The capacity of haem to transfer electrons, bind diatomic gases, and catalyse various biochemical reactions makes it one of the essential biomolecules on Earth and one that was likely used by the earliest forms of cellular life. Since the description of haem biosynthesis, our understanding of this multi-step pathway has been almost exclusively derived from a handful of model organisms from narrow taxonomic contexts. Recent advances in genome sequencing and functional studies of diverse and previously neglected groups have led to discoveries of alternative routes of haem biosynthesis that deviate from the 'classical' pathway. In this review, we take an evolutionarily broad approach to illuminate the remarkable diversity and adaptability of haem synthesis, from prokaryotes to eukaryotes, showing the range of strategies that organisms employ to obtain and utilise haem. In particular, the complex evolutionary histories of eukaryotes that involve multiple endosymbioses and horizontal gene transfers are reflected in the mosaic origin of numerous metabolic pathways with haem biosynthesis being a striking case. We show how different evolutionary trajectories and distinct life strategies resulted in pronounced tensions and differences in the spatial organisation of the haem biosynthesis pathway, in some cases leading to a complete loss of a haem-synthesis capacity and, rarely, even loss of a requirement for haem altogether.

Department of Biochemistry University of Cambridge Hopkins Building Tennis Court Road Cambridge CB2 1QW U K

Faculty of Sciences University of South Bohemia Branišovská České Budějovice 31 Czech Republic

Institute of Parasitology Biology Centre of the Czech Academy of Sciences Branišovská 31 České Budějovice 370 05 Czech Republic

Zobrazit více v PubMed

Akilov, O. E., Kosaka, S., O'Riordan, K. & Hassan, T. (2007). Parasiticidal effect of delta-aminolevulinic acid-based photodynamic therapy for cutaneous leishmaniasis is on direct and mediated through the killing of the host cells. Experimental Dermatology 16, 651-660.

Allen, K. D., Wegener, G. & White, R. H. (2014). Discovery of multiple modified F(430) coenzymes in methanogens and anaerobic methanotrophic archaea suggests possible new roles for F(430) in nature. Applied and Environmental Microbiology 80, 6403-6412.

Alves, J. M., Voegtly, L., Matveyev, A. V., Lara, A. M., Da Silva, F. M., Serrano, M. G., Buck, G. A., Teixeira, M. M. & Camargo, E. P. (2011). Identification and phylogenetic analysis of heme synthesis genes in trypanosomatids and their bacterial endosymbionts. PLoS One 6, e23518.

Archibald, J. M. (2009). The puzzle of plastid evolution. Current Biology 19, R81-R88.

Archibald, J. M. (2015). Endosymbiosis and eukaryotic cell evolution. Current Biology 25, R911-R921.

Arnoult, D., Tatischeff, I., Estaquier, J., Girard, M., Sureau, F., Tissier, J. P., Grodet, A., Dellinger, M., Traincard, F., Kahn, A., Ameisen, J. C. & Petit, P. X. (2001). On the evolutionary conservation of the cell death pathway: mitochondrial release of an apoptosis-inducing factor during Dictyostelium discoideum cell death. Molecular Biology of the Cell 12, 3016-3030.

Atteia, A., Van Lis, R. & Beale, S. I. (2005). Enzymes of the heme biosynthetic pathway in the nonphotosynthetic alga Polytomella sp. Eukaryotic Cell 12, 2087-2097.

Bali, S., Lawrence, A. D., Lobo, S. A., Saraiva, L. M., Golding, B. T., Palmer, D. J., Howard, M. J., Ferguson, S. J. & Warren, M. J. (2011). Molecular hijacking of siroheme for the synthesis of heme and d1 heme. Proceedings of the National Academy of Sciences of the United States of America 108, 18260-18265.

Bali, S., Palmer, D. J., Schroeder, S., Ferguson, S. J. & Warren, M. J. (2014). Recent advances in the biosynthesis of modified tetrapyrroles: the discovery of an alternative pathway for the formation of heme and heme d 1. Cellular and Molecular Life Sciences 71, 2837-2863.

Barbrook, A. C., Howe, C. J. & Purton, S. (2006). Why are plastid genomes retained in non-photosynthetic organisms? Trends in Plant Science 11, 101-108.

Bayeva, M., Khechaduri, A., Wu, R., Burke, M. A., Wasserstrom, J. A., Singh, N., Liesa, M., Shirihai, O. S., Langer, N. B., Paw, B. H. & Ardehali, H. (2013). ATP-binding cassette B10 regulates early steps of heme synthesis. Circulation Research 113, 279-287.

Bencze, K. Z., Yoon, T., Millán-Pacheco, C., Bradley, P. B., Pastor, N., Cowan, J. A. & Stemmler, T. L. (2007). Human frataxin: iron and ferrochelatase binding surface. Chemical Communications (Cambridge, England) 18, 1798-1800.

Bonfio, C., Valer, L., Scintilla, S., Shah, S., Evans, D. J., Jin, L., Szostak, J. W., Sasselov, D. D., Sutherland, J. D. & Mansy, S. S. (2017). UV-light-driven prebiotic synthesis of iron-sulfur clusters. Nature Chemistry 9, 1229-1234.

Bonifacio, A., Martins, M. O., Ribeiro, C. W., Fontenele, A. V., Carvalho, F. E., Margis-Pinheiro, M. & Silveira, J. A. (2011). Role of peroxidases in the compensation of cytosolic ascorbate peroxidase knockdown in rice plants under abiotic stress. Plant, Cell & Environment 34, 1705-1722.

Borza, T., Popescu, C. E. & Lee, R. W. (2005). Multiple metabolic roles for the nonphotosynthetic plastid of the green alga Prototheca wickerhamii. Eukaryotic Cell 4, 253-261.

Boyd, E. S., Thomas, K. M., Dai, Y., Boyd, J. M. & Outten, F. W. (2014). Interplay between oxygen and Fe-S cluster biogenesis: insights from the Suf pathway. Biochemistry 53, 5834-5847.

Bryant, D. A., Hunter, C. N. & Warren, M. J. (2020). Biosynthesis of the modified tetrapyrroles-the pigments of life. The Journal of Biological Chemistry 295, 6888-6925.

Brzezowski, P., Richter, A. S. & Grimm, B. (2015). Regulation and function of tetrapyrrole biosynthesis in plants and algae. Biochimica et Biophysica Acta 1847, 968-985.

Cabello-Donayre, M., Orrego, L. M., Herráez, E., Vargas, P., Martínez-García, M., Campos-Salinas, J., Pérez-Victoria, I., Vicente, B., Marín, J. J. G. & Pérez-Victoria, J. M. (2020). Leishmania heme uptake involves LmFLVCRb, a novel porphyrin transporter essential for the parasite. Cellular and Molecular Life Sciences: CMLS 77, 1827-1845.

Camadro, J. M., Chambon, H., Jolles, J. & Labbe, P. (1986). Purification and properties of coproporphyrinogen oxidase from the Yeast Saccharomyces cerevisiae. European Journal of Biochemistry 156, 579-587.

Castelfranco, P. A. & Jones, O. T. G. (1975). Protoheme turnover and chlorophyll synthesis in greening barley tissue. Plant Physiology 55, 485-490.

Cavallaro, G., Decaria, L. & Rosato, A. (2008). Genome-based analysis of heme biosynthesis and uptake in prokaryotic systems. Journal of Proteome Research 7, 4946-4954.

