title: The glmS ribozyme: use of a small molecule coenzyme by a gene-regulatory RNA.
abstract: The glmS ribozyme is the first known example of a natural ribozyme that has evolved to require binding of an exogenous small molecule for activity. In Gram-positive bacteria, this RNA domain is part of the messenger RNA (mRNA) encoding the essential enzyme that synthesizes glucosamine-6-phosphate (GlcN6P). When present at physiologic concentration, this small molecule binds to the glmS ribozyme and uncovers a latent self-cleavage activity that ultimately leads to degradation of the mRNA. Biochemical and structural studies reveal that the RNA adopts a rigid fold stabilized by three pseudoknots and the packing of a peripheral domain against the ribozyme core. GlcN6P binding to this pre-organized RNA does not induce conformational changes; rather, the small molecule functions as a coenzyme, providing a catalytically essential amine group to the active site. The ribozyme is not a passive player, however. Active site functional groups are essential for catalysis, even in the presence of GlcN6P. In addition to being a superb experimental system with which to analyze how RNA catalysts can exploit small molecule coenzymes to broaden their chemical versatility, the presence of the glmS ribozyme in numerous pathogenic bacteria make this RNA an attractive target for the development of new antibiotics and antibacterial strategies.
authors.affiliation: Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024, USA. aferre@fhcrc.org
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Ferré-D'Amaré
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism; D001483:Base Sequence; D055162:Biocatalysis; D003067:Coenzymes / Q000737:chemistry / Q000378:metabolism*; D005944:Glucosamine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D019298:Glucose-6-Phosphate / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D016337:RNA, Catalytic / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058928:Riboswitch / Q000235:genetics*
chemical_list: D001426:Bacterial Proteins; D003067:Coenzymes; D016337:RNA, Catalytic; D058928:Riboswitch; C001293:glucosamine 6-phosphate; D019298:Glucose-6-Phosphate; D005944:Glucosamine
references.citation: RNA. 2007 Apr;13(4):468-77
references.pmid: 17283212
references.citation: Nature. 2004 Mar 18;428(6980):281-6
references.pmid: 15029187
references.citation: Biophys J. 2004 Nov;87(5):2954-67
references.pmid: 15315950
references.citation: J Am Chem Soc. 2007 Apr 18;129(15):4731-7
references.pmid: 17375926
references.citation: Biochim Biophys Acta. 2002 Jun 3;1597(2):173-92
references.pmid: 12044898
references.citation: J Hered. 2009 Sep-Oct;100(5):618-23
references.pmid: 19617525
references.citation: Nature. 2006 Jun 29;441(7097):1167-71
references.pmid: 16728979
references.citation: Science. 1993 Aug 6;261(5122):709-14
references.pmid: 7688142
references.citation: RNA. 2009 Nov;15(11):1949-64
references.pmid: 19741022
references.citation: Biochemistry. 1979 Feb 20;18(4):592-6
references.pmid: 217419
references.citation: Chem Biol. 1998 Oct;5(10):587-95
references.pmid: 9818150
references.citation: Angew Chem Int Ed Engl. 2006 Oct 13;45(40):6689-93
references.pmid: 16986193
references.citation: Nat Struct Mol Biol. 2008 Feb;15(2):177-82
references.pmid: 18204466
references.citation: Science. 2002 Nov 15;298(5597):1421-4
references.pmid: 12376595
references.citation: Science. 1999 Oct 1;286(5437):123-6
references.pmid: 10506560
references.citation: Curr Opin Chem Biol. 2006 Oct;10(5):455-64
references.pmid: 16935552
references.citation: J Mol Evol. 1976 Mar 29;7(2):101-4
references.pmid: 1263263
references.citation: RNA. 2004 Feb;10(2):151-8
references.pmid: 14730013
references.citation: Biochemistry. 2009 Jun 23;48(24):5669-78
references.pmid: 19449899
references.citation: Nature. 2008 Jul 17;454(7202):358-61
references.pmid: 18548004
references.citation: RNA. 2006 Apr;12(4):607-19
references.pmid: 16484375
references.citation: RNA Biol. 2010 May-Jun;7(3):328-32
references.pmid: 20458165
references.citation: Nat Struct Mol Biol. 2009 Mar;16(3):343-4
references.pmid: 19234468
references.citation: Nucleic Acids Res. 2008 May;36(8):2570-80
references.pmid: 18334534
references.citation: J Mol Biol. 2005 Jun 24;349(5):989-1010
references.pmid: 15907933
references.citation: Science. 2000 Feb 25;287(5457):1493-7
references.pmid: 10688799
references.citation: Curr Opin Struct Biol. 2009 Jun;19(3):251-9
references.pmid: 19303767
references.citation: RNA. 2005 Dec;11(12):1788-94
references.pmid: 16314452
references.citation: Cold Spring Harb Symp Quant Biol. 1972;36:35-43
references.pmid: 4508150
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):1747-52
references.pmid: 8700829
references.citation: J Am Chem Soc. 2007 Dec 5;129(48):14858-9
references.pmid: 17990888
references.citation: Nature. 2008 Aug 14;454(7206):899-902
references.pmid: 18615019
references.citation: Chem Biol. 2007 Jan;14(1):97-105
references.pmid: 17196404
references.citation: Nature. 2001 Nov 1;414(6859):82-4
