The biochemistry of heme biosynthesis

Institute of Microbiology, Technical University of Braunschweig, Spielmannstr. 7, D-38106 Braunschweig, Germany.
Archives of Biochemistry and Biophysics (Impact Factor: 3.02). 07/2008; 474(2):238-51. DOI: 10.1016/
Source: PubMed


Heme is an integral part of proteins involved in multiple electron transport chains for energy recovery found in almost all forms of life. Moreover, heme is a cofactor of enzymes including catalases, peroxidases, cytochromes of the P(450) class and part of sensor molecules. Here the step-by-step biosynthesis of heme including involved enzymes, their mechanisms and detrimental health consequences caused by their failure are described. Unusual and challenging biochemistry including tRNA-dependent reactions, radical SAM enzymes and substrate derived cofactors are reported.

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    • "These steps involve the selective decarboxylation of a number of the peripheral carboxylic acid side-chains, macrocyclic ring oxidation and insertion of iron (Fig. 1) (Heinemann et al., 2008). The haem biosynthetic pathway is initiated by the formation of 5-aminolevulinic acid, the precursor of all naturally occurring tetrapyrroles, which is subsequently transformed into the first macrocyclic intermediate uro'gen III in three enzymatic steps that are catalysed by HemB, C and D (Heinemann et al., 2008). Uro'gen III represents the first major branch point in the formation of modified tetrapyrroles from where the synthesis of molecules such as cobalamin and sirohaem diverge from the synthesis of haem. "
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    ABSTRACT: Haem is a life supporting molecule that is ubiquitous in all major kingdoms. In Staphylococcus aureus, the importance of haem is highlighted by the presence of systems both for the exogenous acquisition and endogenous synthesis of this prosthetic group. In this work, we show that in S. aureus the formation of haem involves the conversion of coproporphyrinogen III into coproporphyrin III by coproporphyrin synthase HemY, insertion of iron into coproporphyrin III via ferrochelatase HemH, and oxidative decarboxylation of Fe-coproporphyrin III into protohaem IX by Fe-coproporphyrin oxidase/dehydrogenase HemQ. Together, this route represents a transitional pathway between the classic pathway and the more recently acknowledged alternative biosynthesis machinery. The role of the haem biosynthetic pathway in the survival of the bacterium was investigated by testing for inhibitors of HemY. Analogues of acifluorfen are shown to inhibit the flavin-containing HemY, highlighting that this as a suitable target for the development of drugs against S. aureus. Moreover, the presence of this transitional pathway for haem biosynthesis within many Gram-positive pathogenic bacteria suggests that this route has the potential not only for the design of antimicrobials but also for the selective discrimination between bacteria operating different routes to the biosynthesis of haem. This article is protected by copyright. All rights reserved.
    No preview · Article · Apr 2015 · Molecular Microbiology
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    • "The condensation of eight molecules of ALA is necessary to form uroporphyrinogen III, which is then converted to protoporphyrin IX. In a reaction catalyzed by ferrochelatase, protoporphyrin IX can incorporate Fe2+ to produce heme [57]. S-adenosylmethionine synthetases are involved in this complex pathway by producing SAM (an essential cosubstrate for many enzymatic reactions, including the final steps of heme synthesis) [42]. "
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    ABSTRACT: Entamoeba histolytica is an ameboid parasite that causes colonic dysentery and liver abscesses in humans. The parasite encounters dramatic changes in iron concentration during its invasion of the host, with relatively low levels in the intestinal lumen and then relatively high levels in the blood and liver. The liver notably contains sources of iron; therefore, the parasite's ability to use these sources might be relevant to its survival in the liver and thus the pathogenesis of liver abscesses. The objective of the present study was to identify factors involved in iron uptake, use and storage in E. histolytica. We compared the respective transcriptomes of E. histolytica trophozoites grown in normal medium (containing around 169 µM iron), low-iron medium (around 123 µM iron), iron-deficient medium (around 91 µM iron), and iron-deficient medium replenished with hemoglobin. The differentially expressed genes included those coding for the ATP-binding cassette transporters and major facilitator transporters (which share homology with bacterial siderophores and heme transporters) and genes involved in heme biosynthesis and degradation. Iron deficiency was associated with increased transcription of genes encoding a subset of cell signaling molecules, some of which have previously been linked to adaptation to the intestinal environment and virulence. The present study is the first to have assessed the transcriptome of E. histolytica grown under various iron concentrations. Our results provide insights into the pathways involved in iron uptake and metabolism in this parasite.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "In 1993, Tai and others began to uncover how the pneumococcus acquires iron from its host during systemic bacteremia (Tai et al., 1993). Free iron levels in the blood are ~10−18 M−1 in the mammalian host, with most iron sequestered within the tetrapyrrole ring of heme, which is bound to hemoglobin (Hb) in erythrocytes (De Domenico et al., 2008; Heinemann et al., 2008). Initial analysis focused on determining whether pneumococcal culture supernatants contain siderophores as do those from multiple Gram-negative and Gram-positive pathogens, including Escherichia coli, Yersinia pestis, Haemophilus influenzae, Bacillus anthracis, and Staphylococcus aureus (Crosa et al., 2004; Honsa and Maresso, 2011; Haley and Skaar, 2012). "
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    ABSTRACT: For bacterial pathogens whose sole environmental reservoir is the human host, the acquisition of essential nutrients, particularly transition metals, is a critical aspect of survival due to tight sequestration and limitation strategies deployed to curtail pathogen outgrowth. As such, these bacteria have developed diverse, specialized acquisition mechanisms to obtain these metals from the niches of the body in which they reside. To oppose the spread of infection, the human host has evolved multiple mechanisms to counter bacterial invasion, including sequestering essential metals away from bacteria and exposing bacteria to lethal concentrations of metals. Hence, to maintain homeostasis within the host, pathogens must be able to acquire necessary metals from host proteins and to export such metals when concentrations become detrimental. Furthermore, this acquisition and efflux equilibrium must occur in a tissue-specific manner because the concentration of metals varies greatly within the various microenvironments of the human body. In this review, we examine the functional roles of the metal import and export systems of the Gram-positive pathogen Streptococcus pneumoniae in both signaling and pathogenesis.
    Full-text · Article · Dec 2013 · Frontiers in Cellular and Infection Microbiology
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