The biochemistry of heme biosynthesis
ABSTRACT 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.
- SourceAvailable from: José Antonio Bárcena
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- "Cancer therapies are increasingly being focused on the biochemistry of cancer cells as opposed to their genetic origins , hence understanding of regulatory mechanisms is essential to effectively target these cells . Uroporphyrinogen decarboxylase, Hem12p, is involved in the 5th step of heme biosynthesis in the cytosol, before biosynthesis is completed within mitochondria (Figure 1(b)) . Beside its well-known roles in oxygen transport, electron transfer, and peroxide metabolism, heme is central to oxygen sensing in many living organisms and plays a signaling role in a wide array of biological processes . "
ABSTRACT: Uroporphyrinogen decarboxylase (Hem12p) and transketolase (Tkl1p) are key mediators of two critical processes within the cell, heme biosynthesis, and the nonoxidative part of the pentose phosphate pathway (PPP). The redox properties of both Hem12p and Tkl1p from Saccharomyces cerevisiae were investigated using proteomic techniques (SRM and label-free quantification) and biochemical assays in cell extracts and in vitro with recombinant proteins. The in vivo analysis revealed an increase in oxidized Cys-peptides in the absence of Grx2p, and also after treatment with H2O2 in the case of Tkl1p, without corresponding changes in total protein, demonstrating a true redox response. Out of three detectable Cys residues in Hem12p, only the conserved residue Cys52 could be modified by glutathione and efficiently deglutathionylated by Grx2p, suggesting a possible redox control mechanism for heme biosynthesis. On the other hand, Tkl1p activity was sensitive to thiol redox modification and although Cys622 could be glutathionylated to a limited extent, it was not a natural substrate of Grx2p. The human orthologues of both enzymes have been involved in certain cancers and possess Cys residues equivalent to those identified as redox sensitive in yeast. The possible implication for redox regulation in the context of tumour progression is put forward.Oxidative Medicine and Cellular Longevity 07/2013; 2013:932472. DOI:10.1155/2013/932472 · 3.36 Impact Factor
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- "2.—Schematic representation of the tetrapyrrole biosynthesis pathway. Based on information from Martens et al. (2002), McGoldrick et al. (2005), Heinemann et al. (2008), Storbeck et al. (2010) and Bali et al. (2011) "
ABSTRACT: An open question regarding the evolution of photosynthesis is how cyanobacteria came to possess the two reaction center (RC) types, RCI and RCII. The two main competing theories in the foreground of current thinking on this issue are that either i) RCI and RCII are related via lineage divergence among anoxygenic photosynthetic bacteria and became merged in cyanobacteria via an event of large scale lateral gene transfer (also called 'fusion' theories), or ii) the two RC types are related via gene duplication in an ancestral, anoxygenic but protocyanobacterial phototroph that possessed both RC types before making the transition to using water as an electron donor. To distinguish between distinguish between these possibilities, we studied the evolution of the core (bacterio)chlorophyll biosynthetic pathway from protoporphyrin IX up to (bacterio)chlorophyllide a. The results show no dichotomy of chlorophyll biosynthesis genes into RCI and RCII-specific chlorophyll biosynthetic clades, thereby excluding models of fusion at the origin of cyanobacteria and supporting the selective-loss hypothesis. By considering the cofactor demands of the pathway and the source genes from which several steps in chlorophyll biosynthesis are derived, we infer that the cell that first synthesized chlorophyll was a cobalamin-dependent, heme-synthesizing, diazotrophic anaerobe.Genome Biology and Evolution 12/2012; 5(1). DOI:10.1093/gbe/evs127 · 4.53 Impact Factor
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- "Heme (iron protoporphyrin IX) is found in almost all organisms and critical for electron transfer reactions (Heinemann et al., 2008). It is the major oxygen-binding molecule in eukaryotes and requires iron as a substrate. "
ABSTRACT: In mammals, hypoxia causes facilitated erythropoiesis that requires increased iron availability with established links between oxygen and iron in regulation of the transcription factor hypoxia-inducible factor. Therefore, cellular responses to hypoxia and iron starvation are linked in mammals and are host conditions that pathogens encounter during infection. In human pathogenic fungi, molecular mechanisms underlying hypoxia adaptation and iron homeostasis have been investigated. However, the interconnected regulation of hypoxia adaptation and iron homeostasis remains to be fully elucidated. This review discusses the potential transcriptional regulatory links between hypoxia adaptation and iron homeostasis in human pathogenic fungi. Transcriptome analyses demonstrate that core regulators of hypoxia adaptation and iron homeostasis are involved in regulation of several common genes responsible for iron acquisition and ergosterol biosynthesis. Importantly, iron starvation increases susceptibility of fungal cells to antifungal drugs and decreased levels of ergosterol, while key hypoxia regulators are also involved in responses to antifungal drugs and mediating ergosterol levels. We suggest that pathogenic fungi have developed a coordinated regulatory system in response to hypoxia and iron starvation through (i) regulation of expression of hypoxia-responsive and iron-responsive genes via cross-linked key regulators, and/or (ii) regulation of factors involved in ergosterol biosynthesis. Thus, both oxygen and iron availability are intimately tied with fungal virulence and responses to existing therapeutics and further elucidation of their interrelationship should have significant clinical implications.Frontiers in Microbiology 11/2012; 3:381. DOI:10.3389/fmicb.2012.00381 · 3.94 Impact Factor