references.pmid: 11689947
references.citation: Nat Struct Mol Biol. 2009 Dec;16(12):1212-7
references.pmid: 19898478
references.citation: Cell. 1995 Jun 30;81(7):991-1002
references.pmid: 7541315
references.citation: Curr Opin Microbiol. 2009 Apr;12(2):161-9
references.pmid: 19250859
references.citation: Nature. 2004 Nov 18;432(7015):411-5
references.pmid: 15549109
references.citation: Science. 2006 Sep 22;313(5794):1752-6
references.pmid: 16990543
references.citation: Nucleic Acids Res. 2005 Apr 14;33(7):2210-4
references.pmid: 15831794
references.citation: Cell. 2002 Nov 27;111(5):747-56
references.pmid: 12464185
references.citation: Science. 2009 Mar 13;323(5920):1436-8
references.pmid: 19286542
references.citation: Curr Opin Struct Biol. 2003 Feb;13(1):49-55
references.pmid: 12581659
references.citation: Biopolymers. 2004 Jan;73(1):71-8
references.pmid: 14691941
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6421-6
references.pmid: 15096624
references.citation: Chem Rev. 1998 May 7;98(3):1045-1066
references.pmid: 11848924
references.citation: Structure. 2006 Sep;14(9):1459-68
references.pmid: 16962976
references.citation: Methods Mol Biol. 2009;540:129-39
references.pmid: 19381557
references.citation: Biochemistry. 2006 Jun 27;45(25):7861-71
references.pmid: 16784238
references.citation: J Mol Biol. 1961 Jun;3:318-56
references.pmid: 13718526
references.citation: Arch Biochem Biophys. 1992 Oct;298(1):1-12
references.pmid: 1524417
references.citation: Nature. 1994 Nov 3;372(6501):68-74
references.pmid: 7969422
references.citation: Nature. 1998 Oct 8;395(6702):567-74
references.pmid: 9783582
references.citation: J Biol Chem. 1979 Nov 10;254(21):10839-45
references.pmid: 387756
references.citation: Methods Enzymol. 1997;277:493-505
references.pmid: 18488321
references.citation: Cell. 1993 Aug 13;74(3):475-82
references.pmid: 8348614
references.citation: Nature. 2008 May 1;453(7191):120-3
references.pmid: 18451863
references.citation: Genes Dev. 2007 Dec 15;21(24):3356-68
references.pmid: 18079181
references.citation: J Bacteriol. 2009 Oct;191(20):6193-202
references.pmid: 19666710
references.citation: Structure. 2008 Sep 10;16(9):1357-67
references.pmid: 18786398
references.citation: RNA. 2010 Mar;16(3):598-609
references.pmid: 20106958
references.citation: J Mol Biol. 1991 Nov 20;222(2):281-300
references.pmid: 1960728
references.citation: Biochemistry. 2003 Mar 4;42(8):2259-65
references.pmid: 12600192
references.citation: Biopolymers. 1998;48(2-3):101-112
references.pmid: 11180044
references.citation: Cell. 2006 Jul 28;126(2):309-20
references.pmid: 16859740
references.citation: Nature. 2009 Mar 12;458(7235):233-7
references.pmid: 19169240
references.citation: Nat Chem Biol. 2005 Jun;1(1):45-52
references.pmid: 16407993
references.citation: Trends Biochem Sci. 2003 Sep;28(9):495-501
references.pmid: 13678961
references.citation: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):4899-903
references.pmid: 11296253
references.citation: RNA. 2004 Mar;10(3):335-43
references.pmid: 14970378
references.citation: Chem Biol. 2008 Oct 20;15(10):1125-37
references.pmid: 18940672
references.citation: Chem Biol. 2002 Apr;9(4):465-73
references.pmid: 11983335
references.citation: Cold Spring Harb Perspect Biol. 2010 Oct;2(10):a003574
references.pmid: 20843979
references.citation: RNA. 2007 Jul;13(7):1052-70
references.pmid: 17488874
references.citation: Nature. 2002 Oct 31;419(6910):952-6
references.pmid: 12410317
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4678-83
references.pmid: 12682299
references.citation: Annu Rev Biophys. 2009;38:271-99
references.pmid: 19416070
references.citation: Genes Dev. 2008 Dec 15;22(24):3383-90
references.pmid: 19141470
references.citation: Int J Syst Evol Microbiol. 2001 Jul;51(Pt 4):1335-1341
references.pmid: 11491330
references.citation: Biochemistry. 2009 Apr 21;48(15):3239-46
references.pmid: 19228039
references.citation: Chembiochem. 2006 Apr;7(4):602-4
references.pmid: 16485317
references.citation: RNA. 1999 Oct;5(10):1308-25
references.pmid: 10573122
references.citation: Science. 2009 Nov 13;326(5955):953
references.pmid: 19965505
references.citation: Nature. 2001 Apr 12;410(6830):780-6
references.pmid: 11298439
references.citation: RNA Biol. 2006 Apr;3(2):77-81
references.pmid: 17114942
references.citation: Mol Cell. 1998 May;1(6):873-81
references.pmid: 9660970
references.citation: Chem Biol. 2005 Nov;12(11):1221-6
references.pmid: 16298301
references.citation: PLoS Biol. 2008 Sep 30;6(9):e234
references.pmid: 18834200
references.citation: J Inorg Biochem. 1993 Feb 15;49(3):171-5
references.pmid: 7679435
references.citation: J Am Chem Soc. 2008 Oct 8;130(40):13240-50
references.pmid: 18785738
references.citation: J Mol Biol. 2007 Oct 12;373(1):178-89
references.pmid: 17804015
references.citation: Genes Dev. 2008 Nov 1;22(21):2914-25
references.pmid: 18981470
references.citation: Curr Opin Struct Biol. 2007 Jun;17(3):273-9
references.pmid: 17574837
references.citation: RNA. 2010 Jan;16(1):186-96
references.pmid: 19948769