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Synthesis, Delivery and Regulation of Eukaryotic Heme and Fees Cluster Cofactors

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Synthesis, Delivery and Regulation of Eukaryotic Heme and Fees Cluster Cofactors Archives of Biochemistry and Biophysics 592 (2016) 60e75 Contents lists available at ScienceDirect Archives of Biochemistry and Biophysics journal homepage: www.elsevier.com/locate/yabbi Review article Synthesis, delivery and regulation of eukaryotic heme and FeeS cluster cofactors Dulmini P. Barupala a, 1, Stephen P. Dzul a, 1, Pamela Jo Riggs-Gelasco b, * Timothy L. Stemmler a, a Departments of Biochemistry and Molecular Biology, and Pharmaceutical Sciences, Wayne State University, Detroit, MI 48201, USA b Department of Chemistry and Biochemistry, College of Charleston, Charleston, SC 29424, USA article info abstract Article history: In humans, the bulk of iron in the body (over 75%) is directed towards heme- or FeeS cluster cofactor Received 2 September 2015 synthesis, and the complex, highly regulated pathways in place to accomplish biosynthesis have evolved Received in revised form to safely assemble and load these cofactors into apoprotein partners. In eukaryotes, heme biosynthesis is 13 January 2016 both initiated and finalized within the mitochondria, while cellular FeeS cluster assembly is controlled Accepted 14 January 2016 by correlated pathways both within the mitochondria and within the cytosol. Iron plays a vital role in a Available online 16 January 2016 wide array of metabolic processes and defects in iron cofactor assembly leads to human diseases. This review describes progress towards our molecular-level understanding of cellular heme and FeeS cluster Keywords: Iron biosynthesis, focusing on the regulation and mechanistic details that are essential for understanding Heme human disorders related to the breakdown in these essential pathways. FeeS clusters © 2016 Elsevier Inc. All rights reserved. Fe homeostasis Fe-cofactor biosynthesis Contents 1. The role of iron in biology . ........................ 61 2. Heme cofactors . ........................ 61 2.1. Introduction . ...................................................61 2.2. Heme structure and types of heme in nature . .......................................61 2.3. Heme biosynthesis pathway . ...........................................61 2.3.1. Important steps in heme biosynthesis . ........................................62 2.3.2. Regulation of heme biosynthesis . .......................................63 2.4. Incorporation of heme into apoprotein recipients . ......................................64 2.5. Heme function . ...................................................65 2.6. Diseases of heme synthesis . ...........................................67 2.6.1. Porphyrias . ...........................................67 2.6.2. Additional diseases . ...........................................67 3. FeeSclusters................................................................ .............................. ........................ 68 3.1. Introduction . ...................................................68 3.2. FeeS cluster structure . ...........................................68 3.3. General FeeS cluster biogenesis pathways . .......................................68 3.3.1. Iron sulfur cluster (ISC) pathway . .......................................68 3.3.2. Cytosolic ironesulfur assembly (CIA) pathway . ............................69 3.3.3. Sulfur assimilation (SUF) pathway . .......................................69 * Corresponding author. Department of Pharmaceutical Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201. E-mail address: [email protected] (T.L. Stemmler). 1 Authors contributed equally to the writing of this manuscript. http://dx.doi.org/10.1016/j.abb.2016.01.010 0003-9861/© 2016 Elsevier Inc. All rights reserved. D.P. Barupala et al. / Archives of Biochemistry and Biophysics 592 (2016) 60e75 61 3.4. FeeS cluster biogenesis regulation . ........................71 3.5. FeeS cluster function . ........................71 3.6. FeeS clusters in human disease . .. ........................72 3.6.1. Friedreich's ataxia . ........................72 3.6.2. ISCU myopathy . ........................72 3.6.3. GLRX5 sideroblastic anemia . ........................72 3.6.4. Additional diseases . ........................72 4. Summary ................................................................. ....... ................................................. 72 Acknowledgments . ........................73 References................................................................. ................................ ........................73 1. The role of iron in biology 2. Heme cofactors Iron's abundance and unique chemical characteristics are often 2.1. Introduction exploited by nature to drive the complex chemistry required by cells to maintain life. Iron is the fourth most abundant element on Among the many metalloporphyrins found in nature, heme is the earth's crust [1], so its high prevalence during early evolution is one of the most abundant. It is utilized in many vital biological certainly a factor for its current ubiquitous presence in nature. The processes including photosynthesis, oxygen transport, biological human body contains 3e4 g of the metal and absorbs 1e2mgofit oxidation and reduction, and many more. Most of the total iron each day [2]. The reactivity and ability of the metal to cycle between content in human body is incorporated into heme-containing the Fe(II), (III) and (IV) oxidation states makes it extremely useful proteins such as hemoglobin, myoglobin, catalases, peroxidases, for driving intricate reactions in biology that include substrate nitric oxide synthases, and cytochromes [9]. The unique structure activation, electron transfer, and oxidationereduction reactions. of heme, which consists of the iron cation coordinated to four ni- Because of this chemical versatility, iron plays a role in nearly every trogen atoms from a tetrapyrrole ring, allows for fine tuning of the biological pathway. While its utility within biology is apparent, the metal's reactivity to carry out the function of the biomolecule to Achilles heel of this essential metal is its tendency to precipitate in which it is attached. Here we discuss the different heme types, their aqueous solutions [3]. Through coordination to biomolecules, biosynthesis and regulation, their function in biology, and finally however, the solubility of the metal can be controlled and its the diseases linked to a loss of heme function. reactivity attenuated. At the elemental level, first coordination sphere ligands stabilize the solubility of the metal while at the 2.2. Heme structure and types of heme in nature same time tune its chemical properties for selective participation in only desired reactions [4]. Ligand variability in this first coordina- Modifications to the basic heme molecule allow for the diverse tion sphere helps control how the metal behaves, however at the array of heme functions found in nature. The parent heme mole- cellular level a complex network of proteins, controlled at the ge- cule, also known as heme b, protoheme IX or protoporphyrin IX, netic level, helps ensure metal availability to specific protein part- serves as the platform in each case. The tetrapyrrole unit of heme ners in the cell [5]. consists of four pyrrole units linked by four methine bridges. A Pathways related to eukaryotic iron homeostasis are shown in nitrogen atom from each pyrrole coordinates the iron atom in the Fig. 1 [6]. Iron is brought into cells either via the transferrin Fe center of the planar tetrapyrrole ring. Distortions from planarity uptake pathway or through direct membrane transporter (ex. the can be critical to heme function and reactivity (examples include DMT1 pathway) [7]. Once in the cell, imported iron can bind to hemoglobin [10] and myeloperoxidase, MPO [11]). Fifth and sixth iron regulatory proteins where it serves to control concentration, ligands to the Fe can be provided by amino acid side chains from the it can be stored within the ferritin complex, it can be exported, or apoprotein or by small inorganic molecules coordinating above and it can be incorporated as cofactors into apoprotein partners. In below the plane of the ring. Eight positions in the tetrapyrrole carry humans, the bulk of iron in the body (over 75%) is directed to- side chain modifications, particularly methyl groups on carbons 2, wards heme- [2] or FeeS cluster cofactor [8] biosynthesis. As- 7, 12, and 18, vinyl groups on carbons 3 and 8, and propionyl groups sembly of the Fe-cofactors follows highly regulated pathways that on carbons 13 and 17 (Fig. 2). Substitutions to the same carbons have evolved to safely build and load these inorganic Fe- with various other side chains create several biologically important containing cofactors into the apoprotein partners while control- heme types found in nature (Fig. 3). Heme A, B, and C are found in a ling metal reactivity. In eukaryotes, heme biosynthesis is initiated wide spectrum of organisms and take part in vital biochemical and completed within the mitochondria, while FeeS cluster as- processes such as respiration, photosynthesis and oxygen trans- sembly is controlled by separate but correlated pathways within port. The additional cofactor types (Heme D, D1, I, M, and O) are both the mitochondria and the cytosol. Iron plays a central role in species-specific and carry out highly specialized functions. Table 1 a wide array of metabolic processes, so it is not surprising that summarizes the structural features, occurrences, and known defects in cofactor assembly lead to human diseases. This review functions of each heme type. details
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