Celis, A. I. & Dubois, J. L. (2015). Substrate, product, and cofactor: the extraordinarily flexible relationship between the CDE superfamily and heme. Archives of Biochemistry and Biophysics 574, 3-17.

Cenci, U., Moog, D., Curtis, B. A., Tanifuji, G., Eme, L., Lukeš, J. & Archibald, J. M. (2016). Heme pathway evolution in kinetoplastid protists. BMC Evolutionary Biology 16, 109.

Chelikani, P., Fita, I. & Loewen, P. C. (2004). Diversity of structures and properties among catalases. Cellular and Molecular Life Sciences: CMLS 61, 192-208.

Chen, H., Ikeda-Saito, M. & Shaik, S. (2008). Nature of the Fe-O2 bonding in oxy-myoglobin: effect of the protein. Journal of the American Chemical Society 130, 14778-14790.

Chen, W., Dailey, H. A. & Paw, B. H. (2010). Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis. Blood 116, 628-630.

Chen, W., Paradkar, P. N., Li, L., Pierce, E. L., Langer, N. B., Takahashi-Makise, N., Hyde, B. B., Shirihai, O. S., Ward, D. M., Kaplan, J. & Paw, B. H. (2009). Abcb10 physically interacts with mitoferrin-1 (Slc25a37) to enhance its stability and function in the erythroid mitochondria. Proceedings of the National Academy of Sciences of the United States of America 106, 16263-16268.

Choby, J. E. & Skaar, E. P. (2016). Heme synthesis and acquisition in bacterial pathogens. Journal of Molecular Biology 428, 3408-3428.

Chow, K. S., Singh, D. P., Roper, J. M. & Smith, A. G. (1997). A single precursor protein for ferrochelatase-I from Arabidopsis is imported in vitro into both chloroplasts and mitochondria. The Journal of Biological Chemistry 272, 27565-27571.

Chow, K. S., Singh, D. P., Walker, A. R. & Smith, A. G. (1998). Two different genes encode ferrochelatase in Arabidopsis: mapping, expression and subcellular targeting of the precursor proteins. The Plant Journal 15, 531-541.

Cihlář, J., Füssy, Z., Horák, A. & Oborník, M. (2016). Evolution of the tetrapyrrole biosynthetic pathway in secondary algae: conservation, redundancy and replacement. PLoS One 11, e0166338.

Cihlář, J., Füssy, Z. & Oborník, M. (2019). Evolution of tetrapyrrole pathway in eukaryotic phototrophs. Advances in Botanical Research 90, 273-309.

Collin, F. (2019). Chemical basis of reactive oxygen species reactivity and involvement in neurodegenerative diseases. International Journal of Molecular Sciences 20, E2407.

Cornah, J. E., Roper, J. M., Pal Singh, D. & Smith, A. G. (2002). Measurement of ferrochelatase activity using a novel assay suggests that plastids are the major site of haem biosynthesis in both photosynthetic and nonphotosynthetic cells of pea (Pisum sativum L.). The Biochemical Journal 362, 423-432.

Corradi, N., Pombert, J. F., Farinelli, L., Didier, E. S. & Keeling, P. J. (2010). The complete sequence of the smallest known nuclear genome from the microsporidian Encephalitozoon intestinalis. Nature Communications 1, 77.

Czarnecki, O. & Grimm, B. (2012). Post-translational control of tetrapyrrole biosynthesis in plants, algae, and cyanobacteria. Journal of Experimental Botany 63, 1675-1687.

Dailey, H. A., Dailey, T. A., Gerdes, S., Jahn, D., Jahn, M., O'brian, M. R. & Warren, M. J. (2017). Prokaryotic heme biosynthesis: multiple pathways to a common essential product. Microbiology and Molecular Biology Reviews 81, e00048-e00016.

Dailey, H. A., Dailey, T. A., Wu, C. K., Medlock, A. E., Wang, K. F., Rose, J. P. & Wang, B. C. (2000). Ferrochelatase at the millennium: structures, mechanisms and [2Fe-2S] clusters. Cellular and Molecular Life Sciences: CMLS 57, 1909-1926.

Dailey, H. A. & Gerdes, S. (2015). HemQ: an iron-coproporphyrin oxidative decarboxylase for protoheme synthesis in Firmicutes and Actinobacteria. Archives of Biochemistry and Biophysics 574, 27-35.

Dailey, H. A., Gerdes, S., Dailey, T. A., Burch, J. S. & Phillips, J. D. (2015). Noncanonical coproporphyrin-dependent bacterial heme biosynthesis pathway that does not use protoporphyrin. Proceedings of the National Academy of Sciences of the United States of America 112, 2210-2215.

Dailey, T. A., Boynton, T. O., Albetel, A. N., Gerdes, S., Johnson, M. K. & Dailey, H. A. (2010). Discovery and characterization of HemQ: an essential heme biosynthetic pathway component. The Journal of Biological Chemistry 285, 25978-25986.

Dailey, T. A., Woodruff, J. H. & Dailey, H. A. (2005). Examination of mitochondrial protein targeting of haem synthetic enzymes: in vivo identification of three functional haem-responsive motifs in 5-aminolevulinate synthase. The Biochemical Journal 386, 381-386.

De Koning, A. P. & Keeling, P. J. (2004). Nucleus-encoded genes for plastid-targeted proteins in Helicosporidium: functional diversity of a cryptic plastid in a parasitic alga. Eukaryotic Cell 5, 1198-1205.

De La Rosa, M. A., Navarro, J. A., Díaz-Quintana, A., De La Cerda, B., Molina-Heredia, F. P., Balme, A., Murdoch Pdel, S., Díaz-Moreno, I., Durán, R. V. & Hervás, M. (2002). An evolutionary analysis of the reaction mechanisms of photosystem I reduction by cytochrome c 6 and plastocyanin. Bioelectrochemistry 55, 41-45.

De Souza, W. & Motta, M. C. (1999). Endosymbiosis in protozoa of the Trypanosomatidae family. FEMS Microbiology Letters 173, 1-8.

Desmond, E. & Gribaldo, S. (2009). Phylogenomics of sterol synthesis: insights into the origin, evolution, and diversity of a key eukaryotic feature. Genome Biology and Evolution 1, 364-381.

Domergue, F., Spiekermann, P., Lerchl, J., Beckmann, C., Kilian, O., Kroth, P. G., Boland, W., Zähringer, U. & Heinz, E. (2003). New insight into Phaeodactylum tricornutum fatty acid metabolism. Cloning and functional characterization of plastidial and microsomal delta12-fatty acid desaturases. Plant Physiology 131, 1648-1660.

Ducluzeau, A. L. & Nitschke, W. (2016). When did hemes enter the scene of life? On the natural history of heme cofactors and heme-containing enzymes. In Cytochrome Complexes: Evolution, Structures, Energy Transduction, and Signaling. Advances in Photosynthesis and Respiration (Volume 41, eds W. A. Cramer and T. Kallas), pp. 13-24. Springer, Dordrecht.

Elder, G. H. & Evans, J. O. (1978). Evidence that the coproporphyrinogen oxidase activity of rat liver is situated in the intermembrane space of mitochondria. The Biochemical Journal 172, 345-347.

Espinas, N. A., Kobayashi, K., Sato, Y., Mochizuki, N., Takahashi, K., Tanaka, R. & Masuda, T. (2016). Allocation of heme is differentially regulated by ferrochelatase isoforms in Arabidopsis cells. Frontiers in Plant Science 7, 1326.

