Glutamine via a-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, Harry A. Dailey

Research output: Contribution to journalArticle

5 Citations (Scopus)

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, ∼109 molecules of heme must be synthesized, consuming 1010 molecules of succinyl-CoA. It has long been assumed that the source of succinyl-coenzyme A (CoA) for heme synthesis in all cell types is the tricarboxylic acid (TCA) cycle. Based upon the observation that 1 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 adenosine triphosphate–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 a-ketoglutarate and conversion to succinyl-CoA by a-ketoglutarate dehydrogenase (KDH) without equilibration or passage through the TCA cycle. This may be facilitated by a direct interaction between ALAS2 and KDH. 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.

Original languageEnglish (US)
Pages (from-to)987-998
Number of pages12
JournalBlood
Volume132
Issue number10
DOIs
StatePublished - Sep 6 2018

Fingerprint

Erythropoiesis
Glutamine
Heme
Oxidoreductases
Succinate-CoA Ligases
5-Aminolevulinate Synthetase
Erythroid Cells
Citric Acid Cycle
Succinic Acid
Deamination
Molecules
Succinate Dehydrogenase
Macrophages
Metabolism
Adenosine
succinyl-coenzyme A
Hemoglobins
Proteins
Cells
Enzymes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Burch, J. S., Marcero, J. R., Maschek, J. A., Cox, J. E., Jackson, L. K., Medlock, A. E., ... Dailey, H. A. (2018). Glutamine via a-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis. Blood, 132(10), 987-998. https://doi.org/10.1182/blood-2018-01-829036

Glutamine via a-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis. / Burch, Joseph S.; Marcero, Jason R.; Maschek, John Alan; Cox, James E.; Jackson, Laurie K.; Medlock, Amy E.; Phillips, John D.; Dailey, Harry A.

In: Blood, Vol. 132, No. 10, 06.09.2018, p. 987-998.

Research output: Contribution to journalArticle

Burch, JS, Marcero, JR, Maschek, JA, Cox, JE, Jackson, LK, Medlock, AE, Phillips, JD & Dailey, HA 2018, 'Glutamine via a-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis', Blood, vol. 132, no. 10, pp. 987-998. https://doi.org/10.1182/blood-2018-01-829036
Burch JS, Marcero JR, Maschek JA, Cox JE, Jackson LK, Medlock AE et al. Glutamine via a-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis. Blood. 2018 Sep 6;132(10):987-998. https://doi.org/10.1182/blood-2018-01-829036
Burch, Joseph S. ; Marcero, Jason R. ; Maschek, John Alan ; Cox, James E. ; Jackson, Laurie K. ; Medlock, Amy E. ; Phillips, John D. ; Dailey, Harry A. / Glutamine via a-ketoglutarate dehydrogenase provides succinyl-CoA for heme synthesis during erythropoiesis. In: Blood. 2018 ; Vol. 132, No. 10. pp. 987-998.
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