title: Noncanonical coproporphyrin-dependent bacterial heme biosynthesis pathway that does not use protoporphyrin.
abstract: It has been generally accepted that biosynthesis of protoheme (heme) uses a common set of core metabolic intermediates that includes protoporphyrin. Herein, we show that the Actinobacteria and Firmicutes (high-GC and low-GC Gram-positive bacteria) are unable to synthesize protoporphyrin. Instead, they oxidize coproporphyrinogen to coproporphyrin, insert ferrous iron to make Fe-coproporphyrin (coproheme), and then decarboxylate coproheme to generate protoheme. This pathway is specified by three genes named hemY, hemH, and hemQ. The analysis of 982 representative prokaryotic genomes is consistent with this pathway being the most ancient heme synthesis pathway in the Eubacteria. Our results identifying a previously unknown branch of tetrapyrrole synthesis support a significant shift from current models for the evolution of bacterial heme and chlorophyll synthesis. Because some organisms that possess this coproporphyrin-dependent branch are major causes of human disease, HemQ is a novel pharmacological target of significant therapeutic relevance, particularly given high rates of antimicrobial resistance among these pathogens.
authors: Biomedical and Health Sciences Institute and Departments of Microbiology and Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602; hdailey@uga.edu.
authors: Harry A
authors: HA
authors: Dailey
authors: Mathematics and Computer Science Division, Argonne National Laboratory, Argonne, IL 60439; and.
authors: Svetlana
authors: S
authors: Gerdes
authors: Biomedical and Health Sciences Institute and Departments of Microbiology and Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602;
authors: Tamara A
authors: TA
authors: Dailey
authors: Biomedical and Health Sciences Institute and.
authors: Joseph S
authors: JS
authors: Burch
authors: Division of Hematology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132.
authors: John D
authors: JD
authors: Phillips
mesh_terms: D039903:Actinobacteria / Q000235:genetics / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003306:Coproporphyrins / Q000502:physiology*; D016680:Genome, Bacterial; D006094:Gram-Positive Bacteria / Q000235:genetics / Q000378:metabolism*; D006418:Heme / Q000096:biosynthesis*; D011524:Protoporphyrins / Q000378:metabolism*
chemical_list: D003306:Coproporphyrins; D011524:Protoporphyrins; D006418:Heme
keywords: Gram-positive bacteria; HemN; HemQ; coproporphyrin; heme synthesis
references: J Bacteriol. 2002 May;184(9):2460-4
references: 11948160
references: Genome Biol Evol. 2014 Aug;6(8):2141-55
references: 25108393
references: EMBO J. 2003 Dec 1;22(23):6214-24
references: 14633981
references: EMBO J. 2004 Apr 21;23(8):1720-8
references: 15057273
references: J Bacteriol. 1971 Jul;107(1):203-9
references: 4935319
references: Trends Biochem Sci. 1988 Apr;13(4):139-43
references: 3075378
references: Mol Microbiol. 1992 Nov;6(21):3159-69
references: 1333567
references: J Bacteriol. 1992 Dec;174(24):8081-93
references: 1459957
references: J Biol Chem. 1994 Jan 14;269(2):813-5
references: 8288631
references: Eur J Biochem. 1994 Feb 15;220(1):201-8
references: 8119288
references: J Bacteriol. 1994 Oct;176(19):5962-70
references: 7928957
references: Structure. 1997 Nov 15;5(11):1501-10
references: 9384565
references: Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):4853-8
references: 9560192
references: Microbiol Mol Biol Rev. 1998 Dec;62(4):1435-91
references: 9841678
references: J Biol Chem. 1957 Feb;224(2):695-705
references: 13405897
references: Int J Syst Evol Microbiol. 2004 Nov;54(Pt 6):2049-51
references: 15545432
references: Bioorg Med Chem Lett. 2005 Oct 15;15(20):4506-9
references: 16061377
references: Nucleic Acids Res. 2005;33(17):5691-702
references: 16214803
references: Biochem J. 2006 Jul 1;397(1):47-52
references: 16548850
references: J Biol Chem. 2006 Dec 15;281(50):38625-33
references: 17046834
references: Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):1789-93
references: 17261801
references: Gene. 2007 Aug 15;398(1-2):42-51
references: 17532149
references: Microbiology. 2007 Oct;153(Pt 10):3548-62
references: 17906152
references: Cell Host Microbe. 2007 Apr 19;1(2):109-19
references: 18005689
references: Bioinformatics. 2007 Nov 1;23(21):2947-8
references: 17846036
references: Methods Enzymol. 2008;436:317-37
references: 18237641
references: Contrib Microbiol. 2009;16:120-35
references: 19494582
references: Biochemistry. 2009 Jul 28;48(29):6705-11
references: 19583219
references: PLoS Comput Biol. 2009 Dec;5(12):e1000605
references: 20011109
references: J Struct Biol. 2010 Apr;170(1):76-82
references: 19944166
references: Protein Sci. 2010 Jun;19(6):1137-61
references: 20506125
references: J Biol Chem. 2010 Aug 20;285(34):25978-86
references: 20543190
references: FASEB J. 2011 Feb;25(2):653-64
references: 21048046
references: Appl Environ Microbiol. 2011 Jul;77(14):4795-801
references: 21642412
references: Antonie Van Leeuwenhoek. 2011 Aug;100(2):171-82
references: 21717204
references: Int J Syst Evol Microbiol. 2011 Aug;61(Pt 8):1944-53
references: 20833875
references: Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18260-5
references: 21969545
references: Biochem J. 2012 Mar 1;442(2):335-43
references: 22142238
references: Biochim Biophys Acta. 2012 Sep;1823(9):1617-32
references: 22575458
references: Genome Biol Evol. 2013;5(1):200-16
references: 23258841
references: Nature. 2013 Jul 4;499(7456):97-101
references: 23803760
references: J Biol Chem. 2013 Aug 9;288(32):23488-504
references: 23737523
references: Archaea. 2014;2014:327637
references: 24669201
references: Cell Mol Life Sci. 2014 Aug;71(15):2837-63
references: 24515122
references: J Biol Chem. 2003 Nov 21;278(47):46625-31
references: 12975365