Ettwig, K. F., Speth, D. R., Reimann, J., Wu, M. L., Jetten, M. S. & Keltjens, J. T. (2012). Bacterial oxygen production in the dark. Frontiers in Microbiology 3, 273.

Ferreira, G. C., Andrew, T. L., Karr, S. W. & Dailey, H. A. (1988). Organization of the terminal two enzymes of the haem biosynthetic pathway: orientation of protoporphyrinogen oxidase and evidence for a membrane complex. The Journal of Biological Chemistry 263, 3835-3839.

Flegontova, O., Flegontov, P., Malviya, S., Audic, S., Wincker, P., De Vargas, C., Bowler, C., Lukeš, J. & Horák, A. (2016). Extreme diversity of diplonemid eukaryotes in the ocean. Current Biology 26, 3060-3065.

Foster, J., Ganatra, M., Kamal, I., Ware, J., Makarova, K., Ivanova, N., Bhattacharyya, A., Kapatral, V., Kumar, S., Posfai, J., Vincze, T., Ingram, J., Moran, L., Lapidus, A., Omelchenko, M., et al. (2005). The Wolbachia genome of Brugia malayi: endosymbiont evolution within a human pathogenic nematode. PLoS Biology 3, e121.

Francklyn, C. S. & Minajigi, A. (2010). tRNA as an active chemical scaffold for diverse chemical transformations. FEBS Letters 584, 366-375.

Fritz-Laylin, L. K., Prochnik, S. E., Ginger, M. L., Dacks, J. B., Carpenter, M. L., Field, M. C., Kuo, A., Paredez, A., Chapman, J., Pham, J., Shu, S., Neupane, R., Cipriano, M., Mancuso, J., Tu, H., et al. (2010). The genome of Naegleria gruberi illuminates early eukaryotic versatility. Cell 140, 631-642.

Füssy, Z., Faitová, T. & Oborník, M. (2019). Subcellular compartments interplay for carbon and nitrogen allocation in Chromera velia and Vitrella brassicaformis. Genome Biology and Evolution 11, 1765-1779.

Füssy, Z. & Oborník, M. (2017). Chromerids and their plastids. Advances in Botanical Research 84, 187-218.

Füssy, Z. & Oborník, M. (2018). Complex endosymbioses I: from primary to complex plastids, multiple independent events. In Methods in Molecular Biology (Volume 1829, ed. E. Maréchal), pp. 17-35. Humana Press, New York.

Füssy, Z., Záhonová, K., Tomčala, A., Krajčovič, J., Yurchenko, V., Oborník, M. & Eliáš, M. (2020). The cryptic plastid of Euglena longa defines a new type of nonphotosynthetic plastid organelle. mSphere 5, e00675-e00620.

Gachotte, D., Pierson, C. A., Lees, N. D., Barbuch, R., Koegel, C. & Bard, M. (1997). A yeast sterol auxotroph (erg25) is rescued by addition of azole antifungals and reduced levels of heme. Proceedings of the National Academy of Sciences of the United States of America 94, 11173-11178.

Gawryluk, R. M. R., Tikhonenkov, D. V., Hehenberger, E., Husnik, F., Mylnikov, A. P. & Keeling, P. J. (2019). Non-photosynthetic predators are sister to red algae. Nature 572, 240-243.

Gornik, S. G., Febrimarsa, Cassin, A. M., Macrae, J. I., Ramaprasad, A., Rchiad, Z., Mcconville, M. J., Bacic, A., Mcfadden, G. I., Pain, A. & Waller, R. F. (2015). Endosymbiosis undone by stepwise elimination of the plastid in a parasitic dinoflagellate. Proceedings of the National Academy of Sciences of the United States of America 112, 5767-5772.

Gould, S. B., Waller, R. F. & Mcfadden, G. I. (2008). Plastid evolution. Annual Review of Plant Biology 59, 491-517.

Gumsley, A. P., Chamberlain, K. R., Bleeker, W., Söderlund, U., De Kock, M. O., Larsson, E. R. & Bekker, A. (2017). Timing and tempo of the Great Oxidation Event. Proceedings of the National Academy of Sciences of the United States of America 114, 1811-1816.

Guo, M. & Chen, Y. (2018). Coenzyme cobalamin: biosynthesis, overproduction and its application in dehalogenation-a review. Reviews in Environmental Science and Bio-technology 17, 259-284.

Hadariová, L., Vesteg, M., Hampl, V. & Krajčovič, J. (2018). Reductive evolution of chloroplasts in non-photosynthetic plants, algae and protists. Current Genetics 64, 365-387.

Hampl, V., Čepička, I. & Eliáš, M. (2019). Was the mitochondrion necessary to start eukaryogenesis? Trends in Microbiology 27, 96-104.

Hamza, I. & Dailey, H. A. (2012). One ring to rule them all: trafficking of heme and heme synthesis intermediates in the metazoans. Biochimica et Biophysica Acta 1823, 1617-1632.

Hansson, M. & Hederstedt, L. (1994). Bacillus subtilis HemY is a peripheral membrane protein essential for protoheme IX synthesis which can oxidize coproporphyrinogen III and protoporphyrinogen IX. Journal of Bacteriology 176, 5962-5970.

Hardison, R. (1998). Hemoglobins from bacteria to man: evolution of different patterns of gene expression. The Journal of Experimental Biology 8, 1099-1117.

Haskamp, V., Karrie, S., Mingers, T., Barthels, S., Alberge, F., Magalon, A., Müller, K., Bill, E., Lubitz, W., Kleeberg, K., Schweyen, P., Bröring, M., Jahn, M. & Jahn, D. (2018). The radical SAM protein HemW is a heme chaperone. Journal of Biological Chemistry 293, 2558-2572.

He, Y., Alam, S. L., Proteasa, S. V., Zhang, Y., Lesuisse, E., Dancis, A. & Stemmler, T. L. (2004). Yeast frataxin solution structure, iron binding, and ferrochelatase interaction. Biochemistry 43, 16254-16262.

Hehenberger, E., Imanian, B., Burki, F. & Keeling, P. J. (2014). Evidence for the retention of two evolutionary distinct plastids in dinoflagellates with diatom endosymbionts. Genome Biology and Evolution 6, 2321-2334.

Heinemann, I. U., Jahn, M. & Jahn, D. (2008). The biochemistry of heme biosynthesis. Archives of Biochemistry and Biophysics 474, 238-251.

Hey, D., Ortega-Rodes, P., Fan, T., Schnurrer, F., Brings, L., Hedtke, B. & Grimm, B. (2016). Transgenic tobacco lines expressing sense or antisense ferrochelatase 1 RNA show modified ferrochelatase activity in roots and provide experimental evidence for dual localization of ferrochelatase 1. Plant & Cell Physiology 57, 2576-2585.

Hofbauer, S., Gysel, K., Bellei, M., Hagmüller, A., Schaffner, I., Mlynek, G., Kostan, J., Pirker, K. F., Daims, H., Furtmüller, P. G., Battistuzzi, G., Djinović-Carugo, K. & Obinger, C. (2014). Manipulating conserved heme cavity residues of chlorite dismutase: effect on structure, redox chemistry, and reactivity. Biochemistry 53, 77-89.

