl-CoA. It has long been assumed that the source of succinyl-CoA for heme synthesis in all cell types is the tricarboxylic acid (TCA) cycle. Based upon the observation that one subunit of succinyl-CoA synthetase (SCS) physically interacts with the first enzyme of heme synthesis (5-aminolevulinate synthase 2, ALAS2) in erythroid cells, it has been posited that succinyl-CoA for ALA synthesis is provided by the ATP-dependent reverse SCS reaction. We have now demonstrated that this is not the manner by which developing erythroid cells provide succinyl-CoA for ALA synthesis. Instead, during late stages of erythropoiesis cellular metabolism is remodeled so that glutamine is the precursor for ALA following deamination to α-ketoglutarate and conversion to succinyl-CoA by α-ketoglutarate dehydrogenase (KDH) without equilibration or passage through the TCA cycle. This may be facilitated by a direct interaction between ALAS2 and KHD. Succinate is not an effective precursor for heme, indicating that the SCS reverse reaction does not play a role in providing succinyl-CoA for heme synthesis. Inhibition of succinate dehydrogenase by itaconate, which has been shown in macrophages to dramatically increase the concentration of intracellular succinate, does not stimulate heme synthesis as might be anticipated, but actually inhibits hemoglobinization during late erythropoiesis.

  • Submitted January 23, 2018.
  • Accepted July 2, 2018.