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• W2951961582 abstract "A half century ago, Max Perutz and John Kendrew determined the crystal structure of two heme-containing proteins – hemoglobin and myoglobin, respectively 1,2. These landmark discoveries created the foundation for a detailed biochemical understanding of how protein structure influences and affects its ability to bind and carry oxygen. Perutz and Kendrew were awarded the Nobel Prize in 1962. Since then, scores of hemoprotein structures have been solved, although the mechanisms and molecules responsible for assembling heme into hemoglobin (Hb) and other hemoproteins remain unknown 3.Heme is the prosthetic group of proteins that perform diverse functions such as oxygen transport (globins), xenobiotic detoxification (cytochrome P450s), oxidative metabolism (cytochrome c oxidase), gas sensing (soluble guanylate cyclases), input/regulation of the circadian clock (nuclear hormone receptor homeostasis, Rev-erb α, mPER2), microRNA processing (DGCR8), antibactericides/microbicides (myeloperoxidase), and thyroid hormone synthesis (thyroperoxidase) 4–17. Heme is also known to directly regulate processes such as cell differentiation and gene expression 18–20. Heme’s function as an acute cell-signaling molecule has been implicated by high affinity binding and inhibition of both the large-conductance calcium-dependent Slo1 BK channels and the epithelial sodium channels 21–24.Hemes are iron-coordinated porphyrins containing four pyrrole rings joined at the alpha position by four methine bridges (=CH-). The iron atom at the center of this organic ring can adopt either the ferric (Fe+3) or the ferrous (Fe+2) oxidation state. Many, though not all, naturally occurring porphyrins contain iron, and a significant portion of porphyrin-containing proteins possess heme as a prosthetic group. The most abundant heme, heme b, is found in the hemoproteins myoglobin and Hb and contains two propionate, two vinyl, and four methyl side chains (Fig. 1A). Oxidation of a methyl side chain to a formyl group and substitution of a vinyl side chain with a 17-carbon isoprenoid side chain coverts heme b to heme a, the prosthetic group of the mitochondrial enzyme cytochrome c oxidase. C-type hemoproteins such as cytochrome c and the bc1 complex contain heme c in which the two vinyl side chains of heme b are covalently attached to the protein.Figure 1The porphyrin moleculeAlthough the thermodynamically favored structure of heme is planar, hemes can assume surprisingly distorted non-planar 3-D structures within proteins 25. Analyses of more than 400 different hemoprotein crystal structures by Shelnutt and co-workers using the Normal-Coordinate Structural Decomposition program revealed nearly 70 different heme shapes or distortions 25. Of these, six shapes, named after how the heme appears in the protein, propellering, saddling, doming, ruffling, and waving in the x- or y- axis, were determined to be important for heme function (Fig. 1B). Only a small amount of energy is required to distort the heme shape. Heme distortions can affect the chelated iron spin-state as well as its absorption properties, fluorescence yields, and reduction potentials 26. More importantly, heme shapes often correlate with hemoprotein function, i.e. dissimilar proteins with “conserved” heme shapes may perform similar functions.This Review focuses on the mechanisms of heme trafficking and transport with specific emphasis on metazoans. Although current knowledge of heme transport pathways in metazoans is limited (Fig. 2), we will derive models of heme trafficking pathways based on recent findings in membrane trafficking and interorganellar transfer of metabolites. We will also draw parallels with paradigms for bacterial heme transport, which has been extensively characterized at the genetic and biochemical levels. The models are provided purely as a conceptual framework to infuse new ideas into the field and permit broad generalization of the principles of heme trafficking from single cell organisms to complex eukaryotes. Finally, we will discuss emerging model systems that are facile and genetically tractable that will permit exploration, identification, and validation of the evolutionary conservation of heme transport and trafficking pathways across metazoa.Figure 2Schematic model of intracellular heme trafficking2. Heme Synthesis2.1. OverviewAlthough the focus of this Review is the transport of porphyrins and heme, the heme biosynthesis pathway is briefly presented to provide a framework for how heme intermediates and heme might be shuttled between the well-characterized enzymes responsible for synthesizing heme. (For a comprehensive review of heme synthesis, see Ref. 27). In most metazoans, fungi, and the alpha proteobacteria, heme is synthesized via a highly conserved eight-step process known as the Shemin pathway 28,29. All eight genes in the heme synthesis pathway have been cloned, and the associated enzymes have been crystallized from a number of organisms 30. In metazoans, the first and the last three conversions take place in the mitochondria, while all remaining steps occur in the cytosol (Fig. 3A). By contrast, only the last two reactions occur in the mitochondria in the budding yeast 31,32. Though slight variations occur, heme synthesis pathways convert the universal precursor δ-aminolevulinic acid (ALA) into iron-protophorphyrin IX (heme).Figure 3Heme biosynthesis in metazoans2.2. δ-aminolevulinic acidThe first step in heme synthesis involves the condensation of glycine with succinyl- coenzyme A (succinyl-CoA), which results in the formation of δ-aminolevulinic acid (ALA). In most prokaryotes and all higher plants, ALA is synthesized via an alternative method – the glutamate C-5 pathway 33–36. In all organisms that produce heme, aminolevulinic acid synthase (ALAS) catalyzes the production of ALA. In most vertebrates, there are two isoforms of ALAS – ALAS1 and ALAS2 37–39. ALAS1 (or ALAS–N) is expressed in all tissues, while ALAS2 (or ALAS–E) is expressed only in erythroid cells 40,41. The activity of ALAS1 is downregulated by heme, but the activity of ALAS2 is not repressed by heme 42,43. Instead, the presence of iron stabilizes the ALAS2 messenger RNA (mRNA) transcript via an iron-response element in the 3′ untranslated region 44. ALAS utilizes the active form of vitamin B6, pyridoxal 5-phosphate, as a cofactor. Recently, it was demonstrated that patients with a form of autosomal recessive nonsyndromic congenital sideroblastic anemia harbored mutations in SLC25A38 45. It was postulated that, at least in erythroid cells, SLC25A38 facilitates glycine import for ALA synthesis or exchanges glycine for ALA across the mitochondrial inner membrane. How nonerythroid cells import glycine is still unanswered. Following synthesis, ALA is exported from the mitochondria by an unknown mechanism." @default.
• W2951961582 created "2019-06-27" @default.
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• W2951961582 date "2010-02-09" @default.
• W2951961582 modified "2023-09-25" @default.
• W2951961582 title "ChemInform Abstract: Trafficking of Heme and Porphyrins in Metazoa" @default.
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• W2951961582 doi "https://doi.org/10.1002/chin.201006263" @default.
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