Holliday, G. L., Akiva, E., Meng, E. C., Brown, S. D., Calhoun, S., Pieper, U., Sali, A., Booker, S. J. & Babbitt, P. C. (2018). Atlas of the radical SAM superfamily: divergent evolution of function using a "Plug and Play" domain. Methods in Enzymology 606, 1-71.

Holliday, G. L., Thornton, J. M., Marquet, A., Smith, A. G., Rébeillé, F., Mendel, R., Schubert, H. L., Lawrence, A. D. & Warren, M. J. (2007). Evolution of enzymes and pathways for the biosynthesis of cofactors. Natural Product Reports 24, 972-987.

Horáková, E., Changmai, P., Paris, Z., Salmon, D. & Lukeš, J. (2015). Simultaneous depletion of Atm and Mdl rebalances cytosolic Fe-S cluster assembly but not heme import into the mitochondrion of Trypanosoma brucei. The FEBS Journal 282, 4157-4175.

Horáková, E., Changmai, P., Vancová, M., Sobotka, R., Van Den Abbeele, J., Vanhollebeke, B. & Lukeš, J. (2017). The Trypanosoma brucei TbHrg protein is a heme transporter involved in the regulation of stage-specific morphological transitions. The Journal of Biological Chemistry 292, 6998-7010.

Hou, S., Reynolds, M. F., Horrigan, F. T., Heinemann, S. H. & Hoshi, T. (2006). Reversible binding of heme to proteins in cellular signal transduction. Accounts of Chemical Research 39, 918-924.

Hug, L. A., Baker, B. J., Anantharaman, K., Brown, C. T., Probst, A. J., Castelle, C. J., Butterfield, C. N., Hernsdorf, A. W., Amano, Y., Ise, K., Suzuki, Y., Dudek, N., Relman, D. A., Finstad, K. M., Amundson, R., et al. (2016). A new view of the tree of life. Nature Microbiology 1, 16048.

Hunt, R. D. (2006). Radical S-adenosyl methionine domain containing-1 (rsad1): a novel gene essential for cell survival during vertebrate development. Texas Medical Center Dissertations (via ProQuest). Paper AAI3328246.

Ilbert, M. & Bonnefoy, V. (2013). Insight into the evolution of the iron oxidation pathways. Biochimica et Biophysica Acta 1827, 161-175.

Imlay, J. A. (2006). Iron-sulphur clusters and the problem with oxygen. Molecular Microbiology 59, 1073-1082.

Iovieno, A., Ledee, D. R., Miller, D. & Alfonso, E. C. (2010). Detection of bacterial endosymbionts in clinical acanthamoeba isolates. Ophthalmology 117, 445-452.

Jabłońska, J. & Tawfik, D. S. (2021). The evolution of oxygen-utilizing enzymes suggests early biosphere oxygenation. Nature Ecology & Evolution 5, 442-448.

Jahn, D., Verkamp, E. & Söll, D. (1992). Glutamyl-transfer RNA: a precursor of heme and chlorophyll biosynthesis. Trends in Biochemical Sciences 17, 215-218.

Janouškovec, J., Gavelis, G. S., Burki, F., Dinh, D., Bachvaroff, T. R., Gornik, S. G., Bright, K. J., Imanian, B., Strom, S. L., Delwiche, C. F., Waller, R. F., Fensome, R. A., Leander, B. S., Rohwer, F. L. & Saldarriaga, J. F. (2017). Major transitions in dinoflagellate evolution unveiled by phylotranscriptomics. Proceedings of the National Academy of Sciences of the United States of America 114, E171-E180.

Janouškovec, J., Paskerova, G. G., Miroliubova, T. S., Mikhailov, K. V., Birley, T., Aleoshin, V. V. & Simdyanov, T. G. (2019). Apicomplexan-like parasites are polyphyletic and widely but selectively dependent on cryptic plastid organelles. eLife 8, e49662.

Jun, S. R., Sims, G. E., Wu, G. A. & Kim, S. H. (2010). Whole-proteome phylogeny of prokaryotes by feature frequency profiles: an alignment-free method with optimal feature resolution. Proceedings of the National Academy of Sciences of the United States of America 107, 133-138.

Kalanon, M. & Mcfadden, G. I. (2010). Malaria, Plasmodium falciparum and its apicoplast. Biochemical Society Transactions 38, 775-782.

Kachroo, A. H., Laurent, J. M., Akhmetov, A., Szilagyi-Jones, M., Mcwhite, C. D., Zhao, A. & Marcotte, E. M. (2017). Systematic bacterialization of yeast genes identifies a near-universally swappable pathway. eLife 6, e25093.

Karnkowska, A., Vacek, V., Zubáčová, Z., Treitli, S. C., Petrželková, R., Eme, L., Novák, L., Žárský, V., Barlow, L. D., Herman, E. K., Soukal, P., Hroudová, M., Doležal, P., Stairs, C. W., Roger, A. J., et al. (2016). A eukaryote without a mitochondrial organelle. Current Biology 23, 1274-1284.

Karunadharma, P. P., Basisty, N., Chiao, Y. A., Dai, D. F., Drake, R., Levy, N., Koh, W. J., Emond, M. J., Kruse, S., Marcinek, D., Maccoss, M. J. & Rabinovitch, P. S. (2015). Respiratory chain protein turnover rates in mice are highly heterogeneous but strikingly conserved across tissues, ages, and treatments. FASEB Journal 29, 3582-3592.

Katinka, M. D., Duprat, S., Cornillot, E., Méténier, G., Thomarat, F., Prensier, G., Barbe, V., Peyretaillade, E., Brottier, P., Wincker, P., Delbac, F., El Alaoui, H., Peyret, P., Saurin, W., Gouy, M., et al. (2001). Genome sequence and gene compaction of the eukaryote parasite Encephalitozoon cuniculi. Nature 414, 450-453.

Katz, A., Elgamal, S., Rajkovic, A. & Ibba, M. (2016). Non-canonical roles of tRNAs and tRNA mimics in bacterial cell biology. Molecular Microbiology 101, 545-558.

Kayama, M., Maciszewski, K., Yabuki, A., Miyashita, H., Karnkowska, A. & Kamikawa, R. (2020). Highly reduced plastid genomes of the non-photosynthetic dictyochophyceans Pteridomonas spp. (Ochrophyta, SAR) are retained for tRNA-Glu-based organellar heme biosynthesis. Frontiers in Plant Science 11, 602455.

Ke, H., Sigala, P. A., Miura, K., Morrisey, J. M., Mather, M. W., Crowley, J. R., Henderson, J. P., Goldberg, D. E., Long, C. A. & Vaidya, A. N. (2014). The heme biosynthesis pathway is essential for Plasmodium falciparum in mosquito stage but not in blood stages. The Journal of Biological Chemistry 289, 34827-34837.

Keeling, P. J., Burki, F., Wilcox, H. M., Allam, B., Allen, E. E., Amaral-Zettler, L. A., Armbrust, E. V., Archibald, J. M., Bharti, A. K., Bell, C. J., Beszteri, B., Bidle, K. D., Cameron, C. T., Campbell, L., Caron, D. A., et al. (2014). The Marine Microbial Eukaryote Transcriptome Sequencing Project (MMETSP): illuminating the functional diversity of eukaryotic life in the oceans through transcriptome sequencing. PLoS Biology 12, e1001889.

Khan, A. A. & Quigley, J. G. (2011). Control of intracellular heme levels: heme transporters and heme oxygenases. Biochimica et Biophysica Acta 1813, 668-682.

