Molecular Biochemistry II

Heme Synthesis

Reading:

Textbook Reading: Voet & Voet, Biochemistry, 3rd Edition, p. 813 & 1013-1022.

Some recent articles (optional reading): 
H. L. Schubert, E. Raux, K. S. Wilson & M. J. Warren (1999) "Common chelatase design in the branched tetrapyrrole pathways of heme and anaerobic cobalamin synthesis," Biochemistry 38: 10660-10669.
G. A. Hunter & G. C. Ferreira (1999) "Pre-steady-state reaction of 5-Aminolevulinate Synthase," J. Biol. Chem. 274: 12222-12228.
S. W. Ryter & R. M. Tyrrell (2000) "The heme synthesis and degradation pathways: Role in oxidant sensitivity" Free Radical Biol. & Med. 28: 289-309.
M. A. A. Mathews, H. L. Schubert, F. G. Whitby, K. J. Alexander, K. Schadick, H. A. Bergonia, J. D. Phillips & C. P. Hill (2001) "Crystal structure of human uroporphrinogen III synthase," EMBO J. 20: 5832-5839.
E. K. Jaffe, J. Martins, J. Li, J. Kervinen & R. L. Dunbrack (2001) "The molecular mechanism of lead inhibition of human Porphobilinogen Synthase," J. Biol. Chem. 276: 1531-1537.
Frre, F., Schubert, W., Stauffer, F., Frankenberg, N., Jahn, R. Neier D., Heinz, D. (2002) "Structure of porphobilinogen synthase from Pseudomonas aeruginosa in complex with 5-fluorolevulinic acid suggests a double Schiff base mechanism," J. Mol. Biol. 320: 237-247.
P. T. Erskine, L. Coates, D. Butler, J. H. Youell, A. A. Brindley, S. P. Wood, M. J. Warren, P. M. Shoolingin-Jordan & J. B. Cooper (2003) "X-ray structure of a putative reaction intermediate of 5-aminolaevulinic acid dehydratase," Biochem. J. 373: 733-738.
K. E. Anderson, J. R. Bloomer, H. L. Bonkovsky, J. P. Kushner, C. A. Pierach, N. R. Pimstone & R. J. Desnick (2005) "Recommendations for the diagnosis and treatment of the acute porphyrias," Ann. Intern. Med. 142: 439-450.
H. Fukuda, A. Casas & A. Batlle (2005) "Aminolevulinic acid: from its unique biological function to its star role in photodynamic therapy," Internat. J. Biochem. & Cell Biol. 37: 272-276.
R. S. Ajioka, J. D. Phillips & J. P. Kushner (2006) "Biosynthesis of heme in mammals," Biochim. Biophys. Acta 1763: 723-736.
G. O. Latunde-Dada, A. T. McKie & R. J. Simpson (2006) "Animal models with enhanced erythropoiesis and iron absorption," Biochim. Biophys. Acta 1762: 414-423.
A. Pietrangelo (2006) "Hereditary hemochromatosis," Biochim. Biophys. Acta 1763: 700-710.

Potential Test Question:

1.a. Write out the reaction leading to formation of d-aminolevulinate (ALA). Include names and structures of substrates and product of the reaction (mechanism not required). What vitamin-derived cofactor participates in the reaction?
    b. Write out the reaction catalyzed by Porphobilinogen Synthase (PBG Synthase), giving names and structures of reactants and product. How are the substrates of the PBG Synthase reaction initially held at the active site? Explain the effect of Pb++ on the PBG Synthase reaction. How are effects of lead poisoning on the brain explained?
    c. Summarize and explain the effect of genetic deficiency of PBG Synthase on synthesis of ALA.

Copyright 2000-2008 by Joyce J. Diwan. All rights reserved.

Lecture Notes on
Heme Synthesis

Interactive Quiz on    
  Heme Synthesis    

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