Heme and Chlorophyll Biosynthetic Pathways

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The Porphin Nucleus


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  • III. The Iron and Magnesium Branches of the Porphyrin Biosynthetic Pathway

  • A. The Iron Branch

  • B. The Mg-Branch

  • C. References

    III. The Iron and Magnesium Branches of the Porphyrin Biosynthetic Pathway

    A. The Iron Branch of the Porphyrin Biosynthetic Pathway: Biosynthesis of Heme


    rheme2.gif - 3.3 K

    Protoporphyrin IX is a branching point for heme and Chl biosynthesis. Insertion of ferrous iron into Proto leads to the formation of protoheme, while insertion of Mg into the Proto macrocycle, lead to the formation of Mg-proto which is the precursor of all Mg-porphyrins and Chls in nature.

    The terminal step in heme biosynthesis involves insertion of ferrous iron into Proto by ferrochelatase to yield protoheme (Goldberg et al 1956). In animal cells, conversion of Proto to protoheme takes place in the mitochondria. In Euglena, It has been reported that protoheme is formed in the mitochondria from ALA formed via the glycine-succcinate pathway, and in the plastid from ALA formed via the C5-pathway (Weinstein and Beale, 1983). In higher plants the enzyme is found in the mitochondria and the plastids, which strongly suggest that protoheme biosynthesis takes place in both organelles (Little and Jones, 1976).

    Ferrochelatase was first purified from rat liver (Taketani and Tokunaga, 1981). Insertion of Fe++ into Proto is accompanied by the release of two protons from the pyrrole nitrogens. Mammalian ferrochelatase has a reported molecular weight of about 40,000. Specificity of the enzyme for Proto is not absolute, as the enzyme is able to handle a variety of porphyrin IX isomers, with substituents at the 2 and 4 positions of rings A and B, that are smaller in size than hydroxyethyl and are uncharged. In is not clear wether the same situation prevails in higher plants.

    B. The Mg-Branch of the Porphyrin Biosynthetic Pathway

    Most of the Chl a in nature is formed via divinyl (DV) and monovinyl (MV) carboxylic biosynthetic routes as depicted in Fig. 1. These routes are referred to as carboxylic routes because the tetrapyrrole intermediates all have one or two free carboxylic groups. Furthermore, most of these routes are heterogeneous. That is the biosynthesis of most of the intermediates can proceed via more than one path. This phenomenon is a manifestation of the overall Chl a biosynthetic heterogeneity (Rebeiz, 2001) that permeates the whole Chl a biosynthetic pathway. Chl biosynthetic heterogeneity was discovered when it was realized that most of the carboxylic and fully esterified tetrapyrrole pools of plants consist of DV and MV components. The biological significance of this phenomenon is becoming clearer as the Chl biosynthetic pathway is increasingly viewed in the context of the structural and functional heterogeneity of photosynthetic membranes.

    Since some of the early biochemical work was done before discovery of the DV and MV Chl biosynthetic heterogeneity, and before development of appropriate analytical methodologies, it is not certain whether the investigated reactions involved only DV or DV and MV tetrapyrroles. To emphasize this ambiguity, the MV and DV connotation will be omitted from the discussion of the early work. In other words, in this context, Mg-Proto would refer either to DV Mg-Proto, to MV Mg-Proto or to a mixture of both. On the other hands, DV and MV Mg-Proto would refer specifically to the DV and MV tetrapyrrole species respectively. The Mg-tetrapyrrole intermediates of the various Chl biosynthetic routes will be discussed in ensuing sections of this review.


    1. Goldberg, A. Ashenbrucker, M., Cartwright, G. E., and Wintrobe, M. M. (1956). Studies on the biosynthesis of heme in vitro by avian erythrocytes. Blood, 11:821-833.
    2. Weinstein. J. D., and Beale, S, I. (1983). Separate physiological roles and subcellular compartments for two tetrapyrrole biosynthetic pathways in Euglena gracilis J. Biol. Chem. 258:6799-6807.
    3. Little, H. N. and Jones, O. T. G. (1976). The subcellular localization and properties of the ferrochelatase of etiolated barley. Biochem. J. 156: 309-314.
    4. Taketani, S., and Tokunaga, R. (1981). Rat liver ferrochelatase. Purification, properties and stimulation by fatty acids. J. Biol. Chem. 256:2748-12753.
    5. Rebeiz, C. A. (2001) Analysis of intermediates and end products of the chlorophyll biosynthetic pathway. In: Heme Chlorophyll and Bilins, Methods and Protocols, edited by A. Smith and M. Witty, Humana Press, Totowa NJ, pp. 111-155.

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