Kleine, T., Maier, U. G. & Leister, D. (2009). DNA transfer from organelles to the nucleus: the idiosyncratic genetics of endosymbiosis. Annual Review of Plant Biology 60, 115-138.

Kobayashi, K., Masuda, T., Tajima, N., Wada, H. & Sato, N. (2014). Molecular phylogeny and intricate evolutionary history of the three isofunctional enzymes involved in the oxidation of protoporphyrinogen IX. Genome Biology and Evolution 6, 2141-2155.

Kolluri, S., Sadlon, T. J., May, B. K. & Bonkovsky, H. L. (2005). Haem repression of the housekeeping 5-aminolaevulinic acid synthase gene in the hepatoma cell line LMH. The Biochemical Journal 392, 173-180.

Kořený, L., Lukeš, J. & Oborník, M. (2010). Evolution of the haem synthetic pathway in kinetoplastid flagellates: an essential pathway that is not essential after all? International Journal for Parasitology 40, 149-156.

Kořený, L. & Oborník, M. (2011). Sequence evidence for the presence of two tetrapyrrole pathways in Euglena gracilis. Genome Biology and Evolution 3, 359-364.

Kořený, L., Oborník, M. & Lukeš, J. (2013). Make it, take it, or leave it: heme metabolism of parasites. PLoS Pathogens 9, e1003088.

Kořený, L., Sobotka, R., Janouškovec, J., Keeling, P. J. & Oborník, M. (2011). Tetrapyrrole synthesis of photosynthetic chromerids is likely homologous to the unusual pathway of apicomplexan parasites. The Plant Cell 23, 3454-3462.

Kořený, L., Sobotka, R., Kovářová, J., Gnipová, A., Flegontov, P., Horváth, A., Oborník, M., Ayala, F. J. & Lukeš, J. (2012). Aerobic kinetoplastid flagellate Phytomonas does not require heme for viability. Proceedings of the National Academy of Sciences of the United States of America 109, 3808-3813.

Kraeva, N., Horáková, E., Kostygov, A. Y., Kořený, L., Butenko, A., Yurchenko, V. & Lukeš, J. (2017). Catalase in Leishmaniinae: with me or against me? Infection, Genetics and Evolution 50, 121-127.

Krishnamurthy, P. C., Du, G., Fukuda, Y., Sun, D., Sampath, J., Mercer, K. E., Wang, J., Sosa-Pineda, B., Murti, K. G. & Schuetz, J. D. (2006). Identification of a mammalian mitochondrial porphyrin transporter. Nature 443, 586-589.

Kumar, S. & Bandyopadhyay, U. (2005). Free heme toxicity and its detoxification systems in human. Toxicology Letters 157, 175-188.

Lakey, B. & Triemer, R. (2017). The tetrapyrrole synthesis pathway as a model of horizontal gene transfer in euglenoids. Journal of Phycology 53, 198-217.

Lamb, D. C., Cannieux, M., Warrilow, A. G., Bak, S., Kahn, R. A., Manning, N. J., Kelly, D. E. & Kelly, S. L. (2001). Plant sterol 14 alpha-demethylase affinity for azole fungicides. Biochemical and Biophysical Research Communications 284, 845-849.

Lane, N. (2014). Bioenergetic constraints on the evolution of complex life. Cold Spring Harbor Perspectives in Biology 6, a015982.

Lane, N. & Martin, W. F. (2010). The energetics of genome complexity. Nature 467, 929-934.

Lane, N. & Martin, W. F. (2012). The origin of membrane bioenergetics. Cell 151, 1406-1416.

Lang, J. M., Darling, A. E. & Eisen, J. A. (2013). Phylogeny of bacterial and archaeal genomes using conserved genes: supertrees and supermatrices. PLoS One 8, e62510.

Lara, F. A., Lins, U., Bechara, G. H. & Oliveira, P. L. (2005). Tracing heme in a living cell: hemoglobin degradation and heme traffic in digest cells of the cattle tick Boophilus microplus. The Journal of Experimental Biology 208, 3093-3101.

Laranjeira-Silva, M. F., Hamza, I. & Pérez-Victoria, J. M. (2020). Iron and heme metabolism at the Leishmania-host interface. Trends in Parasitology 36, 279-289.

Layer, G., Reichelt, J., Jahn, D. & Heinz, D. W. (2010). Structure and function of enzymes in heme biosynthesis. Protein Science 19, 1137-1161.

Lepesheva, G. I., Ott, R. D., Hargrove, T. Y., Kleshchenko, Y. Y., Schuster, I., Nes, W. D., Hill, G. C., Villalta, F. & Waterman, M. R. (2007). Sterol 14alpha-demethylase as a potential target for antitrypanosomal therapy: enzyme inhibition and parasite cell growth. Chemistry & Biology 14, 1283-1293.

Lepesheva, G. I. & Waterman, M. R. (2007). Sterol 14alpha-demethylase cytochrome P450 (CYP51), a P450 in all biological kingdoms. Biochimica et Biophysica Acta 1770, 467-477.

Lermontova, I., Kruse, E., Mock, H. P. & Grimm, B. (1997). Cloning and characterization of a plastidal and a mitochondrial isoform of tobacco protoporphyrinogen IX oxidase. Proceedings of the National Academy of Sciences of the United States of America 94, 8895-8900.

Lhee, D., Ha, J. S., Kim, S., Park, M. G., Bhattacharya, D. & Yoon, H. S. (2019). Evolutionary dynamics of the chromatophore genome in three photosynthetic Paulinella species. Scientific Reports 9, 2560.

Lill, R. (2009). Function and biogenesis of iron-sulphur proteins. Nature 460, 831-838.

Lindsey, J. S., Ptaszek, M. & Taniguchi, M. (2009). Simple formation of an abiotic porphyrinogen in aqueous solution. Origins of Life and Evolution of the Biosphere 39, 495-515.

Lister, R., Chew, O., Rudhe, C., Lee, M. N. & Whelan, J. (2001). Arabidopsis thaliana ferrochelatase-I and -II are not imported into Arabidopsis mitochondria. FEBS Letters 506, 291-295.

Liu, J., Chakraborty, S., Hosseinzadeh, P., Yu, Y., Tian, S., Petrik, I., Bhagi, A. & Lu, Y. (2014). Metalloproteins containing cytochrome, iron-sulfur, or copper redox centers. Chemical Reviews 114, 4366-4469.

Lunetti, P., Damiano, F., De Benedetto, G., Siculella, L., Pennetta, A., Muto, L., Paradies, E., Marobbio, C. M., Dolce, V. & Capobianco, L. (2016). Characterization of human and yeast mitochondrial glycine carriers with implications for heme biosynthesis and anemia. The Journal of Biological Chemistry 291, 19746-19759.

Maio, N., Kim, K. S., Holmes-Hampton, G., Singh, A. & Rouault, T. A. (2019). Dimeric ferrochelatase bridges ABCB7 and ABCB10 homodimers in an architecturally defined molecular complex required for heme biosynthesis. Haematologica 104, 1756-1767.

Maitra, D., Bragazzi Cunha, J., Elenbaas, J. S., Bonkovsky, H. L., Shavit, J. A. & Omary, M. B. (2019). Porphyrin-induced protein oxidation and aggregation as a mechanism of porphyria-associated cell injury. Cellular and Molecular Gastroenterology and Hepatology 8, 535-548.

