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A Pathway for Heme Biosynthesis: the Work of David Shemin

Open AccessPublished:August 25, 2006DOI:https://doi.org/10.1016/S0021-9258(18)95190-2
      The Mechanism of Porphyrin Formation. Further Evidence on the Relationship of the Citric Acid Cycle and Porphyrin Formation (Wriston, J. C., Jr., Lack, L., and Shemin, D. (1955) J. Biol. Chem. 215, 603–611)
      The Succinate-Glycine Cycle. I. The Mechanism of Pyrrole Synthesis (Shemin, D., Russell, C. S., and Abramsky, T. (1955) J. Biol. Chem. 215, 613–626)
      David Shemin (1911–1991) was born in New York City. He attended the City College of New York and received his B.S. in 1932. He then went to Columbia University where he earned his A.M. in 1933 and his Ph.D. in 1938. Shemin remained at Columbia and became an Assistant Professor of Biochemistry in 1945. Around this time he started working with David Rittenberg, using 15N to follow the path of glycine in the body. Shemin himself ingested 66 g of [15N]glycine over a 3-day period. His blood was then drawn at intervals, and its 15N content was assessed. This led to Shemin and Rittenberg's finding that glycine is used to synthesize the pyrrole rings of protoporphyrin, which was the subject of a previous Journal of Biological Chemistry (JBC) Classic (
      • Shemin D.
      • Rittenberg D.
      JBC Classics.
      ).
      Following up on this work, Shemin turned his attention to figuring out which of the carbon atoms of glycine were used in porphyrin synthesis and the particular positions in the porphyrin molecule that they occupied. He found that 8 of the porphyrin carbon atoms came from the α-carbon atom of glycine and the remaining 26 came from acetate (
      • Wittenberg J.
      • Shemin D.
      The location in protoporphyrin of the carbon atoms derived from the α-carbon atom of glycine..
      ,
      • Shemin D.
      • Wittenberg J.
      The mechanism of porphyrin formation. The role of the tricarboxylic acid cycle..
      ).
      Shemin later recalled, “It appeared that some mechanism concerned with the metabolism of acetate should account for our findings which involved an asymmetric four-carbon compound arising from acetate and had the particular distribution of 14C from the methyland carboxyl-labeled carbon atoms. A likely mechanism seemed to be the reactions involved in the tricarboxylic acid cycle, although relative quantitative calculations concerning the distribution of the carbon atoms of acetate in intermediates of the tricarboxylic acid cycle had not previously been done (
      • Shemin D.
      An illustration of the use of isotopes: the biosynthesis of porphyrins.
      ).”
      Shemin speculated the four-carbon compound was most likely an “active” succinyl coenzyme compound, similar to acetyl-CoA, and that this succinyl compound was a product of the tricarboxylic acid cycle that arose from both succinate and α-ketoglutarate (
      • Shemin D.
      • Kumin S.
      The mechanism of porphyrin formation. The formation of a succinyl intermediate from succinate.
      ). At that time, succinyl-CoA was not known to exist nor had its formation from succinate been suggested.
      Further evidence for the relationship between the citric acid cycle and porphyrin synthesis came from experiments Shemin did using α-[1,2-14C]ketoglutarate, α-[5-14C]ketoglutarate, and [1,5-14C]citrate. This is the subject of the first JBC Classic reprinted here. Along with his students, John C. Wriston and Leon Lack, Shemin added the labeled compounds to hemolyzed preparations of duck red blood cells and analyzed the resulting radioactive hemin. The 14C distribution pattern in the porphyrin synthesized from the compounds completely agreed with their theoretical predictions based on the formation of “active” succinate in the citric acid cycle. Their results also confirmed their hypothesis that the 14C distribution pattern found in the “active” succinate synthesized from methyl-labeled acetate was dependent on the number of turns of the citric acid cycle, whereas that synthesized from the 14C carboxy-labeled acetate was independent of the number of turns.
      Having established that two molecules of a succinyl derivative and glycine are involved in the formation of a pyrrole, Shemin next considered possible mechanisms. With the assistance of his postdoctoral student Charlotte Russell, Shemin determined that δ-aminolevulinic acid can replace “active” succinate and glycine in porphyrin synthesis (
      • Shemin D.
      • Russell C.S.
      δ-Aminolevulinic acid, its role in the biosynthesis of porphyrins and purines.
      ). This suggested that δ-aminolevulinic acid was the source of all the atoms of protoporphyrin. In this “succinate-glycine cycle,” “active” succinate condenses on the α-carbon of glycine to yield α-amino-β-ketoadipic acid, which is decarboxylated to yield δ-aminolevulinic acid.
      Shemin's next step was to study the conversion of δ-aminolevulinic acid to porphyrin, which is the subject of the second JBC Classic reprinted here. Shemin, along with Russell and Tessa Abramsky, synthesized δ-aminolevulinic acid and added it to duck red blood cell hemolysate along with either 14C-labeled succinate or [2-14C]glycine. The addition of δ-aminolevulinic acid lowered the 14C activity of the newly formed heme, confirming the involvement of the compound in porphyrin biosynthesis. Similarly, incubation of duck red blood cell hemolysates with δ-[5-14C]aminolevulinic acid produced labeled protoporphyrin whose 14C distribution pattern was similar to that of protoporphyrin synthesized from [2-14C]glycine. Thus, Shemin concluded that condensation of 2 mol of δ-aminolevulinic acid forms a precursor monopyrrole, which is then utilized in the synthesis of a tetrapyrrole compound.
      Shemin remained at Columbia, becoming an Associate Professor in 1949 and a Professor in 1953. He then moved to Evanston, Illinois and joined the faculty of Northwestern University as a Professor of Biochemistry in 1968. He eventually became Chairman of the Department of Biochemistry and Molecular Biology at Northwestern in 1974. Shemin was also Deputy Director of the Cancer Center at the Northwestern Medical School from 1975 to 1987. He became Professor Emeritus at Northwestern in 1979 and continued to do research until his death in 1991.
      Shemin was elected to the National Academy of Sciences and the American Academy of Arts and Sciences. In recognition of his contributions to science he was awarded the Pasteur Medal from the Pasteur Institute (1951), the Stevens Award from Columbia University (1952), and the Townsend Harris Medal from the City College of New York (1982). He received two Guggenheim fellowships and was designated a Fogarty International Scholar. Shemin was Editor of Physiological Reviews and Biochemical Preparations and was a member of the Editorial Boards of the JBC and of Archives of Biochemistry and Biophysics.

