Interaction between succinyl CoA synthetase and the heme-biosynthetic enzyme ALAS-E is disrupted in sideroblastic anemia

J Clin Invest. 2000 Mar;105(6):757-64. doi: 10.1172/JCI6816.


The first and the rate-limiting enzyme of heme biosynthesis is delta-aminolevulinate synthase (ALAS), which is localized in mitochondria. There are 2 tissue-specific isoforms of ALAS, erythroid-specific (ALAS-E) and nonspecific ALAS (ALAS-N). To identify possible mitochondrial factors that modulate ALAS-E function, we screened a human bone marrow cDNA library, using the mitochondrial form of human ALAS-E as a bait protein in the yeast 2-hybrid system. Our screening led to the isolation of the beta subunit of human ATP-specific succinyl CoA synthetase (SCS-betaA). Using transient expression and coimmunoprecipitation, we verified that mitochodrially expressed SCS-betaA associates specifically with ALAS-E and not with ALAS-N. Furthermore, the ALAS-E mutants R411C and M426V associated with SCS-betaA, but the D190V mutant did not. Because the D190V mutant was identified in a patient with pyridoxine-refractory X-linked sideroblastic anemia, our findings suggest that appropriate association of SCS-betaA and ALAS-E promotes efficient use of succinyl CoA by ALAS-E or helps translocate ALAS-E into mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5-Aminolevulinate Synthetase / genetics
  • 5-Aminolevulinate Synthetase / metabolism*
  • Acyl Coenzyme A / metabolism
  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Anemia, Sideroblastic / enzymology*
  • Animals
  • Base Sequence
  • Bone Marrow / chemistry
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • DNA, Complementary / genetics
  • Enzyme Induction
  • Erythroid Precursor Cells / enzymology
  • Heme / biosynthesis*
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Macromolecular Substances
  • Mitochondria, Heart / enzymology
  • Molecular Sequence Data
  • Myocardium / chemistry
  • Point Mutation
  • RNA, Messenger / biosynthesis
  • Succinate-CoA Ligases / metabolism*
  • Two-Hybrid System Techniques


  • Acyl Coenzyme A
  • DNA, Complementary
  • Isoenzymes
  • Macromolecular Substances
  • RNA, Messenger
  • Heme
  • succinyl-coenzyme A
  • Adenosine Triphosphate
  • 5-Aminolevulinate Synthetase
  • Succinate-CoA Ligases
  • SUCLA2 protein, human