Marchetti, P., Hirsch, T., Zamzami, N., Castedo, M., Decaudin, D., Susin, S. A., Masse, B. & Kroemer, G. (1996). Mitochondrial permeability transition triggers lymphocyte apoptosis. Journal of Immunology 157, 4830-4836.

Maréchal, E. (2018). Primary endosymbiosis: emergence of the primary chloroplast and the chromatophore, two independent events. In Methods in Molecular Biology (Volume 1829, ed. E. Maréchal), pp. 3-16. Humana Press, New York.

Marin, B., Nowack, E. C. & Melkonian, M. (2005). A plastid in the making: evidence for a second primary endosymbiosis. Protist 156, 425-432.

Martin, W. & Russell, M. J. (2003). On the origins of cells: a hypothesis for the evolutionary transitions from abiotic geochemistry to chemoautotrophic prokaryotes, and from prokaryotes to nucleated cells. Philosophical transactions of the Royal Society of London. Series B, Biological Sciences 358, 59-83.

Martin, W. F., Sousa, F. L. & Lane, N. (2014). Energy at life's origin. Science 344, 1092-1093.

Martinez, M., Fendley, G. A., Saxberg, A. D. & Zoghbi, M. E. (2020). Stimulation of the human mitochondrial transporter ABCB10 by zinc-mesoporphyrin. PLoS One 15, e0238754.

Masuda, T., Suzuki, T., Shimada, H., Ohta, H. & Takamiya, K. (2003). Subcellular localization of two types of ferrochelatase in cucumber. Planta 217, 602-609.

Matsumoto, T., Shinozaki, F., Chikuni, T., Yabuki, A., Takishita, K., Kawachi, M., Nakayama, T., Inouye, I., Hashimoto, T. & Inagaki, Y. (2011). Green-colored plastids in the dinoflagellate genus Lepidodinium are of core chlorophyte origin. Protist 162, 268-276.

Mathur, V., Kolísko, M., Hehenberger, E., Irwin, N., Leander, B. S., Kristmundsson, Á., Freeman, M. A. & Keeling, P. J. (2019). Multiple independent origins of apicomplexan-like parasites. Current Biology 29, 2936-2941.

Medlock, A. E., Shiferaw, M. T., Marcero, J. R., Vashisht, A. A., Wohlschlegel, J. A., Phillips, J. D. & Dailey, H. A. (2015). Identification of the mitochondrial heme metabolism complex. PLoS One 10, e0135896.

Merli, M. L., Pagura, L., Hernández, J., Barisón, M. J., Pral, E. M., Silber, A. M. & Cricco, J. A. (2016). The Trypanosoma cruzi Protein TcHTE is critical for heme uptake. PLoS Neglected Tropical Diseases 10, e0004359.

Michel, R., Müller, K. D., Hauröder, B. & Zöller, L. (2000). A coccoid bacterial parasite of Naegleria sp. (Schizopyrenida: Vahlkampfiidae) inhibits cyst formation of its host but not transformation to the flagellate stage. Acta Protozoologica 39, 199-207.

Miyagishima, S., Kuroiwa, H. & Kuroiwa, T. (2001). The timing and manner of disassembly of the apparatuses for chloroplast and mitochondrial division in the red alga Cyanidioschyzon merolae. Planta 212, 517-528.

Molina, J., Hazzouri, K. M., Nickrent, D., Geisler, M., Meyer, R. S., Pentony, M. M., Flowers, J. M., Pelser, P., Barcelona, J., Inovejas, S. A., Uy, I., Yuan, W., Wilkins, O., Michel, C. I., Locklear, S., et al. (2014). Possible loss of the chloroplast genome in the parasitic flowering plant Rafflesia lagascae (Rafflesiaceae). Molecular Biology and Evolution 31, 793-803.

Montfort, W. R., Wales, J. A. & Weichsel, A. (2017). Structure and activation of soluble guanylyl cyclase, the nitric oxide sensor. Antioxidants & Redox Signaling 26, 107-121.

Moore, S. J., Sowa, S. T., Schuchardt, C., Deery, E., Lawrence, A. D., Ramos, J. V., Billig, S., Birkemeyer, C., Chivers, P. T., Howard, M. J., Rigby, S. E., Layer, G. & Warren, M. J. (2017). Elucidation of the biosynthesis of the methane catalyst coenzyme F430. Nature 543, 78-82.

Moulin, M. & Smith, A. G. (2005). Regulation of tetrapyrrole biosynthesis in higher plants. Biochemical Society Transactions 33, 737-742.

Nagaraj, V. A., Arumugam, R., Chandra, N. R., Prasad, D., Rangarajan, P. N. & Padmanaban, G. (2009a). Localisation of Plasmodium falciparum uroporphyrinogen III decarboxylase of the heme-biosynthesis pathway in the apicoplast and characterisation of its catalytic properties. International Journal for Parasitology 39, 559-568.

Nagaraj, V. A., Arumugam, R., Prasad, D., Rangarajan, P. N. & Padmanaban, G. (2010a). Protoporphyrinogen IX oxidase from Plasmodium falciparum is anaerobic and is localized to the mitochondrion. Molecular and Biochemical Parasitology 174, 44-52.

Nagaraj, V. A., Prasad, D., Arumugam, R., Rangarajan, P. N. & Padmanaban, G. (2010b). Characterization of coproporphyrinogen III oxidase in Plasmodium falciparum cytosol. Parasitology International 59, 121-127.

Nagaraj, V. A., Prasad, D., Rangarajan, P. N. & Padmanaban, G. (2009b). Mitochondrial localization of functional ferrochelatase from Plasmodium falciparum. Molecular and Biochemical Parasitology 168, 109-112.

Narita, S., Tanaka, R., Ito, T., Okada, K., Taketani, S. & Inokuchi, H. (1996). Molecular cloning and characterization of a cDNA that encodes protoporphyrinogen oxidase of Arabidopsis thaliana. Gene 182, 169-175.

Ng, S. M., Lee, X. W., Mat-Isa, M. N., Aizat-Juhari, M. A., Adam, J. H., Mohamed, R., Wan, K. L. & Firdaus-Raih, M. (2018). Comparative analysis of nucleus-encoded plastid-targeting proteins in Rafflesia cantleyi against photosynthetic and non-photosynthetic representatives reveals orthologous systems with potentially divergent functions. Scientific Reports 8, 17258.

Nowack, E. C., Melkonian, M. & Glöckner, G. (2008). Chromatophore genome sequence of Paulinella sheds light on acquisition of photosynthesis by eukaryotes. Current Biology 18, 410-418.

Nowack, E. C., Price, D. C., Bhattacharya, D., Singer, A., Melkonian, M. & Grossman, A. R. (2016). Gene transfers from diverse bacteria compensate for reductive genome evolution in the chromatophore of Paulinella chromatophora. Proceedings of the National Academy of Sciences of the United States of America 113, 12214-12219.

Nowack, E. & Weber, A. (2018). Genomics-informed insights into endosymbiotic organelle evolution in photosynthetic eukaryotes. Annual Review of Plant Biology 69, 51-84.

Oborník, M. (2018). The birth of red complex plastids: one, three or four times? Trends in Parasitology 34, 923-925.

Oborník, M. (2019). Endosymbiotic evolution of algae, secondary heterotrophy and parasitism. Biomolecules 9, 266.