      References

        • Shemin D.
        • Rittenberg D.
        JBC Classics.
        J. Biol. Chem. 1945; 159 (Shemin, D., London, I. M., and Rittenberg, D. (1950) J. Biol. Chem.183, 757–765; Radin, N. S., Rittenberg, D., and Shemin, D. (1950) J. Biol. Chem.184, 755–767 (http://www.jbc.org/cgi/content/full/280/15/e12)): 67-568
        • Wittenberg J.
        • Shemin D.
        The location in protoporphyrin of the carbon atoms derived from the α-carbon atom of glycine..
        J. Biol. Chem. 1950; 185: 103-116
        • Shemin D.
        • Wittenberg J.
        The mechanism of porphyrin formation. The role of the tricarboxylic acid cycle..
        J. Biol. Chem. 1951; 192: 315-334
        • Shemin D.
        An illustration of the use of isotopes: the biosynthesis of porphyrins.
        BioEssays. 1989; 10: 30-35
        • Shemin D.
        • Kumin S.
        The mechanism of porphyrin formation. The formation of a succinyl intermediate from succinate.
        J. Biol. Chem. 1952; 198: 827-837
        • Shemin D.
        • Russell C.S.
        δ-Aminolevulinic acid, its role in the biosynthesis of porphyrins and purines.
        J. Am. Chem. Soc. 1953; 75: 4873-4874

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