Structure and function of enzymes in heme biosynthesis

Institute of Microbiology, Technische Universität Braunschweig, Braunschweig D-38106, Germany.
Protein Science (Impact Factor: 2.85). 06/2010; 19(6):1137-61. DOI: 10.1002/pro.405
Source: PubMed


Tetrapyrroles like hemes, chlorophylls, and cobalamin are complex macrocycles which play essential roles in almost all living organisms. Heme serves as prosthetic group of many proteins involved in fundamental biological processes like respiration, photosynthesis, and the metabolism and transport of oxygen. Further, enzymes such as catalases, peroxidases, or cytochromes P450 rely on heme as essential cofactors. Heme is synthesized in most organisms via a highly conserved biosynthetic route. In humans, defects in heme biosynthesis lead to severe metabolic disorders called porphyrias. The elucidation of the 3D structures for all heme biosynthetic enzymes over the last decade provided new insights into their function and elucidated the structural basis of many known diseases. In terms of structure and function several rather unique proteins were revealed such as the V-shaped glutamyl-tRNA reductase, the dipyrromethane cofactor containing porphobilinogen deaminase, or the "Radical SAM enzyme" coproporphyrinogen III dehydrogenase. This review summarizes the current understanding of the structure-function relationship for all heme biosynthetic enzymes and their potential interactions in the cell.

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Available from: Joachim Reichelt, Aug 19, 2014
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    • "Nearly all organisms possess heme proteins and can synthesize the cofactor, and in eukaryotes the heme biosynthetic pathway involves both cytosolic and mitochondrial enzymes (Layer et al., 2010). Although it is a eukaryote, the diplomonad protist Giardia intestinalis lacks mitochondria and instead possesses mitosomes, residual organelles of mitochrondrial origin that retain the ability to assemble iron-sulfur clusters but not the capacity for oxidative phosphorylation or heme biosynthesis (Jedelsky et al., 2011; Tovar et al., 2003). "
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    ABSTRACT: Despite lacking mitochondria and a known pathway for heme biosynthesis the micro-aerotolerant anaerobic protozoan parasite Giardia intestinalis encodes four members of the cytochrome b5 family of electron transfer proteins, three of which are small, single-domain proteins. While these are similar in size and fold to their better-known mammalian counterparts the Giardia proteins have distinctly lower reduction potentials, ranging from -125 to -177 mV compared to +6 mV for the bovine microsomal protein. This difference is accounted for by a more polar heme environment in the Giardia proteins, as mutation of a conserved heme pocket tyrosine residue to phenylalanine in the Giardia cytochrome b5 isotype-I (gCYTb5-I Y61F) raises its reduction potential by more than 100 mV. All three isotypes have UV-visible spectra consistent with axial coordination of the heme by a pair of histidine residues, but electron paramagnetic spectroscopy indicates that the planes of their imidazole rings are nearly perpendicular rather than coplanar as observed in mammalian cytochrome b5, which may be due to geometrical constraints imposed by a one-residue shorter spacing between the ligand pair in the Giardia proteins. Although no function has yet to be ascribed to any Giardia cytochome b5, the presence of similar sequences in many other eukaryotes indicates that these represent an under-characterized class of low reduction potential family members. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Aug 2015 · Experimental Parasitology
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    • "Heme synthesis requires also involvement of other Fe/S-containing proteins such as ferredoxins [63]. Also, heme biosynthesis is a NADPH-consuming process [31]. Opposing to this concept, would be the fact that GR deficiency is characterized by similar symptoms that G6PDH deficiency [24]. "

    Full-text · Article · May 2015
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    • "In certain cases, subtle variations of the cofactor pathway may exist. For example, in animals, fungi, and α-proteobacteria, heme synthesis is initiated by 5-aminolevulinate synthase, via condensation of glycine and succinyl CoA, while in photosynthetic eukaryotes and some species of the α-proteobacterial group, it depends on glutamate, via the concerted actions of three enzymes (Layer et al., 2010). Once synthesized, the cofactor is integrated with the apoenzyme, either in a co-translational or post-translational manner, to form the holoenzyme. "
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    ABSTRACT: The manufacture of a diverse array of chemicals is now possible with biologically engineered strains, an approach that is greatly facilitated by the emergence of synthetic biology. This is principally achieved through pathway engineering in which enzyme activities are coordinated within a genetically amenable host to generate the product of interest. A great deal of attention is typically given to the quantitative levels of the enzymes with little regard to their overall qualitative states. This highly constrained approach fails to consider other factors that may be necessary for enzyme functionality. In particular, enzymes with physically bound cofactors, otherwise known as holoenzymes, require careful evaluation. Herein, we discuss the importance of cofactors for biocatalytic processes and show with empirical examples why the synthesis and integration of cofactors for the formation of holoenzymes warrant a great deal of attention within the context of pathway engineering.
    Full-text · Article · Aug 2014 · Frontiers in Bioengineering and Biotechnology
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