Oborník, M. (2020). Photoparasitism as an intermediate state in the evolution of apicomplexan parasites. Trends in Parasitology 36, 727-734.

Oborník, M. (2021). Enigmatic evolutionary history of porphobilinogen deaminase in eukaryotic phototrophs. Biology 10, 386.

Oborník, M. & Green, B. R. (2005). Mosaic origin of the heme biosynthesis pathway in photosynthetic eukaryotes. Molecular Biology and Evolution 22, 2343-2353.

Oliver, T., Sánchez-Baracaldo, P., Larkum, A. W., Rutherford, A. W. & Cardona, T. (2021). Time-resolved comparative molecular evolution of oxygenic photosynthesis. Biochimica et Biophysica Acta - Bioenergetics 1862, 148400.

Orrego, L. M., Cabello-Donayre, M., Vargas, P., Martínez-García, M., Sánchez, C., Pineda-Molina, E., Jiménez, M., Molina, R. & Pérez-Victoria, J. M. (2019). Heme synthesis through the life cycle of the heme auxotrophic parasite Leishmania major. FASEB Journal 33, 13367-13385.

Pánek, T., Eliáš, M., Vancová, M., Lukeš, J. & Hashimi, H. (2020). Returning to the fold for lessons in mitochondrial cristae diversity and evolution. Current Biology 30, R575-R588.

Papenbrock, J., Mock, H. P., Kruse, E. & Grimm, B. (1999). Expression studies in tetrapyrrole biosynthesis: inverse maxima of magnesium chelatase and ferrochelatase activity during cyclic photoperiods. Planta 208, 264-273.

Perally, S., Lacourse, E. J., Campbell, A. M. & Brophy, P. M. (2008). Heme transport and detoxification in nematodes: subproteomics evidence of differential role of glutathione transferases. Journal of Proteome Research 7, 4557-4565.

Perner, J., Gasser, R. B., Oliveira, P. L. & Kopáček, P. (2019). Haem biology in metazoan parasites - 'The bright side of haem'. Trends in Parasitology 35, 213-225.

Perner, J., Sobotka, R., Šíma, R., Konvičková, J., Sojka, D., Oliveira, P. L., Hajdušek, O. & Kopáček, P. (2016). Acquisition of exogenous haem is essential for tick reproduction. eLife 5, e12318.

Pleyer, H. L., Strasdeit, H. & Fox, S. (2018). A possible prebiotic ancestry of porphyrin-type protein cofactors. Origins of Life and Evolution of the Biosphere 48, 347-371.

Ponka, P. (1997). Tissue-specific regulation of iron metabolism and heme synthesis: distinct control mechanisms in erythroid cells. Blood 89, 1-25.

Porcel, B. M., Denoeud, F., Opperdoes, F., Noel, B., Madoui, M. A., Hammarton, T. C., Field, M. C., Da Silva, C., Couloux, A., Poulain, J., Katinka, M., Jabbari, K., Aury, J. M., Campbell, D. A., Cintron, R., et al. (2014). The streamlined genome of Phytomonas spp. relative to human pathogenic kinetoplastids reveals a parasite tailored for plants. PLoS Genetics 10, e1004007.

Pyrih, J., Harant, K., Martincová, E., Šuťák, R., Lesuisse, E., Hrdý, I. & Tachezy, J. (2014). Giardia intestinalis incorporates heme into cytosolic cytochrome b5. Eukaryotic Cell 13, 231-239.

Rafferty, S. P. & Dayer, G. (2015). Heme proteins of Giardia intestinalis. Experimental Parasitology 159, 13-23.

Rangel, H., Dagger, F., Hernandez, A., Liendo, A. & Urbina, J. A. (1996). Naturally azole-resistant Leishmania braziliensis promastigotes are rendered susceptible in the presence of terbinafine: comparative study with azole-susceptible Leishmania mexicana promastigotes. Antimicrobial Agents and Chemotherapy 40, 2785-2791.

Rao, A. U., Carta, L. K., Lesuisse, E. & Hamza, I. (2005). Lack of heme synthesis in a free-living eukaryote. Proceedings of the National Academy of Sciences of the United States of America 102, 4270-4275.

Raux, E., Schubert, H. L. & Warren, M. J. (2000). Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum. Cellular and Molecular Life Sciences 57, 1880-1893.

Rogers, M. B., Gilson, P. R., Su, V., Mcfadden, G. I. & Keeling, P. J. (2007). The complete chloroplast genome of the chlorarachniophyte Bigelowiella natans: evidence for independent origins of chlorarachniophyte and euglenid secondary endosymbionts. Molecular Biology and Evolution 24, 54-62.

Roper, J. M. & Smith, A. G. (1997). Molecular localisation of ferrochelatase in higher plant chloroplasts. European Journal of Biochemistry 246, 32-37.

Sah, J. F., Ito, H., Kolli, B. K., Peterson, D. A., Sassa, S. & Chang, K. P. (2002). Genetic rescue of Leishmania deficiency in porphyrin biosynthesis creates mutants suitable for analysis of cellular events in uroporphyria and for photodynamic therapy. The Journal of Biological Chemistry 277, 14902-14909.

Sanchez-Moreno, M., Lasztity, D., Coppens, I. & Opperdoes, F. R. (1992). Characterization of carbohydrate metabolism and demonstration of glycosomes in a Phytomonas sp. isolated from Euphorbia characias. Molecular and Biochemical Parasitology 54, 185-199.

Sato, S., Clough, B., Coates, L. & Wilson, R. J. (2004). Enzymes for heme biosynthesis are found in both the mitochondrion and plastid of the malaria parasite Plasmodium falciparum. Protist 155, 117-125.

Schenkman, J. B. & Jansson, I. (2003). The many roles of cytochrome b5. Pharmacology & Therapeutics 97, 139-152.

Schulze, J. O., Schubert, W. D., Moser, J., Jahn, D. & Heinz, D. W. (2006). Evolutionary relationship between initial enzymes of tetrapyrrole biosynthesis. Journal of Molecular Biology 358, 1212-1220.

Shanmugan, D., Wu, B., Ramirez, U., Jaffe, E. K. & Roos, D. S. (2010). Plastid-associated porphobilinogen synthase from toxoplasma gondii: kinetic and structural properties validate therapeutic potential. The Journal of Biological Chemistry 285, 22122-22131.

Shirihai, O. S., Gregory, T., Yu, C., Orkin, S. H. & Weiss, M. J. (2000). ABC-me: a novel mitochondrial transporter induced by GATA-1 during erythroid differentiation. The EMBO Journal 19, 2492-2502.

Sinclair, J. & Hamza, I. (2015). Lessons from bloodless worms: heme homeostasis in C. elegans. Biometals 28, 481-489.

Smith, D. R. & Lee, R. W. (2014). A plastid without a genome: evidence from the nonphotosynthetic green algal genus Polytomella. Plant Physiology 164, 1812-1819.

Sousa, F. L., Thiergart, T., Landan, G., Nelson-Sathi, S., Pereira, I. A., Allen, J. F., Lane, N. & Martin, W. F. (2013). Early bioenergetic evolution. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 368, 20130088.

Stairs, C. W., Leger, M. M. & Roger, A. J. (2015). Diversity and origins of anaerobic metabolism in mitochondria and related organelles. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 370, 20140326.

Suzuki, T., Masuda, T., Singh, D. P., Tan, F. C., Tsuchiya, T., Shimada, H., Ohta, H., Smith, A. G. & Takamiya, K. (2002). Two types of ferrochelatase in photosynthetic and nonphotosynthetic tissues of cucumber: their difference in phylogeny, gene expression, and localization. The Journal of Biological Chemistry 277, 4731-4737.

Swenson, S. A., Moore, C. M., Marcero, J. R., Medlock, A. E., Reddi, A. R. & Khalimonchuk, O. (2020). From synthesis to utilization: the ins and outs of mitochondrial heme. Cells 9, 579.

Tanaka, R. & Tanaka, A. (2007). Tetrapyrrole biosynthesis in higher plants. Annual Review of Plant Biology 58, 321-346.

Timmis, J. N., Ayliffe, M. A., Huang, C. Y. & Martin, W. (2004). Endosymbiotic gene transfer: organelle genomes forge eukaryotic chromosomes. Nature Reviews. Genetics 5, 123-135.

Tjhin, E. T., Hayward, J. A., Mcfadden, G. I. & Van Doren, G. G. (2020). Characterization of the apicoplast-localized enzyme TgUroD in Toxoplasma gondii reveals a key role of the apicoplast in heme biosynthesis. The Journal of Biological Chemistry 295, 1539-1550.

Traut, T. (2008). Hemoglobin. In Allosteric Regulatory Enzymes, pp. 105-125. Springer, Boston.

Tripodi, K. E., Menendez Bravo, S. M. & Cricco, J. A. (2011). Role of heme and heme-proteins in trypanosomatid essential metabolic pathways. Enzyme Research 2011, 873230.

Van Dooren, G. G., Kennedy, A. T. & Mcfadden, G. I. (2012). The use and abuse of heme in apicomplexan parasites. Antioxidants & Redox Signaling 17, 634-656.

Vanhollebeke, B., De Muylder, G., Nielsen, M. J., Pays, A., Tebabi, P., Dieu, M., Raes, M., Moestrup, S. K. & Pays, E. (2008). A haptoglobin-hemoglobin receptor conveys innate immunity to Trypanosoma brucei in humans. Science 320, 677-681.

Van Lis, R. V., Atteia, A., Nogaj, L. A. & Beale, S. I. (2005). Subcellular localization and light-regulated expression of protoporphyrinogen IX oxidase and ferrochelatase in Chlamydomonas reinhardtii. Plant Physiology 139, 1946-1958.

Vavilin, D. V. & Vermaas, W. F. (2002). Regulation of the tetrapyrrole biosynthetic pathway leading to heme and chlorophyll in plants and cyanobacteria. Physiologia Plantarum 115, 9-24.

Waller, R. F. & Kořený, L. (2017). Plastid complexity in dinoflagellates: a picture of gains, losses, replacements and revisions. Advances in Botanical Research 84, 105-143.

Wang, Z. & Wu, M. (2017). Comparative genomic analysis of Acanthamoeba endosymbionts highlights the role of amoebae as a "melting pot" shaping the Rickettsiales evolution. Genome Biology and Evolution 9, 3214-3224.

Watanabe, N., Che, F. S., Iwano, M., Takayama, S., Yoshida, S. & Isogai, A. (2001). Dual targeting of spinach protoporphyrinogen oxidase II to mitochondria and chloroplasts by alternative use of two in-frame initiation codons. The Journal of Biological Chemistry 276, 20474-20481.

Watanabe, S., Hanaoka, M., Ohba, Y., Ono, T., Ohnuma, M., Yoshikawa, H., Tanekani, S. & Tanaka, K. (2013). Mitochondrial localization of ferrochelatase in a red alga Cyanidioschyzon merolae. Plant & Cell Physiology 54, 1289-1295.

Williams, B. A., Elliot, C., Burri, L., Kido, Y., Kita, K., Moore, A. L. & Keeling, P. J. (2010). A broad distribution of the alternative oxidase in microsporidian parasites. PLoS Pathogens 6, e1000761.

Williams, P., Hardeman, K., Fowler, J. & Rivin, C. (2006). Divergence of duplicated genes in maize: evolution of contrasting targeting information for enzymes in the porphyrin pathway. The Plant Journal 45, 727-739.

Williams, T. A., Cox, C. J., Foster, P. G., Szöllősi, G. J. & Embley, T. M. (2020). Phylogenomics provides robust support for a two-domains tree of life. Nature Ecology & Evolution 4, 138-147.

Woodson, J. D., Perez-Ruiz, J. M. & Chory, J. (2011). Heme synthesis by plastid ferrochelatase I regulates nuclear gene expression in plants. Current Biology 21, 897-903.

Wu, B., Novelli, J., Jiang, D., Dailey, H. A., Landmann, F., Ford, L., Taylor, M. J., Carlow, C. K., Kumar, S., Foster, J. M. & Slatko, B. E. (2013). Interdomain lateral gene transfer of an essential ferrochelatase gene in human parasitic nematodes. Proceedings of the National Academy of Sciences of the United States of America 110, 7748-7753.

Wu, G. Z. & Bock, R. (2021). GUN control in retrograde signaling: how GENOMES UNCOUPLED proteins adjust nuclear gene expression to plastid biogenesis. Plant Cell 33, 457-474.

Yamauchi, K., Hayashi, N. & Kikuchi, G. (1980). Translocation of delta-aminolevulinate synthase from the cytosol to the mitochondria and its regulation by hemin in the rat liver. The Journal of Biological Chemistry 255, 1746-1751.

Yao, N., Eisfelder, B. J., Marvin, J. & Greenberg, J. T. (2004). The mitochondrion - an organelle commonly involved in programmed cell death in Arabidopsis thaliana. The Plant Journal 40, 596-610.

Yao, N. & Greenberg, J. T. (2006). Arabidopsis accelerated cell death2 modulates programmed cell death. The Plant Cell 18, 397-411.

Yeh, E. & DeRisi, J. L. (2011). Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage Plasmodium falciparum. PLoS Biology 9, e1001138.

Yoon, T. & Cowan, J. A. (2004). Frataxin-mediated iron delivery to ferrochelatase in the final step of heme biosynthesis. The Journal of Biological Chemistry 279, 25943-25946.

Zhang, Y., Ma, A., Liu, W., Bai, Z., Zhuang, X. & Zhuang, G. (2018). The occurrence of putative nitric oxide dismutase (NOD) in an alpine wetland with a new dominant subcluster and the potential ability for a methane sink. Archaea 2018, 6201541.

Zheng, K., Ngo, P. D., Owens, V. L., Yang, X. P. & Mansoorabadi, S. O. (2016). The biosynthetic pathway of coenzyme F430 in methanogenic and methanotrophic archaea. Science 354, 339-342.

Zíková, A., Verner, Z., Nenarokova, A., Michels, P. & Lukeš, J. (2017). A paradigm shift: the mitoproteomes of procyclic and bloodstream Trypanosoma brucei are comparably complex. PLoS Pathogens 13, e1006679.

Genomics of Preaxostyla Flagellates Illuminates the Path Towards the Loss of Mitochondria

Miniature RNAs are embedded in an exceptionally protein-rich mitoribosome via an elaborate assembly pathway

Heme-deficient metabolism and impaired cellular differentiation as an evolutionary trade-off for human infectivity in Trypanosoma brucei gambiense

Leishmania guyanensis M4147 as a new LRV1-bearing model parasite: Phosphatidate phosphatase 2-like protein controls cell cycle progression and intracellular lipid content